Practicals of Organic Chemistry - digit.bibl.u-szeged.hudigit.bibl.u-szeged.hu/eta/00000/00130/00130.pdf · dures are used for recrystallization, for distillation or when reactions

University of Szeged

Practicals of Organic Chemistry

Authors:

Prof. Dr. Ferenc Fülöp

Dr. Loránd Kiss

Dr. István Szatmári

Reviewed by:

Dr. Anikó Borbás

Dr. David Durham

Szeged, 2015.

This work is supported by the European Union, co-financed by the Euro-pean Social Fund, within the framework of "Coordinated, practice-oriented, student-friendly modernization of biomedical education in three Hungarian

universities (Pécs, Debrecen, Szeged), with focus on the strengthening of in-ternational competitiveness" TÁMOP-4.1.1.C-13/1/KONV-2014-0001 pro-

ject.

The curriculum can not be sold in any form!

Preface 1

PREFACE

The Practicals of Organic Chemistry is intended to offer basic knowledge in experi-mental organic chemisty for students in pharmacy. The manual has been written with the aim of facilitating the development of practical skills in organic chemistry and in phar-maceutical sciences. The most important tools and methods of preparative organic chem-istry are demonstrated. The first part of the manual presents the instruments, apparatus and tools of an organic chemistry laboratory and the fire and accident prevention instruc-tions. The second part includes the main laboratory operations, the purification methods and the most important procedures for the identification of the structures of organic mol-ecules. The third part is devoted to qualitative organic chemistry. The study of the reac-tivities of different functional groups of organic compounds is discussed in connection with simple test-tube reactions. The next section, Syntheses, is the main and the largest part of the practical manual and includes the preparation of various types of organic compounds, including simple synthetic methods which are among the most frequent in preparative organic chemistry. They can be carried out easily and rapidly and are not dangerous for the students and the laboratory staff. Apart from the presentation of the synthetic methodology the processes are made understandable by detailed descriptions and interpretations of the reactions. The preparations of several compounds are dealt with which are used as pharmaceuticals. The purpose is not only to provide a view of general organic chemistry, but also to present the practical utility of preparative chemis-try in the field of drug synthesis. At the end of each chapter, the manual contains theo-retical problems and exercises related to the practical work; their solutions are included at the end of the manual. These problems give examples of the transformations of differ-ent functional groups, the structure-reactivity relationships and stereochemical aspects. These problems are discussed during the practicals and are included together with other similar problems in the written tests.

2

1. COMMON INSTRUMENTS AND TOOLS IN THE ORGANIC CHEMISTRY LABORATORY

glass funnels Erlenmeyer flasks

Buchner and glass filters round-bottomed flasks

round-bottomed and three-necked flasks filter flasks

1. Common Instruments and tools in the organic chem istry laboratory 3

beakers glass rods

separating funnel porcelain and pestle mortar

clamps porcelain dishes

4

Petri glasses watch glass

glass stoppers glass connections

dropping funnels spatulas


Pasteur pipette stirring bars

glass filter and filter flask separating funnel in a metal ring

flask containing acetone electrical heater

6

a chemical reaction being carried out under reflux magnetic stirrer

a chemical reaction on an oil bath with a magnetic stirrer and a reflux condenser

a chemical reaction on a magnetic stirrer balance


chromatographic column developing container

cylinders melting point apparatus

rotary evaporators

8

2. LABORATORY NOTEBOOK

The laboratory work must be well planned before any experiment is started. An experi-ment must never be begun unless you understand the overall purpose of the experiment and the reasons for each operation involved. This requires studying the experiment be-fore you come to the laboratory. This helps you not to perform the experiments, but also to avoid any accident during the laboratory work. For successful experimental work, a well-documented notebook needs to be prepared. The work should be started only after the notebook has been prepared. The notebook must contain details of all the tasks of the experimental work, the necessary physical constants, and a description of the experi-ments in such a way that anyone else could repeat it. The laboratory notebook is the most important document of the experimental work performed, and every observation during the practical must therefore be noted down. The basic requirement of a laboratory note-book is to ensure that the experiments are repeatable and understandable on the basis of the written notes. As regards the format, the notebook must contain the date, the title of the experiment, the chemical equation and the physical constants of the materials used (density, molecular weight, and melting and boiling points). A detailed description of the experiment is then included, with the exact amounts of the used materials. The de-scription must also contain the accident prevention and safety measures concerning all the dangerous substances handled during the experiment. A detailed description of the apparatus, all the methods relating to the reaction and the work-up must be included. Finally, the purification of the products, the method of isolation, the physical constants (melting point, Rf, NMR data, etc.) and the yields must be recorded.

3. Accident and fire prevention instructions in the organic chemistry laboratory 9

3. ACCIDENT AND FIRE PREVENTION INSTRUCTIONS IN THE ORGANIC CHEMISTRY LABORATORY

1. The chemical laboratory is potentially a dangerous place, but with proper preparation for the laboratory work, all accidents can be prevented. You should begin the experiment only if you are well prepared and understand the purpose of the experiment and every operation involved in the work. The preparation for the practicals includes a detailed knowledge of the accident and fire prevention instructions.

2. It is a general rule that a student is never allowed to work alone in the laboratory. The experiments can be started only if the instructor is present. No experiment can be com-menced without the permission of the instructor.

3. Eating, drinking and smoking in the laboratory are forbidden. Coats, bags, etc must be left outside the laboratory in the places indicated. Only the materials and equipment that will be used are allowed on the laboratory bench. No materials must ever be taken out of the laboratory.

4. Order must be maintained in the laboratory so that the equipment and other objects do not disturb the work. The laboratory bench and the hood must be kept clean.

5. A laboratory coat and safety glasses must always be worn during the entire practical.

6. Gloves must be worn when dangerous or poisonous materials are handled.

7. All chemicals must be stored properly, in a closed and labelled vial.

8. Strong acids can cause severe burns on the skin. If any acid comes into contact acci-dentally with your skin, the wounded skin must be wiped with a dry cloth and then washed with plenty of water. If a strong base is spilled on the skin, the skin surface must be washed with plenty of water.

9. Glass apparatus should be carefully examined before use; any which is cracked, chipped or flawed must be changed.

10. Glassware must be cleaned with acetone, water and detergent immediately after use.

11. When a test tube is to be heated, it must be filled to only at most half of its volume, while a flask must be filled to at most two-thirds of its volume.

12. All experiments in which toxic or acidic fumes or vapours are formed must be carried out under a fume hood.

13. Flames must be avoided in the laboratory whenever possible. A flammable liquid must never be heated in open glassware. A flame can be used to heat a flask only when the flask is protected by a condenser. A closed, pressure-tight apparatus must never be heated. The increase of pressure as a result of the heating may cause the apparatus to explode. If a flammable organic solvent (e.g. acetone, methanol, diethyl ether, hexane or ethyl acetate) has to be heated, an electrical heating device or a water bath must be used.

10

In the event of an accident, containers of flammable solvents or chemicals must be re-moved from the area of the fire. A minor fire on the laboratory bench can be ex-tingwished by covering it with a fire blanket or coat. In the event of a more serious fire, the main gas taps must be closed and electrical switches must be switched off, and a carbon dioxide extinguisher must be used to extinwish the fire. Water can only be used in special cases, because several organic substances may react with it.

14. In the event of an accident, the instructor must be notified immediately.

15. All waste materials must be placed in suitable containers that are appropriately la-belled. Halogenated solvents should be kept apart from other solvents. Acidic and basic waste must also be stored separately. Burning materials must never be placed in the waste disposal. Organic mixtures and solvents should never be thrown down the sink. After finishing the experiments, before leaving the laboratory, students must check that all apparatus, glassware and the laboratory bench has been cleaned and that the electrical devices have been switched off.

4. Fundamental operations in organic chemistry labo ratory Practicals 11

4.1. Heating

4. FUNDAMENTAL OPERATIONS IN ORGANIC CHEMISTRY LABORATORY PRACTICALS

4.1. Heating

In organic chemistry laboratories mostly electrical devices are employed for heating. They are convenient for heating flammable mixtures. Flammable solvents should never be heated in an open container with a gas flame. Certain glassware, such as glass funnels, filter flasks, cylinders, separating funnels and desiccators, must never be heated. The glass container in some chemical reactions may be heated by means of a water bath (up to 80-90 °C) or an oil bath (above 100 °C). The flask containing the reaction mixture must be immersed in the oil bath so as to attain a lower level of the oil in compar with the solvent level in the flask. Water and other solvents must be prevented from coming into contact with the oil in the bath. For several chemical reactions, a microwave appa-ratus may be used as a heating device.

4.2. Cooling

Cooling is used in an organic chemistry laboratory for two different purposes. A cooling method is applied when a vapour is to be condensed in a glass condenser. Another method is necessary when it is necessary to cool a chemical reaction below the temper-ature of the laboratory by means of a cooling bath. For the condensation of a vapour, different types of condensers are used, with water or air cooling. These cooling proce-dures are used for recrystallization, for distillation or when reactions must be refluxed. The cooling of a reaction mixture or a solvent may usually be achieved with a cooling bath. Crushed ice is used to maintain the temperature at around 0-5 °C. Below 0 °C, a mixture of common salt and ice is used most commonly. This mixture can produce a temperature of about -10 °C to -18 °C. Some reactions require a much lower temperature. Solid carbon dioxide or liquid nitrogen with acetone in a plastic container is suitable to attain temperatures in the range -50 °C to -70 °C.

4.3. Filtration

Filtration in an organic chemistry laboratory of means the separation of a solid from a solvent. Filtration may be used when solid impurities must be removed from a mixture with a liquid, or when the needed material is the solid and it has to be collected. Two different techniques are employed for filtration: gravity filtration and vacum filtration. For gravity filtration, a glass funnel and a fluted filter paper are used most frequently. The paper is fluted to speed up the filtration. Gravity filtration is performed by using a Büchner funnel or a glass filter and a filter flask attached to a vacuum pump. When a

12

4.4. Washing

Büchner funnel is used, the filter paper should be wetted with the solvent and placed into the funnel.

Gravity and vacuum filtration

4.4. Washing

During washing the liquid impurities are removed from a solid or liquid material. Solids are washed after filtration. At the end of a filtration, the last quantity of the material may be transferred into the funnel by washing it in with some mother liquor. The solid mate-rial (often the crystals) should then be pressed with a cork, followed by washing with a cold solvent in which the solid is not soluble. When the cold solvent covers the solid, the pressure should be released. After a few seconds, the total amount of solvent is removed by suction under vacuum. The washing of liquids may be carried out by extraction in a separating funnel. Most frequently, this means removal of the inorganic materials from a mixture at the end of a reaction. This is usually performed by washing the organic layer with water. If acidic or basic impurities have to be removed, the mixture should be washed with water first, and then with a dilute basic or acidic solution, depending on the pH of the mixture. When washing is carried out with a carbonate solution, it is important to open the stopper of the separating funnel in order to avoid overpressure.

4.5. Drying

Organic solids or liquids, which come into contact with water during an operation must be dried. For the drying of organic liquids, inorganic salts which form hydrates with the water are used most frequently (e.g. Na2SO4, MgSO4, CaCl2, etc.). When a drying agent is to be chosen it is important that it should not react with the compound to be dried. It is generally best to shake the liquid first with a small amount of the drying agent. If the water persists, the liquid must be treated with a further portion of the desiccant. The drying agent is then separated from the liquid by filtration.

glass funnel with filter paper

Erlenmeyer flask

glass filter

vacuum

filter flask

4. Fundamental operations in organic chemistry labo ratory Practicals 13

4.5. Drying

When crystals are to be dried most of the solvent may be evaporated off by allowing the aspirator to draw air through the mass of solid on the glass filter for a few minutes. If a solvent with higher boiling point is present, drying can be achieved by placing the solid on a watch glass in an oven, or under an infrared lamp (the temperature of the oven must be about 20 °C below the melting point of the crystals). In some cases, high-boiling solvents can be removed by washing the crystals on a glass filter with another solvent with a lower boiling point. Drying may be carried out with a vacuum desiccator, when the drying temperature is lower.

14

5.1. Distillation

5. PURIFICATION OF ORGANIC COMPOUNDS

5.1. Distillation

Distillation is the method most commonly used to purify liquids. The liquid is vapourized by heating and the vapour is condensed in a separate vessel to yield the distillate. By this method, the components of a mixture of liquid may be separated. The separation is based on the difference in volatility of the components. The boiling point of a liquid is the temperature at which the total vapour pressure is equal to the external pressure.

5.1.1. Simple distillation

If the impurities present in the liquid are non-volatile, they will be left in the residue and in this case a simple distillation will result in the purification of the liquid. Simple distil-lation is employed when the difference between the boiling points of the components is higher than 20 °C. Simple distillation is performed at atmospheric pressure and may be carried out in the apparatus illustrated in the Figure. The apparatus consists of a flask, a still head, a condenser and a receiver flask. To allow temperature control, the apparatus is equipped with a thermometer. A closed system may cause overpressure and the appa-rartus may explode. For this reason, a suction joint is inserted between the condenser and the collecting flask. The flask should contain liquid up to half to two-thirds of its volume. To promote regular boiling of the liquid, porous porcelain is added to the cold liquid. It should never be added to the hot liquid. When the flask is heated, the temperature in-creases, the liquid starts to distil and the distillate is collected in the collecting flask. As long as the temperature remains constant during the process of distillation, the main frac-tion is collected in a separate receiver flask and the determined temperature corresponds to the boiling point of the liquid. When the temperature increases above this constant level, the collection of the main fraction should be stopped. Before the distillation pro-cess is finished, several millilitres of the liquid in the distillation flask should always be left in the flask.

5. Purification of organic compounds 15

5.1. Distillation

Apparatus for simple distillation

5.1.2. Distillation under reduced pressure

In many instances, the boiling temperature at atmospheric pressure is too high, because the compound to be distilled may decompose or undergo unwanted transformations at temperatures below it’s a normal boiling point. These problems may be avoided by car-rying out the distillation at a pressure lower than atmospheric. Under these conditions, the boiling temperature is lower. The apparatus for distillation under reduced pressure is outlined in the following Figure. In this case, magnetic stirrer is employed instead of porous porcelain in order to ensure regular boiling. A reduced pressure may be obtained by connecting water pump or an oil pump to the distillation apparatus. It is recommended to create the vacuum first and start heating afterwards.

thermometer

still head

flask

receiver flask

suction joint

condenser

water

16

5.2. Crystallization

Apparatus for distillation under reduced pressure

5.2. Crystallization

5.2.1. Recrystallization

Recrystallization is a common technique used of purify solid materials. It involves sev-eral steps: a) selection of an appropriate solvent; b) dissolution of the solid to be purified in a solvent near its boiling point, a saturated solution being prepared; c) filtration of the hot solution to remove insoluble impurities; d) crystallization from solution as it is cooled; e) separation of the crystals from the solution by filtration, and washing and drying of the crystals.

Selection of the solvent

The solvent must satisfy several criteria in order to be used for recrystallization. The compound to be purified should be quite soluble in the hot solvent, but almost insoluble in the cold solvent. It is generally preferable for the boiling point of the solvent to be lower than the melting point of the solid. The solvent should not react with the compound to be purified. It is a general principle that polar compounds are insoluble in non-polar solvents, but and soluble in polar solvents, and vice versa (“like dissolves like”).

Solution

thermometer

still head

flask

collector flask

suction joint

condenser

water

magnetic stirrer

vacuum


5.3. Extraction

A small amount of the solvent is first added to the compound to be purified and the mixture is heated. If some solid remains undissolved, more solvent is added slowly until the boiling solvent dissolves the solid completely. In some cases, a mixture of solvents is used. They must be miscible and the solid should be soluble in one of the solvents, but insoluble or only slightly soluble in the second. The crystals are first dissolved in the solvent in which they are readily soluble, and the second solvent is then added to the solution until it becomes cloudy. If coloured impurities are present, these may often be removed by adding a small amount of decolorizing carbon to the warm (not boiling!) solution. The hot solution is filtered by gravity filtration. Precipitation of the crystals starts as the filtrate cools. In general, faster cooling produces smaller crystals while larger crystals are formed on slower cooling. If crystallization does not occur after cooling, several drops of a solvent which does not dissolve the compound can be added. Another method is to add a tiny crystal to the solution which helps the formation of the precipitate (a technique known as seeding). Crystal formation can also be induced by scratching the inside surface of the flask.

Filtration and washing of the crystals

These processes may be performed by the techniques already presented.

5.2.2. Crystallization by acid-base precipitation

In some cases, various materials which react with the compound to be purified are used for the crystallization. For instance, carboxylic acids may be purified in this way. Car-boxylic acids containing a higher number of carbon atoms are not, but their salts are soluble in water. These acids are dissolved in NaOH solution, while the impurities are not soluble. After filtration, followed by acid treatment of the filtrate, the pure carboxylic acid precipitates. Basic substances may be purified analogously by acid treatment.

5.3. Extraction

Extraction is a method of separating and purifying organic compounds. The compound to be purified, which may be solid or liquid, is transferred by extraction into the extract-ing solvent. The extraction is followed by evaporation of the extracting solvent. The compound obtained in this way is then subjected to further purification.

Solid-liquid extraction

By means of solid-liquid extraction, solid compounds are purified from insoluble impu-rities. Organic substances may also be extracted from solid materials. The simplest pro-cedure to accomplish a solid-liquid extraction is when the solvent is allowed to stand or is stirred on the solid material. The solid impurities are then removed by filtration and the solvent is removed by concentration.

Liquid-liquid extraction

18

5.4. Chromatography methods

During liquid-liquid extraction a dissolved compound is extracted from the solution by using a solvent which is not miscible with the first solvent. In general, organic com-pounds are more soluble in organic solvents than in water. For this reason, their extrac-tion from an aqueous solution may be performed with organic solvents. The efficiency of an extraction can be increased by repeating the extraction procedure by using smaller amounts of organic solvents. When an extracting solvent is to be chosen for the isolation of a compound from a solution, there are several general principles to be kept in mind: a) the extracting solvent should be immiscible with the solvent of the solution; b) the compound to be isolated should be well and selectively soluble in the extracting solvent; c) the compound should not react chemically with the extracting solvent; d) the differ-ence between the density of the extracting solvent and that of the solvent of the solution should be large. The following solvents are most frequently used for extraction opera-tion: diethyl ether, ethyl acetate, toluene (with a lower density in comparison with that of water), chloroform and dichloromethane (with a larger density than that of the water). There are several situations when the extracting agent reacts with salt formation with the compound to be extracted. The extraction of organic acids may be performed with basic solutions, and the extraction of organic bases by using inorganic or organic acids. During these operations, the compound to be purified passes into the aqueous phase, while the impurities remain in the organic layer. The compound may be recovered from the aque-ous solution by precipitation with an acid or a base, depending on the pH. In the labora-tory, the extraction is performed in a separating funnel. During the extraction procedure, it is important to open the stopper of the separating funnel carefully from time to time in order to avoid overpressure in it. After 2-3 minutes of shaking, the separating funnel is placed in a metal ring, the stopper is removed, and the layers are allowed to separate. After the separation of the two layers, the lower layer and the upper layer are carefully run off separately into different flaska.


Chromatography is a method of purifying and separating organic compounds on the basis of the principles of phase distribution. During the chromatographic process, one phase (the stationary or immobile phase) is continuously eluted with another phase (the mobile phase).

5.4.1. Column chromatography

This technique is a type of liquid-solid adsorption chromatography. The method is suit-able for the separation or purification of non-volatile organic compounds. For the sepa-ration, a column is used. The column is packed with a solid (the stationary phase), such as alumina or silica gel, and a small liquid sample is applied to the top. The sample will be adsorbed initially at the top of the column. The eluting solvent is then allowed to flow



through the column. This mobile liquid phase carries with it the components of the mix-ture to be separated. As a consequence of the selective adsorption ability of the solid phase, the components will move down the column at different rates. A more weakly adsorbed compound will be eluted more rapidly than a more strongly adsorbed com-pound. The separated components may be recovered by collecting the eluted liquid in different containers, and the combined fractions containing the same compound are then concentrated to give the pure material. The fractions may be analysed by thin-layer chro-matography, for instance. In general, increasing the amount of adsorbent (the solid phase) increases the efficiency of separation.

Column for chromatography

When an eluent (a mixture of solvents) is used the properties of the components to be purified must be kept in mind. The polarity of the eluent can be changed to take into account the properties of the components. The most frequently used solvents, in se-quence of increasing polarity, are: hexane, toluene, dichloromethane, ethyl acetate, ace-tone, ethanol and methanol. If the component has a more polar character, it will be ad-sorbed more strongly to the stationary phase, and a more polar solvent is needed for its elution. In general, the eluent is made by mixing an apolar solvent in different ratios with a more polar solvent.

silicagel (adsorbent)

solvent (eluent)

collected fractions

column

20


5.4.2. Thin-layer chromatography (TLC)

TLC involves the same principles as column chromatography. In this case, the solid ad-sorbent is spread as a thin layer on a glass plate. The method is faster than column chro-matography, and a much smaller amount of eluent is nedeed, but the method is suitable only for the separation of a small amount of compound. The compound is placed with a capillary on the plate, near its edge (1.5 cm, starting level), and the plate is then placed in a developing container with the eluting solvent. The solvent migrates up the plate, carrying the components of the mixture at different rates. The result is a series of spots on the plate. The distance between a spot and the level of the eluent (start level) is the retention factor (Rf). This is the ratio of the distances travelled by the compound and the solvent (to the front). TLC is most frequently used for analytical purposes (e.g. for the monitoring of chemical reactions). Some compounds can be identified through their Rf value. Together with the unknown compound, the known compound, which is presumed to be the same as the unknown compound, is placed on the thin layer, and after the mi-gration of the eluent and the development of the chromatogram, the identity of the reten-tion factors is checked. TLC may be employed for preparative purposes too. In this case, a compound is placed on a plate with a thicker solid phase, and then eluted, identified. This is scratched off and the compound is washed from the solid adsorbent with a sol-vent.

A thin-layer chromatogram

front level

x

yRf = x/y

start level

6. Determination of the structures of organic compo unds 21

6.1. Infrared (IR) spectroscopy

6. DETERMINATION OF THE STRUCTURES OF ORGANIC COMPOUNDS

The identification of an organic compound and the determination of its structure are among the main tasks of synthetic organic chemistry. At the end of every experiment, the exact structures of the reaction products have to be determined. Various physical constants of the compounds (e.g. boiling point, melting point, optical rotation, etc.), and the compositions are therefore determined, or the presence of different functional groups is examined by chemical methods. Methods often used for the identification of the reac-tion products are TLC and gas-chromatographic analyses.

Important and extremely useful tools for the elucidation of the structures of organic com-pounds and for the determination of their purity are the spectroscopic methods, such as infrared (IR) spectroscopy, mass spectrometry (MS), and nuclear magnetic resonance (NMR) spectroscopy. X-ray diffraction analysis is similarly of great importance for this purpose.

During the determination of the structure of an organic compound, it is desirable to carry out more than one analysis and to record various types of spectra. When more infor-mation is available, the structure of a compound can be determined unambiguously.

6.1. Infrared (IR) spectroscopy

IR spectroscopy is based on the interaction of a chemical bond and IR radiation. The distance between atoms (stretching vibrations) or the angle (bending) between them can be modified in this way. In general, different bonds interact with radiation at different frequencies. The most important information in an IR spectrum is provided by the pres-ence or the absence of a functional group in the molecule. The frequency at which a chemical bond in a functional group interacts with the radiation is characteristic of to that bond and is independent of the molecular constitution. Thus, typical ranges of wave-lengths of absorption for each functional group can be determined, as shown in Scheme 6.1.1.. This “correlation chart” provides information about the presence of functional groups in a molecule. Since the chemical surroundings usually have a slight effect on the absorption frequencies, absorption regions are given. A chemical bond has different chemical environments in different molecules, and the IR spectra of two different mole-cules are therefore never the same. This means that an IR spectrum is specific for a mol-ecule. An organic compound has its own unique absorption region between 400 and 1400 cm -1. This part of the spectrum is called the “fingerprint region”.

22

6.2. Mass spectrometry (MS)

Scheme 6.1.1. Correlation chart for group assignments in IR spectra (str = stretching; bend = bending; arom = aromatic)

6.2. Mass spectrometry (MS)

The principle of MS is based on the bombardment of a molecule with electrons, during which a positively charged ion is formed by the loss of an electron. The resulting radical ions are broken down into smaller ions by fragmentation. The different ions with differ-ent relative weights are separated and can be identified. From a masss spectrum the mo-lecular weight of a compound can be determined, while the fragmentation information can be used to deduce the structure of the molecule. MS combined with gas or liquid chromatographic methods (GC or LC) is useful in organic chemistry (GC-MS or LC-MS). The chromatograph functions by separating the components, while their molecular weights can be determined through the MS.

Scheme 6.2.1. An outline of the mass spectrum of acetone

6.3. Nuclear magnetic resonance (NMR) spectroscopy

NMR spectroscopy is one of the most important tools for the identification of organic compounds. The methods most commonly applied to elucidate of the structures of or-ganic molecules are proton and carbon NMR spectroscopy (1H-NMR and 13C-NMR).

800100012001400160018002000220024002600280030003200340036003800

C-Cstr

C-Nstr

C-Ostr

O-Hbend

C-Hbend

N-Hbend

C=Cstr

C=Nstr

C=Ostr

C Nstr

C-Hstr

O-H és N-Hstr

C-Hbend (arom)

C-Xstr

C Cstr



1H-NMR spectroscopy provides information on the number, the character and the en-vironment of the protons in an organic molecule.

The chemical shift: The signals of different types of protons in an organic compound appear at different intensities of the magnetic field (different Hz values) in the 1H-NMR spectra. These differences are only several parts per million (ppm) of the field, but they are significant enough to ensure that these protons can be differentiated. The environ-ments of the protons influence their chemical shifts. In NMR spectroscopy, the positions of the protons in the spectrum are referred to the signal of tetramethylsilane (TMS), whose signal is situated at δ = 0 ppm (higher field). In general, the signals of all the protons in organic compounds appear at lower fields (higher δ values).

Scheme 6.3.1. Specific chemical shifts of different types of protons

From the above scheme, it can be assumed that there are large differences between the chemical shifts of the protons involved in different classes of compounds. This means that 1H-NMR provides information on the chemical environments of the protons, e.g. if they are saturated, unsaturated or bonded to different heteroatoms.

024681012

O

H

O

OH

HR

OHR

R2C=CH

TMS

δ (ppm)

R-OH

R C CH

R-NH2

R-CH2XR-CH3

24


Scheme 6.3.2. The protons in an electronegative environment (an electron-with-drawing group) are deshielded (higher ppm values)

The integrals of the proton signals: the integrals of the proton signals are proportional to the number of protons in a molecule. If the molecular formula of a compound is known, the types of the hydrogens can be deduced. For example, in the 1H-NMR spectrum of ethanol, the ratio of the integrals of the signals of the methyl and methylene protons is 3:2.

Spin-spin coupling: Protons of the same type (chemically and magnetically equivalent) have the same chemical shift in the 1H-NMR spectrum, and their signals appear at the same δ value. For example, the methane molecule (CH4) has four equivalent protons, and its 1H-NMR spectrum therefore contains only one signal (δ = 0.23 ppm). In the case of dimethyl ether (CH3OCH3), the six equivalent protons present one deshielded signal (due to the presence of the electronegative oxygen atom) at δ = 3.24 ppm. The 1H-NMR spectrum of ethanol shows three signals at three different δ values. The signal of the three equivalent methyl protons appears at highest field (δ = 1.22 ppm). The signal at δ = 3.6 ppm is that of the two equivalent methylene protons (they are not equivalent to the three protons of the methyl group), while the position of the hydroxylic proton varies.

It might be expected that there would be three singlets in the 1H-NMR spectrum of eth-anol. In reality, however, as can be observed in Scheme 6.3.3, the signal assigned to the methyl group is split into three (a triplet), while that assigned to the methylene group is split into four (a quartet). The splitting is caused by the spin-spin interactions between the methyl and methylene protons. This interaction is transmitted by the electronic sys-tem of the C-C and C-H bonds.

H3C-F H3C-Cl H3C-Br H3C-I

δ 4.3 δ 3.0 δ 2.7 δ 2.1

increased shielding of H (higher fields)

the deshielding effect increases (higher ppm values)

chemically and magnetically different protons

chemically and magnetically equivalent protons

OHCH

HCHH

H

chemically and magnetically equivalent proton s



Scheme 6.3.3. A simplified representation of the 1H-NMR spectrum of ethanol

In fact n hydrogen atoms on the neighbouring carbon atoms split the signal of one proton into n + 1 peaks, and this multiplicity provides information on the number of protons on the vicinal carbon atoms.

12345 0

-CH3-CH2-OH

3

21

relative ratio of the integrals

ppm

CH3CH2OH

26


Scheme 6.3.4. Spin-spin coupling of protons

The distance between the peaks in a split signal is called the coupling constant (J, Hz). Since the coupling constants of stereoisomers generally have different values, they fur-nish important information about the stereochemical structures of molecules (Scheme

CHb

CHa

doublet for H a doublet for H b

δHa δHb

Jab Jab

ratio of integrals 1:1

HbCHb

CHa

triplet for H a doublet for H b

δHa δHb

Jab


2Jab

HbCHb

Hb

CHa

quartet for H a doublet for H b

δHa δHb

Jab


3Jab



6.3.5). The coupling constant also depends on the dihedral angle, which is of great sig-nificance in the conformational analysis of organic compounds.

Scheme 6.3.5. The coupling constants (J) of different types of protons

13C-NMRspectroscopy is based on the properties of the 13C isotope. 13C-NMR spectra provide important information about the numbers and the characters of the carbon atoms in a molecule.

Scheme 6.3.6. The chemical shift ranges of different types of carbon atoms in vari-ous organic functions

HH

HH

HH

R

H

RH

H

R

H

J (Hz)

cis 6-14

trans 11-18

ortho 8

meta 2

para 0.5

J (Hz)

cis 8-10

trans 4-6

H H

H

H

HH

H

H

H

H

trans (ax-ax)

cis (ax-eq)

trans (eq-eq)

8-10

2-3

2-3

050100150200

TMS

δ (ppm )

alkyl Calkynyl C

C-O, C-N, C-Xalkene and aromatic C

ester, amide, carboxyl C=O

aldehyde and ketone C=O

nitrile C

28


Carbon atoms situated in different chemical surroundings appear at different δ values in the 13C-NMR spectra. These δ values are usually found in the region between 0 and 210 ppm. They depend on the hybridization state of the carbon atom (ethane 5.7 ppm; acet-ylene 71.9 ppm; ethylene 122.1 ppm), whether they are primary, secondary or tertiary, and on the electronegativity of the atoms bonded to the carbon.

Scheme 6.3.7. A simplified representation of the 13C-NMR spectrum of vinyl ace-tate

050100150200

δ (ppm)

-CH3

=CH2

-OCH=

-C=O

H3CC

O

HC

CH2

O

7. Reactivity of the functional groups of organic c ompounds 29

7.1. Hydrocarbons

7. REACTIVITY OF THE FUNCTIONAL GROUPS OF ORGANIC COMPOUNDS

7.1. Hydrocarbons

7.1.1. Alkanes and cycloalkanes

Alkanes and cycloalkanes are organic compounds with low reactivity. Their non-specific transformations usually give mixtures of products. Relatively few reactions are known for their identification. The identification of saturated hydrocarbons (alkanes and cyclo-alkanes) is mainly based on their physical constants and spectroscopic data.

7.1.1.1. Reactions of alkanes with Br2 in the presence of UV light

Alkanes react with halogens in the presence of UV light in a radical substitution (SR) process. On the action of UV light, the Br2 molecule undergoes dissociation to give two bromine radicals (Br·). Br·can attack a C-H bond in a hydrocarbon to give monobromin-ated product. If the process is repeated, polybrominated products are formed. Since Cl2 is more reactive than Br2 in free radical processes, the bromination of an alkane is more selective than the chlorination reaction.

R CH

HCH3 R C

H

BrCH3

Br2, hν+ HBr

Experiment: Dissolve 5-6 drops of the given compound in 1 mL of dichloro-methane in a test tube. Add 6 drops of 2% Br2 solution in dichloromethane to the solution under the hood. Examine the pH of the vapour of the mixture after 10 min with an aqueous pH indicator paper. Then illuminate the test

tube with a UV lamp for 2 min and examine the pH of the vapour again!

7.1.1.2. Spectroscopic characterization of alkanes

Low chemical shifts (higher field, δ < 2 ppm) are characteristic for the 1H-NMR spectra of alkanes. The vicinal coupling constant (J) in alkanes varies between 5 and 10 Hz. The chemical shifts of the vicinal protons in cycloalkanes generally increase in the sequence of the ring size, while the coupling constant for each of the skeletons is generally con-stant.

In the IR spectra of saturated hydrocarbons, three significant bands are present at 2900 (2800-3000), 1460 and 1370 cm-1.

R CH3

R = saturated alkyl chain

30

7.1. Hydrocarbons

7.1.2. Alkenes (olefins)

R

H H

R

R = alkyl chain

Alkenes are unsaturated hydrocarbons with one or more carbon-carbon double bonds in their molecule. The carbon-carbon double bond is very reactive, and reacts with electro-philes to give saturated compounds bearing different functional groups.

7.1.2.1. Oxidation of olefins with KMnO4

In the presence of aqueous KMnO4, alkenes are oxidized via a cyclic ester to give diols (derivatives containing two hydroxy groups). During the Bayer reaction, the carbon-car-bon double bond is hydroxylated, resulting in a brown MnO2 precipitate as a result of the reduction of Mn(VII) (violet) to Mn(IV) (brown). Other compounds bearing oxidiz-able functional groups (phenols, primary and secondary amines, alcohols, enols, aro-matic amines and aldehydes) also give a positive Bayer test. For example,

R

H

R

H

R

HO

R

OH+ MnO2H H

KMnO4

H2O

Experiment: Dissolve the given compound (20-30 mg) in 0.5 mL of acetone in a test tube and add 2-3 drops of 1% aqueous KMnO4. The disappearance of the violet colour and the formation of a brown colour indicate the pres-ence of an oxidizable double bond in the molecule.

7.1.2.2. Addition of Br2 to an olefinic bond

Halogens readily react with the carbon-carbon double bond of olefins to form vicinal dihalogeno derivatives. The reactivity of the halogens increases in the sequence I2 < Br2 < Cl2. Br2 is the most frequently used halogen in the laboratory for the identification of the carbon-carbon double bond of alkenes. Br2 reacts rapidly with alkenes in an electro-philic addition process. During the transformation, the colour of the Br2 disappears. In the first step, Br2 undergoes heterolytic dissociation, resulting in a positively charged bromonium ion (Br+) and a negatively charged bromide ion (Br¯ ). The Br+ attacks the olefinic bond, forming a three-membered intermediate, and attack by the Br¯ then gives a dihalogenated derivative. The halogenation of alkenes is a specific reaction. The struc-ture of the product depends on the structure of the starting olefin.


7.1. Hydrocarbons

HR

H R

Br2R

BrH

Br

RH

Experiment: Dissolve the given compound (20 mg) in 0.5 mL of CH2Cl2 in a

test tube, and then add 4-5 drops of 2% Br2 in CH2Cl2 to the solution (phe-

nols, enols, amines, aldehydes and ketones also react with the Br2)

7.1.2.3. Oxidation of alkenes with KMnO4 in acidic media

KMnO4 in acidic medium is a strong oxidizing agent, which oxidizes alkenes to cleav the carbon-carbon double bond, giving carboxylic acids. During the transformation, the violet colour of the solution (Mn(VII)) disappears and Mn2+ is formed.

R

H H

R' KMnO4

H2SO4

R-COOH + R'-COOH

Experiment: Add to 6 drops of the given compound 1 drop of 1% KMnO4 and 5 drops of 5% H2SO4 in a test tube. Gently heat the mixture and shake

it from time to time for 5-6 min.

7.1.2.4. Spectroscopic identification of olefins

The IR spectra of olefins present the carbon-carbon double bond valence stretching (νC=C) at 1620-1680 cm-1. The positions and intensities of the bands depend on the sub-stituents on the olefinic carbon atoms. In general, in the case of alkenes containing more carbon-carbon double bonds, the absorption bands are shifted toward, higher wave-lengths. The absorption stretching bands of the olefinic C-H bond are found in the region 300-3100 cm-1.

The olefinic protons in the 1H-NMR spectra of alkenes are characteristic and are deshielded at δ = 4.6-7 ppm. The coupling constants (J, Hz) of these protons are also characteristic, depending on their steric arrangement (Z or E, vicinal or geminal protons).

Hx

R Ha

Hb

Jab = 0.5-3.5 HzJax = 6-14 HzJbx = 11-18 Hz

32

7.1. Hydrocarbons

7.1.3. Aromatic hydrocarbons

R

R = saturated or unsaturated alkyl chain or aryl ri ng

Aromatic hydrocarbons contain one or more isolated or condensed aromatic nucleus with or without a saturated or unsaturated carbon side-chain. Aromatic hydrocarbons do not undergo the typical reactions of alkenes. However, they do also present typical reactions. They typically undergo substitution reactions (electrophilic aromatic substitution reac-tion, SEAr). In contrast with alkenes, the aromatic ring undergoes oxidation only under harsh conditions. For example, benzene does not react either with aqueous KMnO4 or with aqueous Br2 (see the reactions of alkenes).

7.1.3.1. Friedel-Crafts alkylation of aromatic hydrocarbons

Aromatic hydrocarbons undergo alkylation reactions (SEAr) with alkyl halides in the presence of Lewis acids. During alkylation with CHCl3 in the presence of anhydrous AlCl3, coloured salts are formed.

Ar-HCHCl3AlCl 3

ArCHCl2Ar-H

AlCl 3

Ar2CHCl Ar-H

AlCl 3Ar3CH

Ar3CHAlCl 3 [Ar 3C+][HAlCl 3

-]

Experiment: Dissolve the given compound (20 mg) in 0.5 mL of CHCl3 in a dry test tube and add several crystals of anhydrous AlCl3. If no transfor-mation is detected after several min, gently heat the mixture. Depending on the aromatic compound used, different coloured solutions are formed. Ben-zene and its homologues give reddish-orange, naphthalene gives blue, and

anthracene gives greenish salts.

7.1.3.2. Reactivity of the side chain of aromatic hydrocarbons

Analogously to alkanes, the aliphatic side-chain of an aromatic hydrocarbon undergoes radical substitution (SR).

CH3 CH2-Br

Br2, hν

Experiment: See the reaction of alkanes with Br2 in the presence of UV light.

The aliphatic side-chain of an aromatic compound can be oxidized with KMnO4 in acidic medium give a benzoic acid derivative.


7.1. Hydrocarbons

Experiment: See the oxidation of olefins with KMnO4 in acidic media.

7.1.3.3. Spectroscopic characterization of aromatic hydrocarbons

The IR spectra of aromatic hydrocarbons contain the C-H bond stretching absorption bands in the region 3000-3100 and 650-900 cm-1, while the carbon-carbon bond gives signals at 1450-1650 cm-1. In the case of substituted compounds, the region 680-1000 cm-1 is analytically important because it gives information about the number and position of substituents on the aromatic nucleus.

The 1H-NMR spectra of aromatic hydrocarbons are very characteristic, with the signals of the aromatic protons in the interval δ = 6.3-8.5 ppm. The coupling constants (J) and the multiplicity are of great significance as concerns the substitution of the aromatic ring (ortho, meta or para-substituted).

In the mass spectra of aromatic hydrocarbons, the peaks with m/e = 77 (C6H5+) and m/e

= 91 (C7H7+) are characteristic.

Compounds for analysis:

n-hexane

cyclohexane

benzene

toluene

styrene

Decide whether the given hydrocarbon is:

saturated

unsaturated

aromatic

aromatic with a saturated side-chain

aromatic with an unsaturated side-chain

7.1.4. Problems and exercises

1) Give the structures of the products of the bromination of Z-2-butene (A) and E-2-butene (B).

2) Give the structure of the product formed in the reaction of 1-methylcyclohexene with HBr.

CH2-R COOH

KMnO4

H2SO4

34

7.1. Hydrocarbons

3) Give the structures of the products formed in the reactions of Z-2-butene (A) and E-2-butene (B) with diazomethane.

4) 2-Methyl-1-propene reacts with Br2 in aqueous solution (A); 2-methyl-2-butene reacts with HBr (B); propene reacts with HBr (C). Give the structures of the main products in each reaction.

5) Give the structures of the products formed in the reaction of (Z)-4-methylpent-2-ene with Br2 (AE). Depict the structures in space and in the plane (Fischer projection), and determine the absolute configurations of the asymmetric carbon atoms.

6) Give the structures of compounds A, B and C formed in the following reactions (stereochemistry):

7) Give the structures of the products formed in the reactions of (E)-3,4-dime-thylpent-2-ene a) with HBr and b) with HBr in the presence of a peroxide. Indi-cate the main products and the reaction type in both cases.

8) Three different test tubes contain cyclohexene, toluene and n-hexane. How can we determine the contents of the three test tubes? Give the equations of the re-actions.

9) Give the structures of the following compounds and indicate the increasing se-quence of their reactivity with Br2 (SEAr): A: benzaldehyde, B: 4-nitrobenzal-dehyde, C: N-methyl-3-methoxyaniline, D: aniline, E: propylbenzene.

10) The following alkenes are reacted with HBr: ethylene (A); 1-butene (B); 2-bu-tene (C); 2-methyl-2-butene (D). Indicate the relative rates of these reactions.

11) Propene reacts with HBr in the presence of benzoyl peroxide (A); 4-methyl-2-pentene reacts with water in the presence of H2SO4 (B); 2-methyl-1-butene re-acts with diborane (B2H6) in the presence of alkaline hydrogen peroxide (C). Give the structures of the main products formed in these reactions.

12) Indicate which of the following alkenes give meso products in their reactions with Br2: 1-butene (A); isobutene (B); 2-butene (C); 3-hexene (D); 2-methyl-2-butene (E).

13) Compound A reacts with KMnO4 in neutral medium to give compound B. When compound A is treated with peroxybenzoic acid, a bicyclic compound C results, which is transformed in alkaline aqueous media to trans-1,2-cyclopentanediol. Give the structures of compounds A, B and C.


7.1. Hydrocarbons

14) 2-Chloro-4-nitrobenzoic acid can be prepared from benzene in a Friedel-Crafts alkylation reaction (A); an oxidation reaction (B); a nitration reaction (C); and a chlorination reaction (D). Give the sequence of these reactions.

15) The following reactions are carried out for the preparation of 2,3-butanediol from 1-butene: KMnO4 oxidation under neutral conditions (A); HBr addition (without peroxides) (B); KOH elimination in ethanol (C). Indicate the sequence of these reactions.

16) The following alkenes are reacted with HCl: propene (A); ethylene (B); isobu-tene (C); 2-butene (D); 2-methyl-2-butene (E). Indicate the increasing sequence of reactivity of these olefins.

17) Give the chemical equation of the chlorination of propene. Indicate the possible mechanisms of this reaction.

18) Put the following compounds in the sequence of increasing reactivity in electro-philic aromatic substitution: A: toluene; B: nitrobenzene; C: benzene; D: phenol, and A: anisole B: benzenesulfonic acid; C: phenol; D: chlorobenzene.

19) Give the mechanisms of the reactions of propene with Br2 (A) and HBr (B).

20) From which of the following compounds can be dicarboxylic acids prepared by oxidation: A: 2-butene; B: 1,3-butadiene; C: propene; D: 3-hexene; E: 1,4-buta-diene?

21) Two alkenes (C4H8) A and B are brominated. Compound A gives a racemic compound, while compound B gives a meso compound. Give the structures of alkenes A and B.

36

7.2. Organohalogeno compounds


X = F, Cl, Br, I; R = alkyl, aryl groups

R-X

Organic compounds containing carbon, hydrogen and a halogen atom (fluorine, chlorine, bromine, iodine) are known as organohalogeno compounds. They may be alkyl halides, aryl halides or vinyl halides. They vary in reactivity.

a) Halogeno compounds derived from alkanes or cycloalkanes have moderate reactivity.

b) Halogeno compounds derived from alkenes or aromatic hydrocarbons containing a methylene group between the halogen and sp2 carbon atom (e.g. allyl chloride CH2=CH-CH2-Cl or benzyl bromide C6H5-CH2-Br), have high reactivity.

The reactivity of this type of halogeno compounds is governed by the polarity of the sp3 carbon-halogen bond (sp3C-X). They undergo nucleophilic substitution (SN1 or SN2 re-actions) when a nucleophilic agent displaces the halogen atom from the molecule, or elimination (E1 or E2 reactions), during which an olefin is formed.

c) Halogeno compounds in which the halogen atom is bonded to a carbon atom of an aromatic ring or to a double bonded carbon atom (e.g. bromobenzene C6H5-Br or vinyl chloride CH2=CH-Cl) have low reactivity. Because of the conjugation effects in such compounds, the carbon-halogen bond has a partial double bond character.

Other halogen-containing organic compounds are also known, such as: acid halides, halogeno alcohols or haloamines.

7.2.1. Reactions of iodo, bromo and chloro compounds with alcoholic AgNO3

Halogeno compounds react with aqueous or alcoholic AgNO3 in a monomolecular nu-cleophilic substitution reaction (SN1) to give silver halides. The relative rate of silver halide precipitate formation depends on the halogen (I > Br > Cl; AgF is soluble) in the molecule and the structure of the alkyl chain.

Formation of a stable carbocation in the transition state of the transformation increases the rate of the reaction.

R-X EtOH

R-OEt + AgX + HNO3

R-ONO2 + AgX + EtOH

AgNO3

C6H5-CH2- (benzyl) = CH2=CH-CH2- (allyl) > (CH3)3C- (tert-butyl) > (CH3)2CH- (isopropyl) >> CH3-CH2- > CH3- > CH2=CH- (vinyl) = C 6H5-



Experiment: Add to the halogeno compound (20-30 mg) 0.5 of mL satu-

rated ethanolic AgNO3 solution in a test tube. Shake the mixture well and

then allow it to stand at room temperature for 5 min. If no reaction occurs, gently heat the test tube. If a precipitate is formed, add 2 drops of 5% nitric

acid (the silver halides are not soluble in nitric acid).

7.2.2. Reactions of bromo and chloro compounds with NaI

NaI reacts with a chloro or bromo derivative in a bimolecular nucleophilic substitution process (SN2).

The rate of the reaction is influenced by the structure of the alkyl halide (primary > sec-ondary > tertiary) and by the nature of the halogen (Br > Cl). The primary bromo deriv-atives, the allylic halogeno derivatives, the acyl halides, and α-haloketones, α-haloesters, α-haloamides and α-halonitriles give a positive test at room temperature. The primary and secondary chloro derivatives and the secondary and tertiary bromo derivatives react on heating (60 °C). The vinylic and aryl halides do not give a positive test. In the case of the 1,2-dihalogeno derivatives, the elimination of I2 after the substitution, leads to the formation of olefins. As a result of the latter reaction, the reaction mixture turns reddish-brown.

acetoneR-X

NaIR-I + NaX X = Br, Cl

Experiment: Add 0.5 mL acetonic NaI solution to the test compound (20-30 mg) in a test tube and allow the mixture to stand at room temperature. If no transformation can be detected after several min. place the test tube in a 50-60 °C water bath for 7-8 min, then allow it to cool to room temper-

ature and examine if any transformation can be observed.

Preparation of acetonic NaI solution: dissolve 15 g of NaI in 100 mL of acetone. The

reagent must be stored in a dark bottle. If the mixture has a reddish-brown colour, do

not use it.

7.2.3. Spectroscopic characterization of halogeno compounds

In the 1H-NMR spectra of the halogeno derivatives, the chemical shifts of the protons on the halogen-substituted carbons are at higher δ values. These chemical shifts increase with the electronegativity of the halogen atom.

-HC-X F Cl Br I

ppm 4-4.5 3-4 2.5-4 2-4

The mass spectra of the monochloro and monobromo derivatives are characteristic be-cause of the presence of isotopes 37Cl (24.4%) and 81Br (49.5%) at the M+2 peak.


38


n-butyl chloride

n-butyl bromide

sec-butyl bromide

tert-butyl bromide

allyl bromide

benzyl chloride

chlorobenzene

Decide whether the given compound is:

a primary, secondary or tertiary halogeno compound

an allylic or benzylic halogeno compound

a bromide or a chloride

an aryl halogeno derivative


1) A halogeno compound is heated in aqueous KOH solution (A), and in ethanolic KOH solution (B). Give sequence the reactions that occur in these cases.

2) Indicate the increasing sequence of reactivity of the following compounds in Friedel-Crafts alkylation reactions: A: methyl chloride; B: t-butyl chloride; C: ethyl chloride; D: allyl chloride; E: isopropyl chloride.

3) Indicate the increasing sequence of reactivity of the following compounds in monomolecular nucleophilic substitution (SN1). A: 1-chloropentane; B: neopentyl chloride; C: 2-chloropentane; D: 2-chloro-2-methylbutane; E: 1-chloro-3-methylbutane.

4) Give the structures of the following halogeno compounds and indicate the in-creasing sequence of reactivity if they react with: a) NaI/acetone (SN2), b) AgNO3/EtOH (SN1): A: benzyl chloride; B: isobutyl chloride; C: benzyl bro-mide; D: chlorobenzene; E: 1-chloro-1-methylcyclohexane; F: sec-butyl chlo-ride.

5) Give the structure of the main product formed in the reaction of allyl chloride with HCl.

6) Give the structure of the main product formed in the reaction of 2-pentene with HCl.

7) How can the formation of the following two alcohols be explained?



BrAgOH

OH OH

+

8) Give the structures of the products in the following transformations and indicate the main products in each case:

BrKOH

NaOEtBr

ClHOH

a)

b)

c)

9) Give the structures of the products formed in the following transformations:

Br BrNaCN

EtOH/H2O

COOEt

BrC6H5SNa

THF, 25 °C

O2N

Cl CH3COONa

AcOH∆

ClNaOMe

MeOH, 50 °C

ClNaCN

MeOH, 50 °C

∆

a)

b)

c)

d)

e)

40


HO ClOH

C6H5ONa

EtOH∆

f)

Cl NaOH

∆g)

Cl

KOtBuDMSO

h)

10) Give the structure of the product formed in the reaction of 1R,2R-1-bromo-1,2-diphenylpropane in the presence of KOEt on heating. Indicate the stereochemi-cal arrangement of this product.

11) Suggest suitable starting materials for the synthesis of the following compounds:

O

S

O

O

O

a)

b)

c)

d)

e)

12) Complete the following chemical reactions:



EtMgBrHOH

EtMgBrD2O

EtMgBrPhCHO

EtMgBrPhCOOMe

EtMgBrPhCOMe

a)

b)

c)

d)

e)

42

7.3. Hydroxy compounds


Alcohols

R = alkyl chain

R-OH

Alcohols are organic compounds containing a hydroxy group (-OH) bonded to an sp3 carbon atom. They can also contain numerous types of side-chain. The reactivity of the hydroxy group in an alcohol is determined by the nature of the alkyl group and the pres-ence of other functional groups in the molecule. Alcohols as O-nucleophiles participate in substitution reactions (they can be alkylated or acylated) or elimination reactions. They can also be oxidized to carbonylic compounds (aldehydes or ketones) or to carbox-ylic acids. The hydrogen of the hydroxy group has an acidic character. In the presence of strong bases, alkoxides are formed. In acidic solutions, alcohols are protonated on the oxygen atom.

Enols

OH

R'

R, R' = alkyl chain

H

R

The hydroxy group in enols is bonded to an sp2 carbon atom. Enols participate in reac-tions analogously to alcohols or phenols, but they also give several characteristic reac-tions for the carbon-carbon double bond (e.g. bromination).

Phenols

OH

R

R = alkyl, aryl chain

The hydroxy group of phenols is bonded to a carbon atom of an aromatic nucleus. The acidity of the OH group and its reactivity are typical for phenols. Phenols undergo reac-tions on the aromatic ring.



7.3.1. Transformation of alcohols to halogeno compounds

Depending on their structure (primary, secondary or tertiary), aliphatic alcohols react with different rates with a hydrochloric acid solution of ZnCl2 (Lucas reagent) in a mono-molecular substitution (SN1). The reactivity of alcohols increases in the primary < sec-

ondary < tertiary. Since the alkyl halide formed is not soluble in HCl, formation of two layers or a cloudy solution can be detected. The Lucas test is given only by water-soluble alcohols (less than 6 carbon atoms in the molecule). Analogously to the tertiary alcohols, the reactions of benzylic and allylic alcohols occur readily. The reaction is not charac-teristic for polyhydroxylic compounds.

R-OHZnCl2 R Zn(OH)Cl2 R-Cl + H2O + ZnCl2

HCl

Experiment: Add 2 mL of Lucas reagent to the given compound (several drops) in a test tube, then shake the mixture well and allow it to stand at room temperature. If no transformation can be detected after 4-5 min, warm the mixture in a 50 °C water bath for 2-3 min. For the benzylic, allylic

or tertiary derivatives the formation of two layers can be observed immediately. In the case of secondary alcohols, the halogeno compound is formed after 4-5 min, while pri-

mary alcohols do not react.

Preparation of the Lucas reagent: dissolve 60 g of dry ZnCl2 in 42 mL of concentrated. HCl.

7.3.2. Oxidation of alcohols with the Jones reagent

The primary and secondary alcohols can easily be oxidized with chromic acid (H2CrO4, H2Cr2O7) to the corresponding aldehydes or ketones. The aldehydes obtained from pri-mary alcohols are further oxidized to carboxylic acids under these conditions.

OHR

R'

OR

R'

CrO3

cc. H2SO4R, R' = H, alkyl-, aryl group

Experiment: Dissolve the given compound (4-5 drops or 20-30 mg) in 1 mL of acetone in a test tube, and then carefully add 1-2 drops of Jones

reagent to this mixture.

Preparation of the Jones reagent: dissolve 5 g of CrO3 in 5 mL of concen-

trated. H2SO4 and add this solution to 15 mL of water.

Precaution: H2CrO4 is carcinogenic! Wear gloves while handling it!

7.3.3. Reactions of polyols with Cu(II)

In contrast with monohydroxy compounds, vicinal diols form bidentate complexes with Cu(II) in alkaline media.

44


OHOH

Cu(OH)2

NaOH

OO O

OCu

2-

+ Na+

Experiment: Add 2 mL of water and 1 drop of 10% CuSO4 solution to the

given compound (4-5 drops or 20-30 mg) in a test tube, and then shake the mixture and add 9-10 drops of 8% NaOH solution. The Cu(OH)2 precipi-

tate dissolves in the presence of vicinal diols.

7.3.4. The iodoform test of ethanol

In the presence of I2, ethanol is oxidized to acetaldehyde, which is then further oxidized by I2 in alkaline media to give the iodoform.

R CH3

OH I2R CH3

O I2

NaOH R CI3

O HOHRCOOH + CHI3

Experiment: Add 5-6 drops of 10% NaOH solution to the given compound (20 mg) in a test tube (if the test compound is not soluble in water, add several drops of dioxane). Place the test tube in a 60 °C water bath for several min and, then add KI/I2 solution dropwise until the brownish colour is persistent. Gently heat the mixture for several minu and then add several

drops of 10% NaOH until yellow iodoform crystals are formed.

Preparation of the KI/I2 reagent: dissolve 25 g of KI and 15.5 g of I2 in 100 mL of water.

7.3.5. Spectroscopic characterization of alcohols

In the IR spectra of alcohols, the stretching vibrational band of the OH group is present in the 3600-3650 cm-1 region. In concentrated solutions, the formation of intermolecular hydrogen-bonds results in a larger band appearing at 3200-3400 cm-1. The intensive stretching band of the C-OH bond is present at 1000-1170 cm-1, increasing in the se-quence primary < secondary < tertiary.

In the 1H-NMR spectra of the alcohols, the chemical shift of the hydroxy proton depends on the concentration of the solution and varies in the interval δ = 1-5.5 ppm. The proton bonded to the hydroxylic carbon in general appears at δ = 3.8-5.7 ppm.

The mass spectra (especially for primary alcohols) present the characteristic M-18 peak, which is a result of the loss of a water molecule. The other characteristic peak for primary alcohols is that at m/e = 31, which reflects the loss of a hydroxymethyl (-CH2OH) frag-ment.

7.3.6. Reactions of enols with Fe(III)

The enolic hydroxy group reacts with FeCl3 to give an intensely coloured solution.



The β-keto esters, whose molecules contain a carbonyl group (C=O) and a mobile hy-drogen in the α position to this carbonyl function, give the above reaction. The mobility of this methylenic hydrogen is due to the electron-withdrawing effect of the carbonyl and carboxylate (-COOR) groups. Keto-enol tautomerization is typical of this class of compounds. The reaction with the FeCl3 occurs in the enol tautomer form.

Experiment: Dissolve the given compound (5-6 drops or 30 mg) in 1 mL of

water in a test tube (if it is not soluble in water, add 1 mL of ethanol) and add 1 drop of 2.5% FeCl3 solution. After several min, a reddish colour ap-pears which is characteristic of enols. Add 1 mL of Br2 in water to this

solution (quickly in one portion), shake the mixture and allow it to stand at room tem-perature until the characteristic colour of enols disappears. After several min, because of the keto-enolic equilibrium, the keto form transforms again to the enol form, and the typical colour of the enol complex can be detected again.

Precaution! Br2 can cause severe burns on the skin! Use gloves and the hood when han-dling it!

7.3.7. Reactions of enols with Cu(II)

1,3-Diketones and β-keto esters form coloured chelate complexes with Cu(II) ions under neutral conditions.

Experiment: Add 5-6 drops of saturated Cu(OAc)2 solution to the given

compound (several drops or 30 mg) in a test tube and shake the mixture well.

R

HOH

RR

HOFeCl2

RFeCl3 R

HOFe2+

R

+ 2Cl

R-CO-CH2-COOR' R-C=CH-COOR'

OH

R-C=CH-COOR'

OH

Br2R-C-CH-COOR'

OH

BrBr

46


7.3.8. Spectroscopic characterization of enols

In the IR spectra of enols (β-keto esters), vibrational bands typical of both keto and enol forms are present. For example, there are two bands for the keto group and the ester function. The enolic form gives the band at lower wavelength due to the intramolecular hydrogen-bonding. The characteristic νC=C band also appears at 1640 cm-1.

In the 1H-NMR spectra of enols, the protons of the OH group are highly deshielded (δ = 15 ppm), which is a result of the intramolecular hydrogen-bonding interactions. The sig-nal of the protons bonded to the olefinic carbon at 5.7-6.5 ppm is also specific.

7.3.9. Reactions of phenols with Fe(III)

Phenols in the presence of aqueous FeCl3 afford coloured complexes. The colours de-pend on the nature of the substituents on the aromatic ring.

Experiment: Dissolve the given compound (4-5 drops or 30 mg) in 1 mL of water in a test tube (if it is not soluble, add 1 mL of ethanol). Then add 1 drop of 2.5% FeCl3 solution. Phenol gives reddish-violet, cresols give blue,

and other substituted phenols give greenish complexes.

7.3.10. Bromination of phenols

In aqueous solution, phenols in the ortho and para positions readily react with Br2 (aro-matic electrophilic substitution, SEA). The electron-donating -OH group on the aromatic nucleus increases the reactivity of phenols towards electrophiles. Subsequently, the bro-mophenols are further transformed by the action of other Br2 molecules to tetrabromo derivatives, which are yellow precipitates.

Experiment: Dissolve the given compound in 4 mL of water in a test tube and add satu-

rated aqueous Br2 solution dropwise.

7.3.11. Synthesis of triarylmethane colorants from phenols

In the presence of KOH in chloroform, phenols are transformed into triphenylmethane compounds.

R R'

O O

R R'

O OH

R

R'

O

OR

R'

O

OCu

Cu2+

OH OHBr Br

Br

OBr Br

BrBr

Br2

SEAr

Br2



Experiment: Take the given compound (50 mg) in a test tube and add 5-6

drops of CHCl3 and several drops of 10% KOH solution. Gently heat the

mixture until a reddish compound is formed.

7.3.12. Spectroscopic characterization of phenols

Because of the conjugation effect between the aromatic π-electrons and the p-electrons of the oxygen atom of the hydroxy function, the OH vibrational band appears at a lower wavelength in the IR spectra of phenols than in the case of alcohols (3390-3600 cm-1). The absorption band of the phenolic OH involved in the hydrogen-bonding is found at 3500 cm-1 (for dimers) and 3320 cm-1 (for polymers)

In the 1H-NMR spectra, the chemical shift of the phenolic proton varies in the interval δ = 4.5-12 ppm. The hydroxy group is involved in intramolecular hydrogen-bonding and in general is deshielded. For example, the chemical shift of the phenolic proton in salic-ylaldehyde appears at δ = 11.1 ppm.

For the mass spectra of phenols, characteristic peaks are m/e = M-28 (loss of a CO func-tion) and m/e = 77 (tropylium ion or C6H5

+).


methanol

ethanol

n-propanol

isopropanol

n-butanol

sec-butanol

tert-butanol

benzyl alcohol

propane-1,2-diol

glycerine

acetylacetone

ethyl acetoacetate

OH

CHCl3KOH

OH

CHOPhOH

OH

HO OH

O

HO OH

oxidáció

48


phenol

2-naphthol

Decide whether the given compound is

a phenol

a polyhydroxy compound

a primary aliphatic alcohol

a secondary aliphatic alcohol (2-alkanol type)

a tertiary aliphatic alcohol

a benzylic alcohol


1) Give the structures of compounds A and B in the following transformations:



2) Indicate which of the following reagents react with o-hydroxybenzyl alcohol in a 1:2 molar ratio: A: NaOH; B: acetic acid; C: Na; D: acetyl chloride; E: metha-nol; F: benzoic acid.

3) Indicate in which of the following cases chemical transformations will be de-tected: A: phenol and acetic acid; B: phenol and acetyl chloride; C: phenol and NaOH; D: phenol and methanol; E: sodium phenoxide and methyl iodide.

4) Give the structures of the following compounds and indicate the sequence of increasing acidity: A: acetic acid, B: propan-1-ol, C: phenol, D: trichloroacetic acid, E: 4-methoxyphenol, F: tert-butanol.

5) Propose a method for the preparation of (R)-2-bromobutane from (S)-butan-2-ol (give the reactions).

OH

H2O, H+ 1. NaBH4

2. H2O, H+

(CH3)2CC6H5

OH

Mg, Et2O

O1.

2. H+

Mg, Et2O 1. HCHO

2. H2O, H+

CH2OH

H2O, H+ H+

TsCl LiBr

Br

H2CrO4 MgBr

3-methylhexan-3-ol

HO

A B

A B

A B

A B

A B

A B

a)

b)

c)

d)

e)

f)

50


6) Indicate the main product of the bromination of phenol when the molar ratio of the components is 1:1. Give the formula of the product in the same reaction when the Br2 is used in a large excess.

7) Propose a method for the preparation of 1-butanol from 1-butene and from ac-etaldehyde.

8) A chemist has only ethanol as an organic compound in his laboratory and other inorganic reagents. How can ethyl acetate be prepared under these conditions?

9) Give the sequence of increasing acidity for the following phenols: A: p-cresol; B: m-chlorophenol; C: picric acid; D: p-aminophenol; E: phenol; F: p-nitrophe-nol.

10) Give the sequence of increasing acidity of the following compounds: A: o-cre-sol; B: phenol; C: m-aminophenol; D: m-nitrophenol; E: 2,4-dinitrophenol.

11) Give the increasing reactivity of the following compounds: A: o-cresol; B: phe-nol; C: p-aminophenol; D: p-nitrophenol; E: 2,4,6-trinitrophenol in electro-philic substitution (SEAr) reactions.

12) Give the sequence of increasing acidity of the following phenols: A: p-chloro-phenol; B: p-nitrophenol; C: p-methoxyphenol; D: p-cresol; E: 2,4-dinitrophe-nol.

13) Indicate which of the following reagents react both with phenols and with alco-hols: A: NaOH; B: MeCOCl; C: MeCOOH; D: Na; E: H2SO4; F: MeOH.

14) A mixture of n-propanol and ethanol is treated with H2SO4 and three compounds (ethers) are formed. Give the structures of these three ethers. Only one ether is formed from t-butanol and ethanol under similar conditions. Give the structure of the latter compound and explain this experimental result.

15) Indicate how the following ethers can be prepared from alcohols: a) n-propyl phenyl ether; b) cyclohexyl methyl ether; c) t-butyl methyl ether.

16) Explain why the first reaction is 600 times faster than the second:

CH3OCH2ClHOH CH3OCH2OH CH2O + MeOH

CH3SCH2ClHOH

CH3SCH2OH CH2O + MeSH

17) Complete the transformations and give the structures of compounds A-D.

18) Complete the transformations and give the structures of compounds A-F.

OH PBr3 Mg

ether

1) CH3CH2CHO

2) HOH, H+

SOCl2A B C D



19) Propose two synthetic methods for the preparation of cis-2,3-dimethyloxirane.

20) Propose synthetic methods for the transformations:

OH

OOH

a)

b)

21) Which of the following reactions is accomplished in the presence of H2SO4:

the synthesis of alkenes (A), ethers (B) and esters (C) from alcohols.

22) Give the chemical structures of the products of the following reactions:

A: of ethyl chloride is heated in ethanolic KOH solution; B: ethanol is heated in the presence of a catalytic amount of H2SO4.

23) Three compounds (A, B and C) react with HIO4. Give the structures of com-pounds A, B and C.

24) Give the conformers of cis-1,3-cyclohexanediol. Which will be the more stable conformer?

OHPBr3 Mg

ether1) CH3CH2CHO

2) HOH, H+HBr KCN

O1)

2) HOH, H+

A B C D E

F

A acetic acid + propionic aldehyde

B CH3COCH2CH2CH2CHO

C formaldehyde + acetone

52

7.4. Amines

7.4. Amines

Amines are organic compounds derived from ammonia in which one or more hydrogen atoms are substituted by alkyl or aryl groups. Depending on the number of alkyl or aryl substituents bonded to the nitrogen, amines can be classified as primary (when one alkyl or aryl group is bonded to the nitrogen), secondary (with two alkyl or aryl groups) or tertiary (three substituents on the nitrogen). Due to the lone electron pair on the nitrogen atom, amines have a nucleophilic and basic character. An aliphatic amine has a stronger basic character than ammonia as a result of the electron-donating effect of the alkyl groups. In contrast, the basicity of aromatic amines is less because of the conjugation effect between the π- and p-electrons, with a decrease in the electron density on the sp2 nitrogen atom.

7.4.1. Reactions of amines with Cu(II)

In the presence of Cu(II), aliphatic amines give blue tetraamino complexes, while the primary aromatic and secondary amines form insoluble complexes.

Experiment: Add 1-2 drops of amino compound to 0.5 mL of water in a test tube and

then add 1 drop of 10% CuSO4 solution and shake the mixture well.

7.4.2. Acylation of amines

Primary and secondary amines react with acid chlorides to form mono- and disubstituted amides. When amines react with sulfonyl chlorides (benzenesulfonyl- or p-toluenesul-fonyl chloride) in alkaline media, sulfonamides are formed. Since the sulfonamides de-rived from primary amines are N-H acids, they are soluble in alkaline solution, but they are crystallized when treated with an acid. The sulfonamides derived from secondary amines are not soluble, while the tertiary amines do not react with sulfonyl chlorides.

R-NH2 NHR'

R

NR'R

R"

R, R', R" = alkyl or aryl group

NHR'

RN

R'

RSO2Ar

Ar-SO2Cl

NaOH

R-NH2

Ar-SO2Cl

NaOHR-NH-SO2Ar

NaOHR-N-SO2Ar

H+

primary amine

secundary amine

Na


7.4. Amines

Experiment (the Hinsberg test): Take 1.5 mL of 10% NaOH solution, 2-3

drops (30 mg) of the given compound and 30 mg of benzenesulfonyl chloride

in a test tube. If no transformation is detected after several min (the pH has to be basic), warm the mixture for 4-5 min, and then allow it to cool to room

temperature. If no transformation is observed, the compound is a tertiary amine. If the

formation of a precipitate is observed from the alkaline solution, but it is not soluble in

2-3 mL of water, the test compound is a secondary amine. If no precipitate is formed,

add 10% HCl solution. A precipitate is proof of the formation of a monosubstituted sul-

fonamide, and the analysed compound is a primary amine.

7.4.3. Schiff-base formation reaction of amines

Schiff-bases (azomethines), which are formed from aliphatic primary amines and ace-tone, give coloured complexes in the presence of sodium pentacyano(nitrosylferrate).

Experiment: Dissolve 2-3 drops of the given compound in 3 mL of water and 1 mL of acetone in a test tube, and then add 1 drop of 1% sodium

pentacyano(nitrosylferrate) solution to this mixture.

7.4.4. Reaction of aniline with Br2

Analogously to phenols, the aromatic nucleus of aniline and of other N-alkylated deriv-atives is strongly activated towards electrophiles (the electron-donating effect of amino groups). They readily react with aqueous Br2 in aromatic electrophilic substitution reac-tions (SEAr).

Experiment: Dissolve 2-3 drops of the given compound in 2 mL of water in

a test tube, and then add (under a hood) aqueous bromine solution drop-

wise, to the mixture until the colour of Br2 is maintained.

R-NH2Me Me

O

Me

MeNR

Schiff-base

Na2[Fe(CN)5(NO)]colored comple x

NH2NH2

Br Br

Br

Br2

54

7.4. Amines

7.4.5. Spectroscopic characterization of amines

For the IR spectra of primary and secondary amines, the vibrational NH2 and NH bands are characteristic. In the case of the primary amines, two bands are present for the νNH in the 3500-3400 cm-1 region. For the secondary aliphatic amines, one stretching band is typical at 3310-3350cm-1, while for the secondary aromatic derivatives it is at 3430-3450 cm-1. The vibrational band for the C-N bond is medium intense; for primary amines it appears at 1028-1190 cm-1, and for secondary amines at 1095-1190 cm-1.

In the 1H-NMR spectra of aliphatic amines, the N-H protons give signals at δ = 0.5-3 ppm. In aromatic amines, these protons are found in the region δ = 3-5 ppm. Since the amino groups can be involved in hydrogen-bonding interactions, the positions of these protons depend on the concentration, solvent and temperature. In general, the N-H ab-sorption is present as a broad peak.

In the mass spectra of primary aliphatic amines, the m/e = 30 peak is characteristic, which is a result of the loss of an aminomethylene group (CH2=NH2

+). For aromatic amines, the m/e = M-1 (C6H5NH+) peak and the loss of a HCN molecule are typical.


aniline

N-methylaniline

N,N-dimethylaniline

piperidine

triethylamine

n-butylamine


a primary aliphatic amine

a primary aromatic amine

a secondary amine

a tertiary aliphatic amine

a tertiary aromatic amine


1) p-(2-Methylaminopropyl)phenol (a vasodepressant) can be prepared according to the following scheme. Give the structures of compounds A-H


7.4. Amines

2) Give the structures of compounds A-F, which are used for the synthesis of 1-(p-hydroxyphenyl)-2-methylaminoethanol (a vasodepressant) according to the fol-lowing scheme:

3) 1-(3,4-Dihydroxyphenyl)-2-methylaminoethanol (a vasodepressant) can be pre-pared from compound A according to the following scheme. Give the structures of compounds A, B, C, D and E.

CHO

OMe

NO2 H2 HCl 1. CH2O

2. H2

OH

NH

OMe

HNO2 1. H2

2. HONH2*HCl

NaHg C6H5CHO

MeI

HBr

A B C

D E F G

H

ClMeNH2

OH

O

1. HCl

NH*HCl

OH

HO

2. H2

CHO

OMe

KCN CrO3 H2 TsCl

Me2SO4

1. HCl

2. H2

A B C D

EF

56

7.4. Amines

4) Give the structures of compounds A, B, C and D used for the synthesis of 1-(3,4-dihydroxyphenyl)-2-aminoethanol (a vasodepressant) according to the follow-ing scheme.

5) Give the structures of compounds A, B and C according to the following scheme:

6) Arrange the following amines in the sequence of increasing basicity: A: dime-thylamine; B: ethylamine; C: p-nitroaniline; D: p-hydroxyaniline; E: methyla-mine; F: aniline.

MeMgI -H2O Br2

OO

BrBr

H2O

HClMeNH2

HOHN

HOOH

A B C

DE

CHO

OO

MeNO2 Br2, KOH, MeOH AlCl 3

H2

NH2

HO

HOOHOH

HO

CHO

HCN H2

A B C

D

O

Br2 AMeNH2 B

H2 C


7.4. Amines

7) Give the increasing sequence of basicity of the following amines: A: propyla-mine; B: isopropylamine; C: aniline; D: p-methoxyaniline; E: m-nitroaniline; F: diethylamine.

8) Give the increasing sequence of basicity of the following amines: A: ethylamine; B: dimethylamine; C: p-nitroaniline; D: propylamine; E: p-toluidine; F: m-tolu-idine.

9) Five test tubes contain the following amines: A: N-ethyl-N-methylaniline, B: pyrrolidine, C: n-butylamine, D: aniline, E: triethylamine. Give the structures of the compounds and determine which of the test tubes contains the aniline (reac-tions).

10) How can the following compounds be prepared from toluene: a) 1-(p-tolyl)ethylamine; b) 2-phenylethylamine?

11) Give a method for the preparation of n-propylamine from a) n-propanol; b) n-butanol.

12) Prepare 3,5-dibromotoluene from toluene?

13) The hydrolysis of N,N-diethylaminoethyl chloride is 1000 times faster than the hydrolysis of ethyl chloride. How can this be explained?

14) Prepare 5-amino-1-butene from 4-bromo-1-butene.

15) Give the structures of compounds A-D according to the following scheme:

ABr2 B

KCN

-KClC

H2D

H2O

-NH3

HOOC-CH2-CH2-COOH

58

7.5. Carbonyl compounds (aldehydes and ketones)


The reactions of aldehydes and ketones take place on the carbonyl group (C=O) and on the methylene in the α-position to the carbonyl function. The identification of carbonyl compounds is based on the following reactions:

a) addition reactions (nucleophlilic addition to the C=O bond)

b) condensation reactions (addition and elimination)

c) oxidation reactions (transformation of the carbonyl group to a carboxylic function)

7.5.1. Identification of carbonyl compounds with 2,4-dinitrophenylhydrazine

Aldehydes and ketones react with 2,4-dinitrophenylhydrazine in a condensation trans-formation (addition and elimination) to give insoluble 2,4-dinitrophenylhydrazones. In the first step of the reaction, the nitrogen atom of the phenylhydrazine attacks the car-bonyl carbon atom in a nucleophilic addition process. This is followed by the elimination of a water molecule to give a hydrazine. A similar reaction is the formation of azome-thines (see Schiff-bases).

Experiment: Add 1 drop or several crystals of the test compound to 7-8 drops of 2,4-dinitrophenylhydrazine in a test tube. A yellow precipitate

or crystals are formed. If no transformation occurs, allow the mixture to

stand for 10-15 min at room temperature or eventually heat it.

Preparation of the 2,4-dinitrophenylhydrazine reagent: dissolve 1 g of

2,4-dinitrophenylhydrazine in 5 mL of concentrated. H2SO4 and then add this mixture carefully to a solution of 10 mL of water and 35 mL of ethanol.

7.5.2. Oxidation of carbonyl compounds

7.5.2.1. Oxidation with KMnO4

Aldehydes are readily oxidized and, in contrast with to ketones, they react rapidly with neutral KMnO4 solution.

R

R'O

R, R' = alkyl, aryl group: ketonesR = H; R' = H, alkyl, aryl group: aldehyde s

R

R'O

HN

NO2O2N

N R'

RHN

NO2O2N

NH2+ H+

R-CHOoxidation

R-COOH



Experiment: Dissolve 5-6 drops (20 mg) of the given compound in 0.5 mL

of N,N-dimethylformamide in a test tube, and then add 1 mL of 1% KMnO4.

If the violet colour of KMnO4 persists, shake the mixture for several min.

7.5.2.2. Oxidation with the Jones reagent

On the action of chromic acid, aldehydes are transformed faster than ketones to the cor-responding carboxylic acids. The aliphatic aldehydes can be distinguished from the aro-matic aldehydes by their reactivity.

Experiment: Dissolve 2-3 drops (20 mg) of the given compound in 0.5 mL of N,N-dimethylformamide in a test tube and add 1-2 drops of the Jones

reagent. Shake the mixture well and allow it to stand for several min at

room temperature. If no transformation is detected after several min warm

the mixture.

7.5.2.3. Oxidation with the Tollens reagent

In the presence of the Tollens reagent, aliphatic aldehydes are readily oxidized to the corresponding carboxylic acids, while metallic silver (a silver mirror) is formed. The aromatic aldehydes also give a positive test, but only on heating, with the formation of black metallic silver.

Experiment: Add 1 drop of the given compound to 1 mL of the Tollens re-agent in a test tube and then shake the mixture for 5 min. If no transfor-

mation is observed, warm the mixture on a 60 °C water bath.

Preparation of the Tollens reagent: To 10 mL of 5% aqueous AgNO3, add 10 drops of 10% NaOH solution and then concentrated. NH3 solution until

the dark precipitate is dissolved.

7.5.2.4. The Fehling reaction

During the Fehling reaction, aldehydes are oxidized by the action of Cu(OH)2, and a reddish Cu2O precipitate is formed.

Experimental: Add 5-6 drops of the Fehling-reagent to several drops of

aldehyde in a test tube. Boil the mixture for 2-3 min until a red precipitate

is formed.

Preparation of the reagent: Fehling I: dissolve 14 g of CuSO4 in 200 mL of

water. Fehling II: dissolve 70 g of sodium potassium tartrate and 52 g of KOH in 200 mL of water. The two solutions are stored separately. Just before use, mix equal volumes

of the two solutions.

R-CHO R-COOH + Ag + H 2O + NH3[Ag(NH 3)2]+OH

R-CHOCu(OH)2 R-COOH + Cu2O + H2O

60


7.5.2.5. The Benedict reaction

The Benedict reaction is similar to the Fehling reaction: aldehydes are oxidized to car-boxylic acids in the presence of Cu(II).

Experiment: Take 3-4 drops (50 mg) of the given compound, 3 mL of water

and 3 drops of Benedict reagent in a test tube. Boil the mixture for 1 min

and then allow it to stand at room temperature.

Preparation of the reagent: dissolve 17.3 g of sodium citrate and 10 g of

Na2CO3 in 80 mL of warm water and then add 1.73 g of CuSO4 in 10 mL of water drop-wise. Cool the mixture to room temperature and dilute it with water to 100 mL. The

advantage of the Benedict reagent is that it can be stored for a longer time than the

Fehling reagent.

7.5.3. Iodoform test of methyl ketones

In alkaline media, methyl ketones undergo α-iodination with I2. Thi is followed by C-C bond cleavage to give iodoform.

Experiment: Add 5-6 drops of 10% NaOH solution to the given compound (20 mg) in a test tube (if the test compound is not soluble in water, add several drops of dioxane). Place the test tube for several min in a 60 °C water bath, and then add KI/I2 solution dropwise until the brownish colour persists. Gen-

tly heat the mixture for several min and then add several drops of 10% NaOH until yel-

low iodoform crystals are formed.

7.5.4. Reactions of carbonyl compounds with Br2

Carbonyl compounds react with Br2 via their enolic tautomer form in an addition-elimi-nation process and are transformed to α-bromo carbonyl compounds. In this type of re-action, aldehydes (having an α-hydrogen) react more rapidly than the corresponding ke-tones.

Experiment: Add 3-4 drops of saturated aqueous Br2 solution to 2-3 drops

of the given compound in a test tube and shake the mixture for several min.

Precaution! Br2 cause severe burns on the skin! Wear gloves and handle it under the hood!

R CH3

O I2

NaOH R CI3

O HOHRCOOH + CHI3

RR'

O

RR'

OHR

R'O

Br

Br2



7.5.5. Spectroscopic characterization of carbonyl compounds

In the IR spectra of carbonyl compounds, an intensive νC=O absorption band is charac-teristic at 1650-1740 cm-1. In the case of unsaturated aliphatic aldehydes, the νC=O band appears at 1720-1740 cm-1, while for the unsaturated aromatic derivatives it is at 1680-1720 cm-1. The vibrational C=O band of saturated aliphatic ketones is found at 1700-1730 cm-1, for the unsaturated derivatives at 1665-1695 cm-1, for the alkyl-aryl ketones at 1685-1690 cm-1 and for the diaryl ketones at 1640-1670 cm-1.

In the 1H-NMR spectra of aldehydes, the aldehyde proton is highly deshielded (δ = 9-10.5 ppm).

In the mass spectra of aldehydes the M-H (M-1) peak, and in the mass spectre of ketones the M-R peak is characteristic. The m/e = 105 (C6H5CO+) and the m/ e = 77 (C6H5

+) peaks are typical for aromatic aldehydes and aromatic ketones.


acetone

acetophenone

cyclohexanone

benzaldehyde

propionaldehyde

formaldehyde

acetaldehyde


an aliphatic aldehyde

an aromatic aldehyde

a methyl ketone

another ketone

7.5.6. Problems and exercises:

1) Give the structures of compounds A and B, which are used for the synthesis of 3,4-dihydroxy-α-methylaminoacetophenone (a vasodepressant) according to the following scheme:

ClCOCH2Cl

OHOH

ONH

NH2CH3A B

62


2) Arrange the following carbonyl compounds in the increasing sequence of their reactivities in nucleophilic addition (AN) reactions: A: chloral, propionaldehyde, acetone; B: benzophenone, benzaldehyde, formaldehyde; C: chloral, butanone, benzophenone.

3) Give the structures of compounds A-D in the following scheme:

4) Indicate the sequence of reactivity of the following carbonyl compounds in nu-clephilic addition reactions: A: butanal; B: isobutyraldehyde; C: propanone; D: propanal.

5) Which of the following alkenes give acetone in an energic oxidation reaction A: 2-methyl-2-pentene; B: 2,3-dimethyl-2-butene; C: 3-methyl-1-butene; D: 4-me-thyl-1-pentene; E: 3-methyl-2-pentene.

6) Prepare 2-amino-1-phenylethanol from benzaldehyde.

7) How can it be explained that, the in the presence of NaOH, phenylglyoxal (PhCOCHO) is transformed to mandelic acid sodium salt (PhCH(OH)COONa)?

8) Starting from toluene, synthesize 2,4-dinitrobenzaldehyde.

9) Synthesize 4-nitrobenzophenone from 4-nitrobenzoic acid.

10) Prepare ethylbenzene from acetyl chloride.

11) How can 2-hydroxybutanoic acid be prepared from 1-propanol?

12) Prepare 2-phenyl-2-pentanol from propanoic acid.

13) Give the structures of the following compounds and indicate the increasing se-quence of reactivity with 2,4-dinitrophenylhydrazine: A: acetophenone, B: bu-tanal, C: cyclohexanone, D: benzophenone, E: formaldehyde, F: acetaldehyde.

14) Vanillin can be prepared according to the following scheme. Identify com-pounds A-D.

KOH Ac2O K2Cr2O7 HOH

OHOMe

CHO

A B C D

15) How can the following olefins be prepared from carbonyl compounds?

ACH3Cl B

[O]C

PCl5 (SN)D

C10H8 (SE)

C6H5 O



Pha) b)

16) Identify the compounds in the following chemical transformations:

O

O 1. PhMgBr

2. HOH, H+

H+, ∆

-H2OA B + Ca)

O 1) NaBH4

2) HOH, H+

H2SO4, ∆ NBS 1. PPh3

2. BuLi

O

A B C D Eb)

O Cl2, H+KOH, EtOH

∆

HOH, H+ H2CrO4c) A B C D

17) Identify the compounds in the following chemical transformations:

OHH2CrO4

HBr

Mg, ether

2) HOH, H+

1)

a) A

B CA

D

Ob)Br2, H+

∆A B

t-BuOK

64

7.6. Carboxylic acids and carboxylic acid derivativ es

7.6. Carboxylic acids and carboxylic acid derivatives

The carboxylic acids contain one or more carboxylic groups (COOH). The monocarbox-ylic acids containing one or two carbon atoms, the di- or polycarboxylic acids and the hydroxy acids are soluble in water, whereas the aromatic carboxylic acids and those with a higher number of carbon atoms in the molecule are insoluble. In general, they are weak acids, but on increase of the number of electron-withdrawing functional groups in the molecule, the acidity of carboxylic acids is increased. The acidity of the carboxylic pro-ton means that they react readily with bases to form salts. The melting points and the boiling points of the esters are lower than those of the corresponding carboxylic acids and the esters are insoluble in water. The carboxylic acid derivatives undergo character-istic nucleophilic substitution (SN) reactions involving the C=O group of the carboxylic function.

The reactivity of the carboxylic acid derivatives towards nucleophilic reagents is deter-mined by the electron-withdrawing or donating effects of the functional groups bonded to the C=O carbon atom. The most reactive with nucleophiles are the acid halides (the strong electron-withdrawing effect of the halogen atom), while the amides are much less reactive (the electron-donating effect of the amino group).

7.6.1. Ester formation of carboxylic acids

In the reactions of the carboxylic acids with alcohols, carboxylic esters are formed in equilibrium transformations. The reactions are carried out in the presence of a catalytic amount of sulfuric acid.

R Y

O

Y = OH - carboxylic acidY = halogen - acid halide sY = OR' - estersY = NR1R2 - amides OCOR3 - anhydridesR = alkyl- or aryl group

R NH2

O

R OH

O

R OR'

O

R OCOR'

O

R Cl

O< < < <

R-COOH + R'-OH R-COOR' + H2OH+


7.6. Carboxylic acids and carboxylic acid derivati ves

Experiment: Mix 1 mL of ethanol, 1 mL of glacial acetic acid and 1 mL of

concentrated H2SO4 in a test tube. Warm the mixture in a 70 °C water bath

for 3-4 min. After cooling the mixture to room temperature, add 3 mL of saturated NaCl solution and allow the mixture to stand for several min.

Two layers are formed, and the smell of the ester can be detected.

Precaution! Concentrated sulfuric acid causes burns on the skin! Wear gloves while han-dling it!

7.6.2. Hydrolysis of esters

In an acid-catalysed equilibrium process, esters are transformed to carboxylic acids and alcohols. In alkaline media, the hydrolysis proceeds to completion. Detection of a clear solution and the disappearance of the two layers is an indication of complete hydrolysis.

Experiment: Take 2 mL of water and 4-5 drops (30 mg) of the given com-pound in a test tube. Add 0.5 mL of 20% NaOH solution and warm the mixture until the disappearance of the two layers. Add several drops of concentrated HCl to the cooled solution until acidic pH is attained. If the carboxylic acid is not soluble in water and it is a solid, it precipitates from

the solution.

7.6.3. Hydrolysis of acid halides and acid anhydrides

The acid halides and anhydrides react with water (a nucleophile) at different rates. In the hydrolysis of an acid halide, silver halide precipitates (not soluble in HNO3) from the reaction mixture on treatment with AgNO3.

Experiment: Carefully add 4-5 drops (30 mg) of the given compound to 2 mL distilled water in a test tube. Examine the changes and the pH of the

solution after 3 min. If different layers are still present, boil the mixture

and then allow it to cool to room temperature. Add 1 drop of 2% AgNO3 and then 0.5 mL of 1:1 HNO3:H2O to the solution and examine the solubility of the pre-

cipitate.

7.6.4. Formation of an amide (benzamide) from an acid chloride

The acid chlorides react with NH3 to form amides.

R-COOH + R'-OHR-COOR' + H2O1. NaOH

2. H+

R Y

O

R OH

OH2O+ HY Y = Cl, Br, OCOR'

O

Cl NH3

O

NH2

-HCl

66


Experiment: Mix 5 mL of concentrated NH4OH and 5 mL of water in a test

tube under cooling on an ice-water bath. Add benzoyl chloride dropwise to

this mixture. Filter off the crystals formed, wash them with water, dry them

and determine the melting point.

7.6.5. Hydroxamic acid complex formation

Hydroxamic acid reacts with Fe(III) to give reddish complexes.

Experiment: Add 0.5 mL of a 0.5 M alcoholic solution of hydroxylamine and then 4 drops of 20% NaOH solution to the given compound (2-3 drops or 20 mg) in a test tube. Boil the solution for 1 min amd then allow it to cool to room temperature. Add 5% HCl solution until pH 3-4 is attained

and finally add 2-3 drops of 5% FeCl3 solution.

7.6.6. Spectroscopic characterization of carboxylic acids

In the IR spectra of carboxylic acids, an intense absorption band of the C=O function is present at 1710-1790 cm-1. The band corresponding to the OH group is found in the region 3500-3570 cm-1. In the solid state or in concentrated solutions, because of the hydrogen-bonding interactions, a broad absorption band is detected at 2500-3000 cm-1.

In the 1H-NMR spectra of carboxylic acids, the carboxylic proton is deshielded and ap-pears at δ = 10.5-12 ppm.

The mass spectra of aliphatic carboxylic acids are characterized by the m/e = 60 [CH2=COH(OH)+] or the m/e = 60 + R [CHR=COH(OH)+] peak. For aromatic acids, the m/e = 105 (C6H5CO+) peak is typical.

7.6.7. Spectroscopic characterization of esters

In the IR spectra of esters, the most characteristic signals are the intense C=O absorption band at 1720-1780 cm-1, and two other intense bands νC-O at 1050-1300 cm-1.

In the mass spectra of esters, the R-CO+ and the R-O-CO+ peaks are typical.

7.6.8. Spectroscopic characterization of amides

There are three typical bands in the IR spectra of amides, belonging to C=O, C-N and NH vibrational bands, at 1260-1720 cm-1 (for the tertiary amides, the NH bands are miss-ing). The C=O stretching band is found at 1650-1715 cm-1. This value is somewhat lower

R Y

ONH2OH/KOH

R NHO-K+

O

R NHOH

OH+

R O

HNO

R

O NHO

Fe

R

O

NH

O



than that for carbonyl compounds due to the NH-CO conjugation effect. The νN-H shows two bands at 3520 cm-1 (νN-H asymm.) and at 3400 cm-1 (νN-H symm.).

In the 1H-NMR spectra of amides, the signal of the amide proton appears at 4.5-7.5 ppm, depending on the substituents on the nitrogen atom.

In the mass spectra of amides, m/e = 44 (O=C=NH2+) and the intense m/e = 59 [CH2=C-

(OH)+.-NH2] peaks are characteristic.


1) For the synthesis of ethyl 1-methyl-4-phenylpiperidine-4-carboxylate and 1,3-dimethyl-4-phenyl-4-piperidinepropionate (anaesthesics), compounds A and B

are transformed according to the following scheme. Give the chemical structures of these compounds:

2) Diethyl allyl acetamide (a sedative) can be prepared from compounds A and B. Identify these two compounds:

3) Give the structures of compounds A and B which are used for the preparation of ethynyl cyclohexyl urethane (a sedative):

NC

NaNH2 NCOOEt

EtOH

H2SO4A Ba)

C6H5MgBr

N

OOCCH2CH3

CH3CH2COClA Bb)

K

CH2=CH-CH2Br

H2O

H2SO4 CONH2

A B

O

OH2N

C2H2

NaNH2

ClCONH2A B

68


4) Give the structures of compounds A, B and C, which are the starting compounds for the preparation of diethyl bromoacetamide (a sedative):

5) It is known that the starting compound (lactic acid) of the following reactions is optically active. Which of the resulting compounds will also be optically active?

6) Arrange the following compounds in the sequence of increasing acidity: A: ben-zoic acid; B: o-nitrobenzoic acid; C: p-hydroxybenzoic acid; D: p-chlorobenzoic acid; E: o,p-dinitrobenzoic acid; F: p-methylbenzoic acid.

7) Arrange the following acids in the sequence of increasing acidity: A: propionic acid; B: isobutanoic acid; C: chloroacetic acid; D: hydroxyacetic acid; E: 2,2-dimethylpropionic acid.

8) Give the structures of compounds A, B, C, C’, E and E’ in the following scheme:

9) It is known that compound A in the following scheme does not react with the Tollens reagent. Give the structures of compounds A-D.

-CO2

∆

Br2 H2O CONH2

BrA B C

HCH3C COOHOH

PCl5

SN1

HCH3C COClCl

A:

HCH3C COOHOH

CH3OH

H+

HCH3C COOMeOH

B:

HCH3C COOHOH

(O)CH3C COOHO

C:

A Ba

AlCl 3

b

H2SO4

C

C'

dSR

dSR

E

E'

e

SN

e

SN

COOHNO2

COOH

NO2

A + HCN BH2O

C-CO2

D-H2O

C6H5CH=CH2



10) Give the structures of compounds a, B, b, C and D in the following scheme:

11) Give the sequence of increasing reactivity of the following carboxylic acids: A: pentanoic acid; B: α-nitropentanoic acid; C: hexanoic acid; D: β-nitropentanoic acid; E: heptanoic acid.

12) Give the structures of compounds A-D and A-E in the following schemes:

13) Which of the following compounds contain an amide bond in their structure: A: acetanilide; B: acetamide; C: carbamide; D: glycyl-glycine; E: benzoylaniline?

14) Which of the following compounds has an ionic character: A: sodium phenox-ide; B: aniline hydrochloride; C: ethyl benzoate; D: dimethylaniline; E: sodium ethoxide.

15) Which of the following compounds is acetic acid formed on hydrolysis? A: acetanilide; B: acetonitrile; C: 2,3-butanedione; D: ethyl acetate; E: 2,4-pentanedione.

16) Which of the following compounds are suitable for the acylation of phenol in order to prepare phenyl acetate? A: acetic acid; B: acetyl chloride; C: acetic an-hydride; D: ethyl acetate; E: acetamide.

17) Which of the following compounds are soluble in water at room temperature? A: acetic acid; B: benzamide; C: adipic acid; D: ethyl acetate; E: oxalic acid; F: benzoic acid.

18) Which of the following compounds react with ammonia? A: acetic acid; B: ac-etyl chloride; C: acetamide; D: acetic anhydride; E: methyl acetate; F: acetoni-trile.

19) How can the following compounds be distinguished from each other by simple test tube experiments?

a) propionic acid and methyl acetate

b) n-butyl chloride and butyryl chloride

c) p-nitrobenzamide and ethyl p-nitrobenzoate

d) acetic anhydride and butanol

C6H6a (SE)

-HClB

b-HCl

CKCN (SN)

DH2O (AN)

phenylacetic acid

COOEtEtOOC EtONaA B

isoPrBr H2OC

-CO2D

CH3CH2CH2CH2OHH2SO4

ABr2

B CKCN H2O

D-H2O

E

70


e) p-bromobenzoic acid and benzoyl bromide

20) How can cyclopropanoic acid be prepared from diethyl malonate?

21) Synthesize pentanoic acid from propanoic acid.

22) The following compounds are given: A: benzoyl chloride, B: acetic anhydride, C: propyl benzoate, D: acetamide. a) Give the structures of compounds A, B, C, D and the increasing sequence of reactivity if they react with water. b) Give the reactions between A or B and N-methylaniline. Give the names of the com-pounds formed (the reactions and types of the reaction).

23) Synthesize propanoic acid from: a) 1-bromopropane; b) 1-propanol; c) 1-butene

24) Propose synthetic methods for the following transformations:

HOCl

HOCOOH

a)

Br COOH

b)


7.7. Carbohydrates

7.7. Carbohydrates

7.7.1. The Molisch reaction of carbohydrates

Monosaccharides undergo dehydration in a multistep acid-catalyzed process to furnish furfurol derivatives, which give coloured condensation products with 1-naphthole. In general, the reaction is more sensitive for ketoses. The test is also given by oligo- and polysaccharides.

Experiment: Add 0.1 mL of 15% ethanolic 1-naphthol solution to 1 mL of 1% carbohydrate solution in a test tube. Hold the test tube in an oblique position while carefully adding 0.5 mL of concentrated H2SO4 down the glass of the test tube. Between the two layers, the formation of a violet ring

can be observed.

7.7.2. The Fehling reaction of mono- and disaccharides

Saccharides can be oxidized in the presence of Cu(II), which is reduced to Cu(I). From the blue Cu(II) complex, the red Cu2O is formed.

Experiment: Add 4 drops of 1% carbohydrate solution to 8-9 drops of the

Fehling reagent in a test tube. Boil the mixture for several seconds, and

then allow it to cool to room temperature. In a positive test, red Cu2O is

formed.

7.7.3. The Tollens reaction of mono- and disaccharides

Sugars can reduce Ag(I) to metallic silver. A silver mirror or a black precipitate of silver is proof of a positive test.

R CHO

HO OHH+

-H2OOHOH

OR CHO1-naphtol O

R

O

OH

R = H: pentoseR = CH2OH: hexose

CHO(CHOH)nCH2OH

COOH(CHOH)nCH2OH

Cu(OH)2 + Cu2O

CHO(CHOH)nCH2OH

COOH(CHOH)nCH2OH

[Ag(NH 3)2]OH+ Ag

72

7.7. Carbohydrates

Experiment: Add 3 drops of 1% carbohydrate solution to 1 mL of the Tollens reagent in

a test tube. Shake the mixture and place the tube it in an 80 °C water bath. After 3-4 min,

a silver mirror or a black silver precipitate is formed.

7.7.4. The Selivanov reaction of mono- and disaccharides

This reaction allows the identification of ketoses. The test is given by disaccharides whose hydrolysis furnishes a ketose. The formation of a dark-reddish precipitate is proof of a positive test.

Experiment: Add 4 drops of 1% carbohydrate solution to 8 drops of the Se-livanov reagent in a test tube and warm the mixture for 2 min on a water bath.

Then allow it to cool to room temperature.

Preparation of the Selivanov reagent: dissolve 0.5 g of resorcine in 100 mL

of concentrated HCl.

7.7.5. The Bial reaction of mono- and disaccharides

This reaction allows the differentiation of pentoses and hexoses. Pentoses and disaccha-rides which lead to pentoses by hydrolysis afford greenish-blue triarylmethane com-plexes. For hexoses, the colour of the complex varies from greenish-yellow to reddish-brown.

Experiment: Add 8 drops of the Bial reagent to 4-5 drops of 1% saccharide solution in a test tube, and then boil it for several seconds. Cool the mixture

and note the changes.

Preparation of the Bial reagent: dissolve 0.3 g of 1,3-dihydroxy-5-

methylbenzene in 100 mL of concentrated HCl and add 0.3 mL of 10% FeCl3 solution.

7.7.6. Formation of osazones

Monosaccharides react with phenylhydrazine in acidic media on heating to give the cor-responding osazones. In the first step, the saccharide reacts with phenylhydrazine to af-ford the corresponding phenylhydrazone. In the presence of another molecule of phenyl-hydrazine, this phenylhydrazone is oxidized to a keto compound, and reacts with a fur-ther molecule of phenylhydrazine to give the osazone.

Experiment: Take glucose, galactose and saccharose (100 mg) in three test tubes. Add to each test tube 200 mg of phenylhydrazine hydrochloride, 300 mg of NaOAc and 2 mL of water. Warm the mixtures in a 70 °C water bath,

until osazone crystals are formed.

CHOH

(CHOH)nCH2OH

CHOH2N-NHC6H5 CHOH

(CHOH)n

CH2OH

CH=N-NHC6H5

C=O(CHOH)n

CH2OH

CH=N-NHC6H5

C=N-NHC6H5

(CHOH)nCH2OH

CH=N-NHC6H5H2N-NHC6H5 H2N-NHC6H5


7.7. Carbohydrates


D-glucose

D-fructose

saccharose

galactose

D-arabinose


a mono- or a disaccharide

a reducing or a non-reducing saccharide

an aldose or a ketose (if a monosaccharide)


1) Give the conformational structures of the anomers of D-glucopyranose and D-galac-topyranose.

2) Complete the following chemical reactions:

O

OHO

HOHO

HOH2C

Ac2Opyridine

H

O

OMeO

HOHO

HOH2C

H

CH3I, Ag2O

MeOH

H

OMe

H

CH2OH

OH H

H OHO HIO4

OMe

H

H

CH2OH

OH H

H OHO HIO4

a)

b)

c)

d)

3) Give the Fischer structure of the following compound:

74

7.7. Carbohydrates

H3C H

COOHOH

4) Give the spatial structure of the following compound:

CHOH OH

CH2OH

5) Give all the possible stereoisomers (in 3 and 2 dimensions: Fischer projection) of the aldotetrose corresponding to the formula C4H8O4 (erythrose, threose).

8. Syntheses 75

8.1. Benzoic acid

8. SYNTHESES

8.1. Benzoic acid

Carboxylic acids are synthetized from alcohols in oxidation reactions:

COOH

Benzoic acid can be prepared by the oxidation of benzyl alcohol with KMnO4 under neutral conditions. During this process, the hydroxymethylene function of the alcohol is oxidized to a carboxylic function, while the KMnO4 (Mn(VII)) is reduced to manganese dioxide (Mn(IV)).

CH2OH COOH

1. KMnO4, Na2CO3/H2O

80 °C, 1 h2. cc. HCl

Experiment: Place 1 g (12.5 mmol) of Na2CO3, 10 mL of water and 1.3 mL (12.5 mmol, d = 1.05) of benzyl alcohol in a two-necked 250 mL round-bottomed flask. Instal a reflux condenser on the flask. Under gentle heat-ing, add 3 g (19.1 mmol) of KMnO4 in 60 mL of water to this mixture via a dropping funnel over a period of 1 h. During the reaction, the violet colour of the KMnO4 turns to brown as MnO2 is formed. Then filter the hot solu-

tion and addconcentrated HCl to the filtrate until pH 1 is attained. After cooling the filtrate, filter off the benzoic acid precipitate formed and recrystallize the crude product

from water (TLC: Rf = 0.5, dichloromethane:methanol 10:1; mp = 118-119 °C).

Materials: sodium carbonate

benzyl alcohol

KMnO4

concentrated HCl

Equipments: 250 mL round-bottomed two-necked flask

5 mL pipette

25 mL cylinder

pH indicator

oil bath

reflux condenser

76

8.1. Benzoic acid

100 mL dropping funnel

glass filter

250 mL filter flask

Precaution! Concentrated HCl can cause severe burns! Avoid its inhalation! Always wear gloves while handling it!

Problems and exercises

1) Indicate how benzoic acid can be prepared from compounds other than benzyl alcohol.

2) Why is HCl added to the filtrate?

3) It is known that the hydrolysis of compound C furnishes benzene. Give the chemical structures of compounds A-D in the following scheme:

4) Prepare p-iodotoluene and p-methylbenzoic acid from p-toluidine.

5) Acetic acid, formic acid, isobutanoic acid and propionic acid are esterified with methanol. Give the increasing sequence of reactivity of these compounds.

6) Prepare butanoic acid from propanoic acid.

ABr2

BMg

CCO2 D

8. Syntheses 77

8.2. Cyclohexanol

8.2. Cyclohexanol

The synthesis of alcohols from ketones involves reduction via nucleophilic addition (AN).

OH

Cyclohexanol (a hydroxy compound) can be prepared by the reduction of cyclohexanone (a carbonyl compound) with NaBH4. As a nucleophile, the hydride ion (H‾) attacks the carbonyl carbon atom of the ketone, while the carbon-oxygen double bond is hydrogen-ated to form the alcohol.

O OH1. NaBH4/H2O

20 °C, 20 min2. 10% HCl

OHδ+

OH

Experiment: Place 6 mL of water and 2 mL (19.4 mmole, d = 0.95) of cyclohexanone in a 100 mL Erlenmeyer flask. Place the flask in a cold wa-ter bath and under stirring with a magnetic stirrer add 200 mg (5.3 mmol) of NaBH4) in portions. Stir the mixture for another 20 min and then add 1

mL of 10% HCl dropwise via a Pasteur pipette to decompose the excess of the NaBH4. Extract the aqueous phase with 2 x 10 mL of ethyl acetate, and dry the combined organic layers over Na2SO4. Filter off the solid, and concentrate the dried organic phase on a rotary evaporator under reduced pressure (TLC: Rf = 0.6, n-hexane:ethyl acetate 2:1; bp = 160 °C).

Materials: cylohexanone

NaBH4

10% HCl

ethyl acetate

Na2SO4

Equipments: 100 mL Erlenmeyer flask

10 mL cylinder

water bath

78

8.2. Cyclohexanol

TLC plates

3 mL pipette

50 mL separating funnel

filter paper

glass funnel

50 mL round-bottomed flask

rotary evaporator

Precaution! During the extraction procedure, open the stopper of the separating funnel from time to time to avoid overpressure.


1) Give other methods for the preparation of cyclohexanol from cyclohexanone.

2) Why is the above reaction regarded as a nucleophilic addition process? What is the nucleophilic agent in this transformation?

3) Which alcohol in the following pairs has the stronger acidic character:a) 2-chlo-roethanol, ethanol; b) p-nitrobenzyl alcohol, benzyl alcohol; c) propan-1-ol, glycerine

4) The following alcohols react with aqueous HCl. Indicate their relative reactivity in this transformation:a) 1-phenylpropan-1-ol, 3-phenylpropan-1-ol, 1-phe-nylpropan-2-olb) benzyl alcohol, p-nitrilobenzyl alcohol, p-hydroxybenzyl al-coholc) 2-buten-1-ol, 3-buten-1-old) 1-methylcyclopentanol, trans-2-methylcy-clopentanole) benzyl alcohol, methanol

5) Indicate how the following compounds can be prepared: a) 3-chloro-2-methyl-butane and 2-chloro-2-methylbutane from 3-methylbut-1-ene? b) 1,2-dimethyl-cyclohexene and 1-isopropylcyclopentene from 2,2-dimethylcyclohexanol

6) Give the chemical structures of the compounds in the following scheme:

O

O

O

AlCl 3

Zn(Hg)

HCl

SOCl2

AlCl 3

Pd/H2H2SO4

A B C

DEF

8. Syntheses 79

8.2. Cyclohexanol

7) tert-Butyl alcohol reacts with Na. The substance formed reacts with ethyl bro-mide, and a compound with the molecular formula C6H14O is formed. Give the chemical structure of this compound. In another experiment, ethanol reacts with Na, and the substance formed is reacted with tert-butyl bromide. What is the reaction product of this transformation?

8) Compare the reactivities of the following two compounds towards HBr. Give the chemical structures of the products formed.

OH HBr

OH HBr

a)

b)

80

8.3. tert-Butyl chloride


This synthesis involves nucleophilic substitution (SN1) at an sp3 carbon:

CH3

H3C ClCH3

tert-Butyl chloride can be prepared by reacting tert-butanol with HCl. The hydroxy group of the alcohol is protonated in acidic medium to form a tertiary carbocation through the loss of one molecule of water. The chloride ion (Cl‾) then attacks this inter-mediate as a nucleophile, leading to the halogenated derivative.

CH3

H3C OHCH3

CH3

H3C ClCH3

cc. HCl

20°C, 20 min

CH3

H3C OHCH3

H+ (HCl)CH3

H3C OH2

CH3-H2O H3C CH3

CH3 ClCH3

H3C ClCH3

Experiment: Place 5 g (3.6 mL, 67.6 mmole, d = 1.39) of tert-butyl al-cohol in a separating funnel and add 20 mL of concentrated HCl in 3-4 portions. After adding each portion of acid, shake the funnel intensely for 1 min. When all the acid has been added to the funnel, shake the mixture for another 4-5 min. To avoid overpressure, open the tap of the funnel from time to time. Then wait until the two phases have separated

and separate the two layers. Wash the organic layer with 10 mL of brine, with 2 x 10 mL of saturated NaHCO3 solution (formation of CO2!!) and finally with water. Dry the or-ganic layer over CaCl2, filter off the drying agent and distil the crude product (bp = 51

°C).

Materials: tert-butanol

concentrated HCl

NaCl

NaHCO3

CaCl2

Equipments: 50 mL separating funnel

25 mL beaker


distillation apparatus

8. Syntheses 81


Precaution! During the extraction procedure, open the stopper of the separating funnel from time to time to avoid overpressure (formation of CO2). Concentrated HCl can cause severe burns! Avoid its inhalation! Always wear gloves while handling it!


1) The above reaction is a relatively fast transformation. What can be expected if butan-1-ol or butan-2-ol is used instead of tert-butyl alcohol?

2) Propose a mechanism for the above reaction.

3) a) cis-2-Phenylbut-2-ene; b) trans-2-phenylbut-2-ene; c) 1-methyl cyclohexene is submitted to the hydroboration reaction. Give the chemical structures of the products.

4) Indicate the increasing sequence of reactivity of the following alcohols towards aqueous HBr:a) benzyl alcohol, p-methylbenzyl alcohol, p-nitrobenzyl alco-holb) benzyl alcohol, α-phenylethyl alcohol, β-phenylethyl alcohol

5) When but-3-en-2-ol reacts with aqueous HBr, two products are formed: 3-bro-mobut-1-ene and the 1-bromobut-2-ene. How can this experimental observation be explained? What is the reaction product if but-2-en-1-ol reacts with HBr?

6) When 2,2-Dimethylcyclohexanol is reacted with water in the presence of a cat-alytic amount of H2SO4 a mixture of olefins is formed. One of the products is a pentacyclic alkene. Give the chemical structure of this product.

82

8.4. 2,3-Dibromo-3-phenylpropanoic acid


This is a halogenation reaction involving electrophilic addition (AE) to a carbon-carbon double bond.

PhCOOH

Br

Br

2,3-Dibromo-3-phenylpropanoic acid can be prepared by bromination of the carbon-car-bon double bond of cinnamic acid. In the first step of the reaction, the positively charged bromonium ion (Br+) as an electrophilic agent attacks the carbon-carbon double bond of cinnamic acid, forming a positively charged cyclic intermediate. The negatively charged bromide ion (Br‾) then attacks from the opposite side of the bromine atom in the inter-mediate, giving the dibrominated derivative.

COOH

HPh

H

PhCOOH

Br

BrBr2, CHCl3

20 °C, 20 min

Br Br

Ph H

COOHH

Ph H

COOHH BrBr

H COOH

Br

HPh

Experiment: Dissolve 1.85 g (12.5 mmole) of cinnamic acid in 15 mL of chloroform in a 100 mL Erlenmeyer flask. Under stirring add 1.4 mL of a 10 M solution of Br2 in chloroform from a pipette. Carry out this experiment under the hood! When all the Br2 has been added, the mix-ture is kept at room temperature for 20 min. The brownish mixture be-comes colourless. Cool the mixture on an ice-water bath and collect the

crystals formed by filtration. Wash the solid with several milliliters of chloroform (TLC:

Rf = 0.4, dichloromethane:methanol 10:1; mp = 206-208 °C).

Materials: cinnamic acid

chloroform

Br2


5 mL pipette

25 mL cylinder

8. Syntheses 83


water bath

glass filter

100 mL filter flask

Precaution! Br2 may cause severe burns on the skin! Its inhalation may cause serious respiratory irritation! Use the hood and gloves when handling Br2!

The 1H-NMR spectrum of 2,3-dibromo-3-phenylpropanoic acid

84


The 13C-NMR spectrum of 2,3-dibromo-3-phenylpropanoic acid


1) The above transformation is an electrophilic addition reaction (AE). Explain this process and indicate the electrophilic agent in this reaction.

2) During the above reaction, the attack of the Br2 occurred on the carbon-carbon double bond. Explain why aromatic electrophilic bromination is not observed under these conditions. How can cinnamic acid be submitted to on SEAr reac-tion?

3) Prepare cyclohexa-1,3-diene from cyclohexene.

4) Give the chemical structures of compounds A-C in the following scheme:

5) Give the structures of compounds A-C in the following scheme:

COOH KOH H2SO4Br LiAlH 4A B C

∆

8. Syntheses 85

8.5. Acetylsalicylic acid


This synthesis illustrates O-acylation with acid anhydrides through nucleophilic substi-tution (SN) on a carbonyl carbon (C=O) atom:

COOH

OCOCH3

Acetylsalicylic acid can be synthesized by acetic anhydride-mediated esterification (ac-ylation) of the hydroxy function of salicylic acid. The phenolic hydroxy group of sali-cylic acid as a nucleophile attacks the partially positively charged carbonyl carbon atom. The carbon-oxygen bond is broken and acetylsalicylic acid is formed.

COOH

OH

COOH

OCOCH3

Ac2O, cc. H2SO4

60 °C, 25 min

COOH

OH

OH3C

O

OH3C

COOH

O

O OCH3

OH3C

COOH

O

H3C O

CH3COOH+

Experiment: Take 1 g (7.2 mmol) of salicylic acid and 1.4 mL (14.8 mmol, d = 1.08) of acetic anhydride in a 50 mL round-bottomed flask. Add 2 drops of concentrated H2SO4 and heat the mixture with a reflux condenser, on a water bath, at 60 °C for 30 min. Then add 20 mL of water and cool the mixture to room temperature. Collect the precipitate by filtration under vacuum, and recrystallize the crude product from a

1:1 mixture of acetic acid:water (TLC: Rf = 0.4, dichloromethane:methanol 10:1; mp =

138-140 °C).

Materials: salicylic acid

acetic anhydride

concentrated H2SO4

acetic acid

Equipments: 50 mL round-bottomed flask

3 mL pipette

86


water bath

reflux condenser

25 mL cylinder

glass filter

filter flask

Precaution! Acetic anhydride is an irritating compound! Use the hood while handling it!

Note. Acetylsalicylic acid (aspirin, 2-acetoxybenzoic acid) is an analgetic and antipy-retic.


1) Compare the acidic characters of salicylic and benzoic acids. Which is the stronger acid?

2) Mention another suitable reagent for the acylation of a phenolic –OH group.

3) Give the chemical structures of compounds A-G featuring in the synthesis of p-aminosalicylic acid (an antitubercular agent):

4) Give the chemical structures of compounds A-D in the schemes:

NO2

H2SO4 NaOH H2 HCl

NaOH∆

HClCO2, K2CO3HClp-aminosalicylic acid

A B C D

EFG

OH

CH2O

ANA + B

A + CH3COOHSN

-H2OC

C6H5COCl (SN)D

A[O] salicylic acid

8. Syntheses 87

8.6. Acetanilide

8.6. Acetanilide

This is an example of N-acylation with an acid anhydride to form an amide through nu-cleophilic substitution (SN) on a carbonyl carbon atom.

NHCOCH3

Acetanilide can be synthesized by the acetylation of aniline with acetic anhydride. Through its amino group, aniline as a nucleophilic agent attacks the carbonyl carbon atom of the anhydride and the carbon-oxygen bond is broken, resulting in acetanilide.

NH2 NHCOCH3

Ac2O, NaOAc

20°C, 20 min

NH2

OH3C

O

OH3C

NH

O OCH3

OH3C

HN

H3C

O CH3COOH+

Experiment: Take 0.5 mL (5.5 mmole, d = 1.02)of aniline, 6 mL of water and 0.5 mL of concentrated HCl in a 25 mL Erlenmeyer flask and put the flask in an ice-water bath. Dissolve 450 mg (5.49 mmole) of NaOAc in 2 mL of water in another Erlenmeyer flask and add to this mixture 1 mL (10 mmol, d = 1.08) of acetic anhydride. Add this mixture to the one containing the aniline solution. After stirring the mixture for

several min, acetanilide precipitates as a white solid. Collect this solid by filtration un-

der vacuum and wash it with water. Recrystallize the crude mixture from water (TLC: Rf = 0.5, n-hexane:ethyl acetate 2:1; mp = 114-116 °C)..

Materials: aniline

concentrated HCl

sodium acetate

acetic anhydride


1 mL pipette

88

8.6. Acetanilide

10 mL cylinder

water bath

glass filter

50 mL filter flask

Precaution! Intoxication may occur from the inhalation of aniline! Concentrated HCl may cause severe burns! Avoid its inhalation! Always wear gloves while handling it!

Note! Acetanilide and its derivatives are analgetics.


1) Propose methods for the synthesis of amides.

2) Aniline is an aromatic amine with a basic character. Compare the basicity of aniline with those of aliphatic amines.

3) Indicate how the reactivity of the aromatic nucleus towards electrophilic rea-gents is influenced by the amino group.

4) The synthesis of p-acetaminophenetole (phenacetin, an analgetic and antipy-retic) is presented in the following scheme. Give the chemical structures of com-pounds A, B and C.

5) Prepare m-nitrotoluene from p-nitrotoluene.

6) Complete the following scheme:

COOH SOCl2 Me2NH 1. LiAlH 4

2. H2O, H+A B C

7) During experimental work, when amino group-containing molecules are sub-mitted to transformations, the amino group must be protected in several cases to avoid side-processes. After the chemical reaction of the protected amino group-containing compound, the protecting group is removed and the desired product is obtained. For instance, if o-aminotoluene is submitted to nitration, the free amino group is first acetylated, and the acetylated product is then nitrated. Give the chemical equations of these transformations. What transformation occurs under similar conditions if the amino group is not protected?

8) IdentifyA-C in the following scheme:

EtOK Fe, HCOOH Ac2O

OEt

NHAc

A B C

8. Syntheses 89

8.6. Acetanilide

CH3

NH2

AcCl

-HClA B

H2O

-CH3COOHC

KMnO4

90

8.7. N-Benzoylglycine (hippuric acid)


This type of synthesis, N-acylation with an acid chloride involves to form an amide, nucleophilic substitution (SN) on a carbonyl carbon atom.

COOH

OCOCH3

COOH

NH2

COOH

NHCOPh

Cl

O

1.

10% NaOH, 20 °C, 20 min

2. cc. HCl

In the first step of the reaction, the amino group of the glycine attacks the carbonyl group of benzoyl chloride in a nucleophilic addition process. The intermediate undergoes HCl elimination to give hippuric acid. The reaction can be regarded as nucleophilic substitu-tion (the amino group replaces the chlorine).

COOHH2N

Cl

OHN

OH

ClCOOH

-HCl

COOH

NHCOPh

Experiment: Dissolve 0.5 g (6.7 mmole) of glycine in 5 mL of 10% NaOH in a 25 mL Erlenmeyer flask. Add 0.9 mL (7.8 mmol, d = 1.21) of benzoyl chloride from a Pasteur pipette under stirring. Allow the mix-ture to stand at room temperature for 20 min. Then place the flask in an

ice-water bath and add concentrated HCl until pH ~ 2-3 is attained. Collect the precipitate by filtration and wash it with 3 x 3 mL of water.

Recrystallize the crude product from water (TLC: dichloromethane:methanol 10:1; mp

= 191-193 °C).

Materials: glycine

10% NaOH solution

benzoyl chloride

concentrated HCl


3 mL pipette

8. Syntheses 91


magnetic stirrer

10 mL cylinder

water bath

glass filter

50 mL filter flask

Precaution! Concentrated NaOH solution is very corrosive to the tissues! Handle it with care, using gloves! Benzoyl chloride is irritating to the skin and eyes (a lacrimator). Use the hood when handling it!


1) Why are NaOH and HCl used in the above reaction?

2) In the above transformation, the amino group is acylated with an acid chloride. The amino group of aniline is acylated with acetic anhydride. Which of these two acylating agents is more reactive?

3) Give the chemical structures of compounds A-C which feature in the preparation of leucine in the following scheme:

Br COOEt

COOEt

1. NaOEt

Br2.

1. HOH, H+

2. ∆

COOH

NH2

A B C

92

8.8. p-Toluenesulfonyl morpholide


This synthesis exemplifies N-acylation with a sulfonyl chloride to form a sulfonamide, by means of nucleophilic substitution (SN).

O N SO

OCH3

p-Toluenesulfonyl morpholide can be prepared from morpholine in a reaction with p-toluenesulfonyl chloride. During the N-tosylation process, morpholine attacks the par-tially positively charged sulfur atom of toluenesulfonyl chloride via its nitrogen atom as a nucleophilic agent.This is followed by HCl elimination to afford the sulfonamide.

ONH

SO2ClH3CO N S

O

OCH3

10% NaOH100 °C, 10 min

S CH3ClO

OONH

S CH3

OH

OO

N

Cl

O N SO

OCH3

-HCl

Experiment: Take 0.5 mL (5.8 mmole, d = 1) of morpholine and 1.8 mL of 10% NaOH in a test tube. Measure 1 g (5.3 mmole) of p-tol-uenesulfonyl chloride and add one-third of this reagent to the test tube. Mix the compounds and heat the test tube for 1 min. Then add the re-maining tosyl chloride to the mixture and stir it for several min. Place the test tube in a cold water bath, add 5 mL of water and collect the

crystals formed by filtration under vacuum. Then wash the crystals with 2 x 2 mL of

water (TLC: Rf = 0.7; dichloromethane:methanol 10:1; mp = 148-150 °C).

Materials: morpholine

10% NaOH

p-toluenesulfonyl chloride

Equipments: test tube

glass rod

3 mL pipette

glass filter

8. Syntheses 93


50 mL filter flask

Precaution! Concentrated NaOH solution is corrosive to the skin!

The 1H-NMR spectrum of p-toluenesulfonyl morpholide

94


The 13C-NMR spectrum of p-toluenesulfonyl morpholide


1) What is the role of NaOH in this reaction?

2) What reaction may be expected if no morpholine is added to the mixture?

3) Give the increasing sequence of reactivity of the following compounds:a) chlo-robenzene, m-chloronitrobenzene, p-chloronitrobenzene, 2,4-dinitrochloroben-zene, 2,4,6-trinitrochlorobenzene in reaction with NaOHb) benzene, chloroben-zene, nitrobenzene, toluene with HNO3 in the presence of H2SO4c) 1-bromobut-1-ene, 3-bromobut-1-ene, 4-bromobut-1-ene with AgNO3 in ethanold) bromo-benzene, p-bromotoluene, p-dibromobenzene, toluene with H2SO4e) benzyl chloride, chlorobenzene, ethyl chloride with KCN

4) Identify A-C in the following scheme:

5) How can S-2-butylamine be prepared stereospecifically from R-butan-2-ol?

OHOH ClCH2COCl

POCl3

CH3NH2 H2A B C

8. Syntheses 95


6) The solvolysis of 2-octyl tosylate is performed in ethanol (a) and in acetic acid (b). Propose mechanisms for these processes.

7) Give a method for the preparation of S-butan-2-ol from R-butan-2-ol?

8) trans-2-Methylcyclopentanol is reacted with tosyl chloride and the product is treated with potassium tert-butylate. Give the chemical structure of the com-pound formed and explain its formation.

96

8.9. 4-Nitroacetanilide


This synthesis is aromatic electrophilic substitution (SEAr) through nitration of an aro-matic ring:

NHCOCH3O2N

NHCOCH3

NHCOCH3

NO2

HNO3/H2SO4

AcOH, 0 °C, 1 h

The nitration of acetanilide can be effected with a mixture of concentrated HNO3 and concentrated H2SO4 (nitration mixture). Since the amino group of acetanilide increases the electron density on the aromatic nucleus, the nitration does not need harsh conditions. In the first step, the electrophilic agent (NO2

+) attacks at position 4 (para), where there is a higher electron density of the aromatic ring, forming the σ-complex intermediate. In the next step, a proton is lost and substitution occurs to furnish the 4-nitro-substituted product.

NHCOCH3

NO2+

NCHOCH3 NHCOCH3 NCHOCH3 NHCOCH3 NCHOCH3

NHCOCH3 NHCOCH3

+

NO2H

-H+

NHCOCH3

NO2H

Experiment: Take 2.5 g (18.5 mmole) of acetanilide and 2.5 mL of gla-

cial acetic acid in a 25 mL Erlenmeyer flask. Carefully add 5 mL of con-

centrated H2SO4. Place the Erlenmeyer flask in an ice bath and add the reagent (1.3 mL of concentrated HNO3 and 0.8 mL of concentrated H2SO4) dropwise. Check the temperature, which must not exceed 10 °C.

Allow the mixture to stand at room temperature, stirring from time to

time. After 1 h, pour the mixture onto 20 g of ice, and wait until the ice has melted.

Collect the precipitate by filtration under vacuum, and wash it with cold water. Recrys-tallize the crude product from methanol. Check the purity of the product by TLC (eluent

system n-hexane:ethyl acetate 2:1; Rf = 0.45; mp = 209-212 °C).

Materials: acetanilide

8. Syntheses 97


acetic acid

concentrated H2SO4

concentrated HNO3

toluene

methanol


water bath

5 mL pipette

thermometer

Pasteur pipette

5 mL cylinder

100 mL beaker

100 mL filter flask

TLC instrument

glass filter

Precaution! Concentrated HNO3 and concentrated H2SO4 are strong acids! The prepara-tion of their mixture should be done caerfully under the hood, using gloves!


1) Compare the reactivities of acetanilide, benzene, nitrobenzene and toluene in a nitration reaction.

2) In the above reaction, the nitro group attacks at position 4 (para). Why is the 3-nitro-substituted (meta) derivative not formed in this reaction?

3) Give the increasing sequence of reactivity of the following compounds in a ni-tration reaction: a) benzene, mesitylene, toluene, m-xylene, p-xyleneb) benzene, bromobenzene, nitrobenzene, toluenec) acetanilide, acetophenone, aniline, ben-zened) phthalic acid, toluene, p-xylene, p-methylbenzoic acide) chlorobenzene, p-chloronitrobenzene, 2,4-dinitrochlorobenzenef) 2,4-dinitrochlorobenzene, 2,4-dinitrophenolg) m-dinitrobenzene, 2,4-dinitrotoluene

4) What mononitro products are formed from the following compounds during a nitration reaction?a) p-methoxychlorobenzene, b) m-xylene, c) p-nitrobiphenyl, d) 1-nitronaphthaline, e) phenyl benzoate, f) 1-naphthol

98


5) 2,4-Dinitrochlorobenzene is synthesized from chlorobenzene, HNO3 and H2SO4. Which base would be suitable to neutralize the mixture during the work-up of the reaction, NaOH or NaHCO3?

6) Complete the following chemical equations:

Br

SO3/H2SO4

NO2

Br2/FeBr3

CH3

AcCl/AlCl 3

CH3O

AcCl/AlCl 3

a)

b)

c)

d)

COOEt

Cl2/FeCl3

NHCH3

HCl

e)

f)

NHCOCH3

CH2=CH2/HCl

AlCl 3

g)

8. Syntheses 99


7) Prepare o-propylphenol and salicylic acid from phenol.

8) Give a method for the preparation of the following compounds from benzene:a) m-chloroaniline; b) 1,2-diphenylethane; c) triphenylmethane; d) 2,4,6-tribromo-phenol

100

8.10. 4-Bromoacetanilide


This is an example of aromatic electrophilic substitution (SEAr) involving the bromina-tion of an aromatic nucleus.

NHCOCH3

Br

NHCOCH3NHCOCH3

Br

Br2, AcOH

25 °, 30 min

During the bromination of acetanilide, the activating effect of the amide group has the result that bromine can bind to the aromatic nucleus in the ortho and para positions. The main product of this reaction is the 4-substituted derivative. The small amount of o-bro-moacetanilide can be removed by crystallization from methanol. The reaction (SEAr) occurs in a similar way to the nitration.

Experiment: Dissolve 1 g (7.4 mmole) of acetanilide in 5 mL of glacial acetic acid in a 50 mL Erlenmeyer flask. Add 1.34 g of bromine in 6 mL of glacial acetic acid to this mixture under stirring (use the hood) and allow it to stand at room temperature. After 30 min, pour the mixture un-der stirring into 60 mL of cold water. Collect the precipitate by filtration under vacuum and recrystallize it from methanol (TLC: Rf = 0.5, n-hex-

ane:ethyl acetate 2:1; mp = 170-171 °C).

Materials: acetanilide

glacial acetic acid

Br2

methanol


10 mL cylinder

3 mL pipette

150 mL beaker

glass filter

200 mL filter flask

8. Syntheses 101


TLC instrument


reflux condenser

Precaution! Br2 may cause severe burns on the skin! Its inhalation may cause serious respiratory irritation! Use the hood and gloves when handling it!


1) Give the chemical structures of the products of the following transformations:

2) The nitroso (-N=O) group activates the ortho and para positions on the aromatic nucleus towards both electrophilic and nucleophilic agents. How can this phe-nomenon be explained?

3) Prepare the following compounds a) benzene, b) benzyl alcohol, c) 1-phenyleth-anol, d) 2-phenylpropan-2-ol, e) 2,4-dinitrophenol, f) allylbenzene, g) benzoic acid, h) aniline from bromobenzene

4) Give the chemical structures of the products of the following transformations:a) 2,3-dibromopropene + NaOH (aqueous)b) p-bromobenzyl bromide + aqueous NH3c) 3,4-dichloronitrobenzene + 1 mol sodium methylated) p-bromochloro-benzene + Mge) p-bromobenzyl alcohol + concentrated HBrf) α-(o-chloro-phenyl)ethyl bromide + KOH (alcohol)g) p-bromotoluene + 1 mole of Cl2 (hν)h) o-bromotrifluoromethylbenzene + NaNH2 (NH3)

5) Give the chemical structures of the main products formed in the following trans-formations. Compare the rates of these reactions.

102


Br

OH

CH3

AlCl 3

Cl

AlCl 3

Cl

AlCl 3

Cl

AlCl 3

Cl

a)

b)

c)

d)

6) Give the chemical structures of the possible reaction products in the following transformations:

NH2

Cl Cl2

OMe

NO2

MeCl, AlCl 3

OHN

HNO3/H2SO4

a)

b)

c)

8. Syntheses 103


7) Propose a method for the preparation of 1,3,5-tribromobenzene from aniline.

104

8.11. Phenyl benzoate


This synthesis comprises O-acylation with an acid chloride and the formation of an ester through nucleophilic substitution (SN) on a carbonylic carbon atom.

O

O

Phenyl benzoate can be prepared from phenol in a reaction with benzoyl chloride. The carbonyl carbon atom of benzoyl chloride is very reactive towards nucleophiles. Through its hydroxy function, phenol attacks this partially positively charged carbon atom in ben-zoyl chloride (C=O) in a nucleophilic addition step, followed in the next step by elimi-nation of the chloride to give the ester.

OHO

Cl

OO

NaOH/H2O, 20 °C, 20 min

OH Cl

O

O

HO

Cl O

O

Experiment: Dissolve 1 g (10.6 mmole) of phenol in 5 mL 5% of NaOH solution and 2 mL of water in a 25 mL Erlenmeyer flask. Place the flask

in an ice-water bath add under stirring and 1 mL (8.6 mmole, d = 1.21)

of benzoyl chloride. Stir the mixture for 15 min and then collect the solid by filtration and wash it with 2 x 3 mL of water. Check the purity of the product by TLC (eluent system toluene:ethyl acetate 4:2; Rf = 0.35; mp

= 69-70 °C).

Materials: phenol

NaOH

benzoyl chloride

toluene

8. Syntheses 105


ethyl acetate


water bath

10 mL cylinder

3 mL pipette

magnetic stirrer

glass filter

100 mL filter flask

TLC instrument

Precaution! Concentrated NaOH solution is very corrosive to the tissues! Handle it with care, using gloves! Benzoyl chloride is a lacrimator to the eyes and irritating to the skin. Use it under the hood!


1) Propose other methods for the synthesis of esters.

2) What is the role of NaOH in the above reaction?

3) Give the chemical structures of compounds A-F in the following scheme:

4) Give the chemical structures of compounds A-F :

5) Complete the following transformations:

Cl2 (AlCl 3)A

MgB

CO2 C HClD

PCl5E

C6H6 (AlCl 3)F

COOH

CH3

Na, ethanolH2SO4A

KOH

∆B C

HBrD

EEtOH

tert BuOK

H+F

MeMgI

HOH

CH3

OH

106


OO

MeOH

H+OO

COOEtH2O/H2SO4

∆

KOH/H2OCOOEt

MeOa)

b)

c)

d)

COOEtizoPrOH/H 2SO4

∆

COOEtLiAlH 4

COOEt C6H5CH2ONa

COOEtC6H5MgBr

e)

f)

g)

h)

8. Syntheses 107

8.12. Ethyl p-aminobenzoate (benzocaine)


This formation of an ester takes place through nucleophilic substitution (SN) on a car-bonyl carbon atom.

COOEtH2N

Ethyl 4-aminobenzoate can be synthesized by the esterification of 4-aminobenzoic acid. The carbonyl carbon atom of a carboxylic acid is less reactive than those in acid chlorides or acid anhydrides. The esterification therefore needs harshes conditions, such as higher temperature and the presence of an acid catalyst (H2SO4). In the first step of the acid-catalysed reaction, the carbonyl oxygen of the carboxylic function is protonated. This is followed by the attack of the nucleophilic hydroxy group of the alcohol. In the next step, the ester is formed through elimination of a molecule of water.

COOH

NH2

COOEt

NH2

EtOH, cc H 2SO4

70 °C, 1 h

H2NOH

O H+H2N

OH

OH

δ+EtOH

H2NOH

OHOEt

δ−

H2NOEt

O

-H2O

Experiment: Dissolve 1.2 g (8.7 mmole) of 4-aminobenzoic acid in 12 mL of anhydrous ethanol in a 100 mL round-bottomed flask. Add 1 mL of con-centrated H2SO4 from a pipette under stirring on a magnetic stirrer. Instal

a reflux condenser on the flask and heat the mixture under reflux for 1 h. Then cool the mixture and pour it into 30 mL of water. Add 15 mL of Na2CO3 solution until pH 8 is attained. Collect the crystals, which are

formed under stirring, by filtration under vacuum. Recrystallize the crude product from

hot water.

Materials: 4-aminobenzoic acid

ethanol

108


concentrated H2SO4

10% Na2CO3 solution


magnetic stirrer

1 mL pipette

oil bath

25 mL cylinder

reflux condenser

100 mL beaker

glass filter

150-mL filter flask

Precaution! Concentrated H2SO4 may cause severe burns on the skin! Protect your hands by wearing gloves! When Na2CO3 is added to the reaction mixture, CO2 is formed!

Note. Benzocaine is an analgetic and anaesthesic.

The 1H-NMR spectrum of benzocaine

8. Syntheses 109


The 13C-NMR spectrum of benzocaine


1) Give other methods for the preparation of esters.

2) How can it be explained that the product crystallizes only from a basic mixture?

3) Prepare the following compounds from benzene or toluene:a) m-chloronitroben-zene; b) p-chloronitrobenzene; c) 3,4-dibromonitrobenzene; d) m-iodotoluene; e) 2-(p-tolyl)propane

4) What is the explanation of the experimental result that benzenediazonium chlo-ride reacts with phenol, but not with anisole, while 2,4-dinitrobenzenediazo-nium chloride reacts with anisole?

5) Different para-substituted ethyl benzoates are reacted with aqueous NaOH. The rates of the reactions vary in the following sequence:

How can these results be explained?

p-NO2 > -Cl > -H > -CH3 > OCH3

110 4 1 0.5 0.2

110


6) During the alkaline hydrolysis of the following esters, the indicated rates were obtained:

CH3COORHOH/NaOH

CH3COOH

R: Me > Et > iPr > tBu 1 0.6 0.15 0.009

How can these results be explained?

7) Benzoic acid, 2,3-dimethylbenzoic acid and 2-methylbenzoic acid are subjected to esterification with ethanol. Give the sequence of the rates.

8) Identify compounds A-C in the following scheme:

9) Identify compounds A-I in the following reactions:

CH3COOHMeCOMe

EtONaAB

CCH3COOH E

F

CH3CH2Br

CH3COOEtNaOEt

GNaNH2

CH3CH2BrH

HOH/H+

I∆

D

O O

H

H

1. MeMgBr

2. CO2

HOH/H+ KMnO4A B C

8. Syntheses 111

8.13. Methyl salicylate


This ester formation involves nucleophilic substitution on a carbonyl carbon atom

COOMe

OH

COOH

OH

COOMe

OH

MeOH, cc. H2SO4

65 °C, 1.5 h

OH

OH

O

H+ OH

OH

MeOH

OH OH2OHOH

OMe-H2O

-H+

COOMe

OH

Experiment: Take 2.8 g (20.3 mmole) of salicylic acid and 6 mL of meth-anol in a 100 mL round-bottomed flask. Under stirring on a magnetic stirrer, add 2 mL of concentrated H2SO4. Instal a reflux condenser on the flask and heat the mixture for 1.5 h. Then allow the mixture to cool to room temperature and pour it into 20 mL of ice-water. Extract this solu-tion with 2 x 10 mL of diethyl ether. Wash the organic layer with water

(30 mL), then with 5% Na2CO3 (25 mL) and then again with water (30 mL). Dry the organic layer on Na2SO4. After filtering off the drying agent, concentrate the filtrate

under reduced pressure in a round-bottomed flask. The residual oil is methyl salicylate.

Materials: salicylic acid

methanol

H2SO4

diethyl ether

Na2CO3

Na2SO4


reflux condenser

25 mL cyclinder

3 mL pipette

water bath

112


100 mL beaker

100 mL separating funnel

50 mL Erlenmeyer flask

glass filter

filter paper


rotary evaporator

Precaution! Concentrated H2SO4 can cause severe burns. Handle it with care, using gloves!

Note. Methyl salicylate is an antipyretic and analgetic.

The 1H-NMR spectrum of methyl salicylate

8. Syntheses 113


The 13C-NMR spectrum of methyl salicylate


1) Propose methods for the synthesis of salicylic acid from methyl salicylate.

2) Which product results when methyl salicylate is treated with aqueous NaOH?

3) Give the chemical structures of A-D in the following scheme:

CH3CH=CH2 + Cl2 AH2O/OH

BCl2/H2O

CH2O/OH

D

4) When p-iodotoluene is treated with aqueous NaOH at 340 °C, a mixture of p-cresol (51%) and m-cresol (49%) is obtained. At 250 °C the reaction is slower and only p-cresol is formed. Explain this experimental result.

5) Complete the following transformations:

114


OO

NH3

LiAlH 4

OO

OO

EtOHH+

a)

b)

c)

6) Identify compounds A-D in the following scheme:

OH

HBr Mg CO2 EtOH/H+A B C D

7) Benzoic acid is esterified with propan-1-ol, sec-butyl alcohol, methanol and tert-butyl alcohol. Give the sequence of the rates of these reactions.

8) Propose two methods for the synthesis of methyl butanoate from butanoic acid.

8. Syntheses 115

8.14. 3-Nitrobenzoic acid


This synthesis is an example of the hydrolysis of an ester through nucleophilic substitu-tion (SN) on a carbonyl carbon atom.

COOH

NO2

COOCH3

NO2

COOH

NO2

1. NaOH, H2O

100 °C, 1 h2. cc. HCl

NO2

O OMe

OH

NO2

O OMeOH

-MeO

COOH

NO2(NaOH)

Experiment: Take 4.5 g (24.8 mmole) of ethyl 3-nitrobenzoate and 2 g (50 mmole) of NaOH in 40 mL of water in a 250 mL round-bottomed flask. Instal a reflux condenser on the flask and heat the mixture until a homogeneous solution is obtained. Add 40 mL of water to this warm solution and then cool the mixture on an ice-water bath. To the cooled solution, add concentrated HCl dropwise until pH 2 is attained. Collect

the precipitate by filtration under reduced pressure and recrystallize the crude product

from 1% HCl.

Materials: ethyl 3-nitrobenzoate

NaOH

concentrated HCl



magnetic stirrer

50 mL cylinder

water bath

Pasteur pipette

reflux condenser

116


pH indicator

oil bath

glass filter

200 mL filter flask

Precaution! NaOH solution is corrosive to the skin! Wear protective gloves while han-dling it!


1) Propose other methods for the transformation of esters to carboxylic acids.

2) Why is the mixture made acidic at the end of the reaction?

3) What reaction can be expected when a methyl carboxylate is heated in ethanol in the presence of NaOH?

4) How can p-cresol, p-toluidine and p-nitrotoluene be separated from a mixture of them?

5) Prepare 3-bromotoluene from toluene.

8. Syntheses 117

8.15. Phenylacetic acid


COOH

Phenylacetic acid can be prepared by the acidic hydrolysis of benzyl cyanide (benzyl nitrile). In the first step of the transformation, the nitrogen of the cyano functionality is protonated under acidic conditions. Water, as a nucleophilic agent, attacks the carbon atom in the cyano group, forming an amide. In the next step, through the attack of another water molecule, the amide group is hydrolysed, giving phenylacetic acid.

C6H5-CH2-CNH2O/ H2SO4

100 °C, 45 minC6H5-CH2-COOH

NH+

HOH

NH

OH

O

NH2

H+

HOH OH2

NH2

OH

OHNH3

OHO

OH -NH3

-H+

Experiment: Take 2 g (17.1 mmole) of benzyl cyanide, 6 mL of water and 6 mL of glacial acetic acid in a 50 mL round-bottomed flask. Care-fully add 6 mL of concentrated H2SO4, and heat the mixture under re-flux condenser for 45 min. After cooling, pour the mixture under stir-

ring into 50 mL of cold water. Collect the solid by filtration in vacuo

and recrystallize it from methanol-water (mp = 76-78 °C).

Materials: benzyl cyanide

acetic acid

concentrated H2SO4

methanol


100 mL cylinder

150 mL beaker

glass filter

118


200 mL filter flask


1) Propose a method for the preparation of 1-naphtylmethanol and 2-(1-naph-tyl)ethanol from 1-bromonaphtalene.

2) Indicate the increasing sequence of acidity of the following compounds: a) ben-zenesulfonic acid, benzoic acid, benzyl alcohol, phenolb) carbon dioxide, phe-nol, sulfuric acid, waterc) m-bromophenol, m-cresol, m-nitrophenol, phenold) p-chlorophenol, 2,4-dichlorophenol, 2,4,6-trichlorophenol

3) Identify compounds A-D in the following scheme:

4) Identify compounds A-I in the following scheme:

Br

Mg

éter

OPBr3 NaCN H2O/H2SO4

SOCl2

AlCl 3H2/NiH2SO4

A B C D E

FGHI

5) Give the structures of the products of the following transformations:

H3CCOOH

H

H

Br2/CCl4

PhCOOH

OHH

∆

COOHCH2OH

H

∆

a)

b)

c)

6) Give the structures of compounds A-E:

NBS KCN HOH/H+ H2/Ni CrO3A B C D E

PrOHKMnO4 MeOH

H+ H+

Br2/P PPh3

DBUA B C D

8. Syntheses 119


7) Prepare 1,5-pentanedicarboxylic acid from 4-chlorobutanoic acid.

120

8.16. Benzimidazole

8.16. Benzimidazole

NH

N

Benzimidazole can be prepared by the reaction of o-phenylenediamine with formic acid.

In the first step of the transformation, one amino group in o-phenylenediamine attacks the carbonyl carbon atom in formic acid in a nucleophilic addition process (AN). In the following displacement of the hydroxy group, an amide is formed. The next step involves intramolecular attack of the other amino group on the carbonyl carbon atom and water elimination to give benzimidazole.

NH2*HCl

NH2*HCl NH

N1. HCOOH

100 °C, 1.5 h2. NH4OH

Experiment: Take 1.55 g (8.6 mmole) of o-phenylenediamine dihydro-chloride, 6 mL of water and 1.3 mL of concentrated formic acid in a 50

mL round-bottomed flask. Heat the mixture for 1.5 h and then cool it by using an ice-water bath. Slowly add 2 mL of concentrated NH4OH and then further 1 mL portions until basic pH is attained. Allow the mixture to stand at room temperature until white crystals are formed. Collect

the crystals by filtration under reduced pressure (mp = 169-171 °C).

Materials: phenylenediamine dihydrochloride

concentrated formic acid

NH4OH


NH2

NH2

H O

OHH2N

NH2

O-

OH

HN

NH2

O

H

N+H2

HN

O-

NH

HN

OHNH

N

-H2O

-H2O

8. Syntheses 121

8.16. Benzimidazole

10 mL cylinder

water bath

5 mL pipette

oil bath

pH paper

glass filter

100 mL filter flask

Precaution! When handling formic acid and NH4OH, use gloves!


1) Give several reactions that are specific for benzimidazole.

2) Compare the reactivities of benzimidazole, imidazole, pyrrole and pyridine in aromatic electrophilic (SEAr) and nucleophilic substitution (SNAr) reactions.

3) 3-Phenyl-3,4-dihydroquinazoline (active against bilious and gastric diseases) can be prepared according to the following scheme. Give the structures of A, B

and C.

NO2

Cl H2N

HCOOH H2

N

NA B C

122

8.17. 3,5-Dimethylpyrazole


This is an example of condensation and ring closure (cyclocondensation) through nucle-ophilic addition-elimination (AN-E) at a carbonyl carbon atom.

NH

N

H3C

CH3

In an addition process, the amino groups of N2H4 attack the carbonyl groups of 1,3-diketone. This is followed by elimination of 2 molecules of water, and the pyrazole skel-eton is formed.

H3C CH3

O O

NH

N

H3C

CH3NH2-NH2/H2O

0 °C, 15 min

Experiment: Take 5 g (50 mmole) of acetyl acetone and 50 mL of water in a 100 mL Erlenmeyer flask. Place the flask in an ice-water bath and add slowly 2.5 mL of 64% N2H4 solution in 0.5 mL portions. Check the temperature of the mixture with a thermometer. It must not exceed 40 °C. After several min, the product crystallizes as white needles. Collect

the crystals by filtration in vacuo (mp = 105-108 °C).

Materials: acetyl acetone

N2H4


water bath

50 mL cylinder

1 mL pipette

CH3H3C

OO

NH2-NH2H3C NH

O OHCH3

NH2NH

NH

H3C

HO CH3

HO

NH

N

H3C

CH3 -2H2O

8. Syntheses 123


thermometer

glass filter

100 mL filter flask

Precaution! N2H4 is irritating to the skin! Avoid its inhalation! Use the hood and wear gloves while handling it!


1) Give the structure of the compound formed in the reaction of phenylhydrazine with ethyl acetoacetate.

2) Give the possible products of the reaction of pyrazole with an electrophilic agent. Indicate the position where the electrophile attacks the pyrazole.

3) 5,5-Diethylbarbituric acid (5,5-diethylbarbital, a sedative) can be prepared ac-cording to the following scheme. Identify compounds A, B, C and D.

4) Give the structures of compounds A, B and C which are used for the synthesis of 1-phenyl-2,3-dimethyl-5-pyrazolone (antipyrine, an analgetic and antipy-retic) according to the following scheme:

5) For the synthesis of 2-phenylquinoline-4-carboxylic acid (an antipyretic and an-algetic), an aldehyde (A), an oxocarboxylic acid (B) and aniline are used. Iden-tify the compounds A and B.

6) Identify compounds A and B which can be used for the synthesis of 2,4-diamino-5-(p-chlorophenyl)-6-ethylpyrimidine (active against malaria) in the follwing scheme:

NaCN EtOH

H2SO4

Et-Br

NaOEt

H2N NH2

O

HN

NH

O

O

EtEt

ONaOEtA B C D

CH3COOEt

NaOEt

HN

NH2N

NO

CH3

Me2SO4CH3

A B C

124


Cl

CN

CH3CH2COOEt CH2N2 N

NH2N

Et

NH2

Cl

NH

NH2

H2N

A B

8. Syntheses 125

8.18. 4-Benzylidene-2-methyloxazol-5-one


This synthesis is condensation through nucleophilic addition-elimination (AN-E) at a car-bonyl carbon atom.

NO

CH3

O

Ph

In basic medium, acetylglycine attacks the carbonyl carbon of benzaldehyde via its ac-tive methylene group. Through the elimination of 2 molecules of water, benzylidene ox-azolone is formed.

COOH

NHCOCH3N

O

CH3

O

PhPhCHO, NaOAc, Ac 2O

70 °C, 1 h

COOH

NHCOCH3

O

H

OH

HN

COOH

CH3

O

OH

N

CH3

OH

O

OH

NO

CH3

O

Ph

-2H2O

Experiment: Take 2.9 g (24.8 mmole) of N-acetylglycine, 3.9 g (3.75 mL, 18.3 mmole) of benzaldehyde, 1.5 g of sodium acetate and 6.7 g (6.2 mL, 65.7 mmole) of acetic anhydride in a 100 mL round-bottomed flask.

Instal a reflux condenser on the flask and heat the mixture for 1 h at 70

°C. Then allow the reaction mixture to cool to room temperature and add 60 mL of water to it. Collect the precipitate by filtration under re-

duced pressure and recrystallize it from ethyl acetate-n-hexane (mp = 157-160 °C).

Materials: N-acetylglycine

benzaldehyde

sodium acetate

126


acetic anhydride

ethyl acetate

n-hexane


reflux condenser

100 mL cylinder

5 mL pipette

oil bath

glass filter

200 mL filter flask

Precaution! Acetic anhydride is irritating to the skin!


1) The title compound is an azalactone. What is its synthetic utility in organic chemistry?

2) What is the role of NaOAc in the reaction?

3) Propose methods for the synthesis of N-acetylglycine.

4) The acylation of amines can be accomplished with acyl halides or anhydrides. Compare the reactivities of the two acylating agents. Explain the difference.

5) If p-methoxybenzaldehyde or p-bromobenzaldehyde is used instead of benzal-dehyde in the above reaction, what will the effect be on the relative rates of these transformations?

6) Identify compounds A-C in the following schemes:

PhCH2CHONH3 HCN H2O/H+/∆

A B C

COOEt

COOEt

Br

NK

O

O 1. NaOEt

2. PhCH2Br

H2O/H+/∆A B C

a)

b)-CO2

8. Syntheses 127

8.19. N-Benzylidene-3-nitroaniline


This synthesis is an example of Schiff-base formation (condensation of an amine with an aldehyde) through a nucleophilic addition-elimination (AN-E) reaction.

HC

N NO2

During the condensation between an aldehyde and a primary amine, an azomethine (Schiff-base) is formed. Through its amino group, 3-nitroaniline attacks the carbonyl group of the aldehyde in an addition step. From the intermediate formed after water elimination, the Schiff-base results.

H

O NO2HC

N NO2

H2N

EtOH, 0 °C, 20 min

H

ONO2H2N

NH2

O

NO2 NH

OH

NO2

N NO2

-H2O

Experiment: Dissolve 0.4 g (2.9 mmole) of 3-nitroaniline in 4 mL of eth-anol in a test tube. Add 0.8 mL (7.9 mmole, d = 1. 4) of benzaldehyde and

allow the mixture to stand under cooling in an ice-water bath. Collect the

crystals by filtration in vacuo (mp = 71-72 °C).

Materials: 3-nitroaniline

benzaldehyde

ethanol

Equipments: test tube

glass filter

128


100 mL filter flask

2 mL pipette

100 mL beaker

Precaution! 3-Nitroaniline is a toxic compound! Avoid its inhalation and wear protective gloves while handling it!


1) Compare the reactivities of benzaldehyde, benzophenone and acetophenone to-wards nucleophilic agents.

2) In the above reaction, an aldehyde reacted with an amine. What is the synthetic importance of this type of reaction in organic chemistry?

3) Indicate how the following transformations can be effected:

O?

CHOOHC

CHO ?

O

a)

b)

OH?

c)

O

?O

d)

8. Syntheses 129

8.20. 5,5-Diethylbarbital


This nucleophilic substitution (SN) on a carbonyl carbon atom results in amide formation.

HN

NH

O

O

EtEt

O

COOEtEtOOC

EtEt

H2N NH2

O

HN

NH

O

O

EtEt

ONaOEt∆, 3 h

Experiment: Take 2 g (9.3 mmole) of diethyl malonate, 30 mL of abso-lute ethanol, 0.56 g (9.3 mmole) of urea and 1.26 g (18.5 mmole) of sodium ethylate in a 100 mL round-bottomed flask. Heat the mixture under reflux and stirring for 3 h, and then evaporate off the ethanol on a rotary evaporator. Dilute the residue with 50 mL of water and add 10% HCl until pH 4 is attained. Collect the crystals by filtration under re-

duced pressure (mp = 189-191 °C).

Materials: diethyl malonate

absolute ethanol

urea

sodium ethylate

10% HCl


50 mL cylinder

reflux condenser

magnetic stirrer

rotary evaporator

Pasteur pipette

pH indicator

glass filter

200 mL filter flask

Note: the diethylbarbital is a sedative compound.

130



1) Identify compounds A-B and A-D in the following schemes:

OEt

O ONaOEt

-EtOH

Bra)

b) Ph OEt

O ONaOEt

-EtOHMeI HOH, H+

∆∆

-CO2

A B

A B C D

2) Identify compounds A-C and A, B in the following schemes:

COOEtO 1. NaOEt

2. Br

1. NaOEt

2. MeI

HOH, H+

∆A B Ca)

1. NaOEt

BrBr

NaOEt CN

CNA Bb)

COOEt

t-Bu

EtOOC COOEt1.

2. NaOEt3. HOH, H+

HOH, H+

∆c)

-CO2

A B

8. Syntheses 131

8.21. 1-Phenyl-3-methyl-pyrazol-5-one


In this type of synthesis, nucleophilic addition –elimination (condensation) occurs on a carbonyl carbon atom.

NN

O

CH3

CH3COCH2COOEt

HN

NH2N

NO

CH3

Experiment: Take 2.3 g (17.7 mmole) of ethyl acetoacetate, 10 mL of ethanol, 10 mL of water and 6 g (55.5 mmole) of phenylhydrazine in a 100 mL round-bottomed flask. Stir the mixture under reflux for 4 h and then cool it at 0 °C. Collect the crystals by filtration under reduced pres-

sure.

Materials: ethyl acetoacetate

ethanol

phenylhydrazine


25 mL cylinder

oil bath

reflux condenser

water bath

thermometer

magnetic stirrer

glass filter

200 mL filter flask

Note: 1-Phenyl-3-methyl-5-pyrazolone is a starting material for the synthesis of analget-ics and antipyretics.

132



1) Complete the following reactions:

N

Cl

NaOEt/EtOH

SH3C

HNO3/Ac2O

N

CH3

HCl

a)

b)

c)

N Br

NH3

∆d)

NH

EtMgBr

N

Br2

∆

N

PhLi

NH

HNO3/Ac2O

e)

f)

g)

h)

8. Syntheses 133

8.22. Isolation of caffeine


Caffeine, a compound with a purine skeleton, is the main alkaloid in tea and coffee. It is slightly basic and soluble in water. Apart from caffeine, tea leaves contain tannin and cellulose. Cellulose is not soluble in water. Tannin (phenolic compounds with high mo-lecular weights) is soluble in water, but in alkaline solutions it forms the corresponding salt. From the above mixture, caffeine can be extracted with organic solvents.

N

N N

N

O

O

H3C

CH3

CH3

Caffeine (1,3,7-trimethylxanthine)

Experiment: Boil 100 mL of water in a 300 mL beaker and add 2 tea bags. Allow the mixture to stand for 15 min stirring it from time to time. Remove the tea bags and add 2 g of Na2CO3 to the solution. Extract the solution with 2 x 20 mL of dichloromethane, then dry the organic layer on MgSO4, filter off the solid and concentrate the filtrate under reduced pressure on a rotary evaporator. Check the purity of the product by

TLC (eluent system toluene:methanol 4:1).

Materials: tea bags

Na2CO3

MgSO4

dichloromethane

toluene

methanol

Equipments: 300 mL beaker

separating funnel


glass funnel

filter paper


rotary evaporator

134



1) List other compounds of biological importance that have a purine skleton.

2) Caffeine can be prepared according to the following scheme. Identify com-pounds A-G.

NH2O

NH2

MeNH2

∆

COOHNC

Ac2O

NaOH HNO2

Zn, H2SO4

HCOOHNaOHMe2SO4N

O N

O

N

N

A B C D

EFG

8. Syntheses 135

8.23. Isolation of piperine


Piperine is the amide of piperic acid with piperidine. Piperine can be isolated from black pepper. The hot taste of the pepper is caused by the Z-Z isomer, chavicine.

O

O

N

O

Experiment: Take 10 g of powdered black pepper and 30 mL of di-

chloromethane in a 100 mL round-bottomed flask and heat the mixture

under reflux for 30 min. Filter off the solid from the cooled mixture and wash it with 5 mL of dichloromethane. Concentrate the filtrate on a

rotary evaporator and triturate the residue with 5 mL of diethyl ether.

Filter off the yellowish solid and check its purity by TLC (eluent system

toluene:methanol 4:1).

Materials: black pepper

dichloromethane

diethyl ether

toluene

methanol


reflux condenser

rotary evaporator


oil bath

glass filter

filter flask


1) Why is the spicy taste of black pepper lost on standing?

2) Identify compounds A-F in the following scheme:

136


OHH2CrO4 SOCl2

HBr

KCN 1. LiAlH 4

2. H2O, H+

A B

C D E FB

3) Which of the following compounds are E isomers?

Cl

F COOH

H H3C

O2N CH3

H F

H3CO CH2OH

HA: B: C:

4) Which of the following compounds are Z isomers?

5) Identify the following compounds as E or Z isomers:

H

H3C CH2CH3

COOH H

Cl COOH

ClA: B:

H

O2N F

ClC:

H

H3C CH3

izoPr H

H3C CH2OH

COOH Cl

F H

CH3

A: B: C:

References 137

REFERENCES

1. L.P. Donald, G.M. Lampman, G.S. Kriz, R.G. Engel, Introduction to organic labora-tory techniques: A small scale approach. Brooks Cole Publishing Company, Pacific Grove, California, 1988.

2. Zsigmond Á., Mastalir Á., Notheisz F. Szerves Kémiai Gyakorlatok, JATEPress, Sze-ged, 2003.

3. Felföldi K. Szerves Kémiai Praktikum, JATEPress, Szeged, 2000

4. Berényi S., Patonay T. Szerves Kémiai Praktikum, Kossuth Egyetemi Kiadó, Debre-cen, 2000.

5. D.W. Mayo, R.M. Pike, S.S.Butcher, Microscale organic laboratory, John Wiley, USA, 1989.

6. R. J. Fessenden, J. S. Fessenden, Organic Chemsitry, Brooks Cole Publishing Com-pany, California, 1994.

7. R.T. Morrison, R.N. Boyd, Organic Chemistry, Allyn and Bacon Inc., USA, 1974.

8. F.A. Carey, Organic Chemistry, McGraw-Hill Book Company, USA, 1987.

138

ANSWERS TO THE PROBLEMS

7.1.4.1.

a) A: erythro-2,3-dibromobutane; B: threo-2,3-dibromobutane

7.1.4.2.

1-bromo-1-methylcyclohexane

7.1.4.3.

A: cis-dimethylcyclopropane; B: trans-dimethylcyclopropane

7.1.4.4.

A: 1-bromo-2-methyl-2-propanol

B: 2-bromo-2-methylbutane

C: 2-bromopropane

7.1.4.5.

7.1.4.6.

7.1.4.7.

Answers to the problems 139

7.1.4.8.

7.1.4.9.

7.1.4.10.

A < B < C < D

7.1.4.11.

A: 1-bromopropane

B: 3-methylpenten-3-ol

C: 2-methyl-1-butanol

7.1.4.12.

C, D

7.1.4.13.

A: cyclopentene; B: cis-1,2-cyclopentanediol; C: epoxycyclopentane

7.1.4.14.

A, C, D, B

7.1.4.15.

B, C, A

7.1.4.16.

140

B < A < D < C < E

7.1.4.17.

SR, AE, AR

7.1.4.18.

B < C < A < D

B < D < C < A

7.1.4.19.

A: electrophilic addition (AE); B: electrophilic addition (AE)

7.1.4.20.

B, E

7.1.4.21.

A: 1-butene, B: 2-butene

7.2.4.1.

A: substitution, B: elimination

7.2.4.2.

A < C < E < B < D

7.2.4.3.

A < E < B < C < D

7.2.4.4.

7.2.4.5.

1,3-dichloropropane

7.2.4.6.

3-chloropentane

7.2.5.7.

SN1: carbocation intermediate, intramolecular methyl shift (formation of a more stabi-lized carbocation)


7.2.4.8.

BrKOH

OH

NaOEtBr OEt

a)

b)

7.2.4.9.

Br BrNaCN

NC CNEtOH/H2O

COOEt

BrC6H5SNa

THF, 25 °C COOEt

SC6H5

O2N

Cl CH3COONa

AcOH∆ O2N

O CH3

O

ClNaOMe

OMeMeOH, 50 °C

ClNaCN

MeOH, 50 °C

∆

NC

a)

b)

c)

d)

e)

HO ClOH

C6H5ONa

EtOH∆

HO OOH

f)

Cl NaOH

∆g)

ClHOH

OH

OH

SN1c)

142

Cl

KOtBu

DMSOh)

7.2.4.10.

7.2.4.11.

OH IO

SC6H5CH2Br

CH3SNa

C6H5CH2SNaCH3I S

O

O

C6H5COONa

Br

a)

b)

c)

d)

OOHEtBr

Br NaOMe

MeOH

Br

KOtButBuOH

e)

f)

g)

7.2.4.12.

H

Ph CH3

Br

HPh

1R,2R-1-bromo-1,2-diphenylpropane

H

PhPh

CH3

KOEt

∆

Z-1,2-diphenyl-prop-1-ene


EtMgBrHOH Et-H

EtMgBrD2O Et-D

EtMgBrPhCHO

Ph

OH

EtMgBrPhCOOMe

Ph Et

OHEt

EtMgBrPhCOMe

Ph Me

OHEt

a)

b)

c)

d)

e)

7.3.13.1.

OOH

H2O, H+ 1. NaBH4

2. H2O, H+

(CH3)2CC6H5

OH

I Mg, Et2O MgIO

1.

2. H+

Br Mg, Et2O MgBr 1. HCHO

2. H2O, H+

CH2OH

H2O, H+

OH

H+

OH

TsCl

OTs

LiBr

DMF, 50 °CpyridineBr

OH H2CrO4O MgBr

3-methyl-hexan-3-o l

HO

a)

b)

c)

d)

e)

f)

144

7.3.13.2.

C és D

7.3.13.3.

B, C, E

7.3.13.4.

7.3.13.5.

7.3.13.6.

2-bromophenol, 4-bromophenol, 2,4,6-tribromophenol

7.3.13.7.

hydroboration reaction of 1-butene; self-condensation of acetaldehyde, catalytic hydro-genation

7.3.13.8.

CH3CH2OHH2CrO4

CH3COOHCH3CH2OH, H+

∆CH3COOEt

7.3.13.9.

D < A < E < B < F < C

7.3.13.10.

A < B < C < D < E

7.3.13.11.

E < D < B < A < C

7.3.13.12.

C < D < A < B < E

7.3.13.13.

B, D, F

7.3.13.14.


tBuOHH+

tBu+

7.3.13.15.

n-PrOHPBr3 n-PrBr

PhOHNaOH

PhONa

n-Pr-OPha)

OH Na ONa

MeOHPBr3 MeBr

O

b)

Na

MeOHPBr3 MeBr

c)

t-BuOH t-BuONa

t-BuOMe

7.3.13.16.

7.3.13.17.

7.3.13.18.

7.3.13.19.

HH

CH3

CH3

C6H5COOOH H

Cl

CH3

CH3

OH

H

KOH/HOHO H

CH3

H

CH3

7.3.13.20.

CH3OCH2ClSN1

CH3OCH2+

increasing electrondonating effect: I, Br, Cl, F, S, O, N

CH3O=CH2

ClOH PBr3 Br

Mg

diethyletherMgBr

1) CH3CH2CHO

2) HOH, H+OH

SOCl2

OHPBr3

BrMg

diethyletherMgBr

1) CH3CH2CHO

2) HOH, H+

OH HBr Br

KCN

CN

O1)

2) HOH, H+

OH

146

COOOHCl

(MCPBA)

O 1. EtMgBr

2. HOH, H+

OH

COOOHCl

(MCPBA)

O NaOEt/EtOH OOH

a)

b)

7.3.13.21.

all of them

7.3.13.22.

A: ethylene; B: diethyl ether

7.3.13.23.

7.3.13.24.

a,a; intramolecular hydrogen-bond

7.4.6.1.


CHO

OMe

NO2

OMe

NO2

H2

OMe

NH2

HCl

OH

NH2

1. CH2O

2. H2

OMe

HNO2

OMe

O2N

1. H2

2. HONH2*HCl

OMe

HON

NaHg

OMe

NH2

C6H5CHO

OMe

N

MeI

OMe

N

I

HBr

OH

NH

7.4.6.2.

Cl

MeNH2

NH

OHOH

O O

1. HCl

NH*HCl

OH

HO

2. H2

CHO

OMe

KCN

OMe

HO CN

CrO3

OMe

O CN

H2

OMe

ONH2

TsCl

OMe

ONHTs

Me2SO4

OMe

ONTs

1. HCl

2. H2

7.4.6.3.

148

CHO

OO

MeMgI

OO

HO

-H2O

OO

Br2

OO

BrBr

H2O

OO

HOBr

HCl

HOBr

HOOH

MeNH2

HOHN

HOOH

7.4.6.4.

CHO

OO

MeNO2

OO

NO2

Br2, KOH, MeOH

OO

NO2

MeO

MeO

AlCl 3

NO2

O

H2

NH2

HO

HOOH

HOOH

OHHO

CHO

OHHO

HCN

HO CN H2

7.4.6.5.

O

Br2

OBr

MeNH2

ONH

H2

HONH

7.4.6.6.

C < F < D < E < B < A

7.4.6.7.

E < C < D < A < B < F

7.4.6.8.


C < E < F < A < B < D

7.4.6.9.

7.4.6.10.

CH3

CH3COCl

AlCl 3

CH3

H3C O

NH3

H2, Ni

CH3

H3C NH2

a)

CH3

Cl2

CH2Cl

CN

CH2CN

H2/Ni

CH2CH2NH2

b)

7.4.6.11.

a) 1. K2Cr2O7, 2. NH3, 3. H2; b) 1. K 2Cr2O7, 2. SOCl2, 3. NH3, 4. NaOBr

7.4.6.12.

CH3CH3

HNO3

H2SO4

NO2

H2

CH3

NH2

Br2

CH3

NH2

Br Br

1. HONO

2. H3PO2

CH3

Br Br

7.4.6.13.

7.4.6.14.

BrKCN NC

1. LiAlH 4

2. HOH, H+H2N

150

7.4.6.15.

H2NNH2

Br2 KCN

-KCl

H2

H2O

-NH3

HOOC-CH2-CH2-COOH

NCCN

BrBrCH2=CH2

7.5.6.1.

OHOH ClCOCH2Cl

OHOH

OCl

OHOH

ONH

NH2CH3

7.5.6.2.

B

7.5.6.3.

CH3 COOH COCl

CH3Cl [O] PCl5 (SN) C10H8 (SE)

C6H5 O

7.5.6.4.

C < B < A < D

7.5.6.5.

A, B

7.5.6.6.

O

H

KCN, H+ OH

NC

H2/Ni OH

H2N

7.5.6.7.

C6H5H

O

O

HO

C6H5O

O

OHHC6H5

OHO

O

C6H5CH(OH)COONa

7.5.6.8.


CH3

HNO3

H2SO4

CH3

NO2

NO2

Cl2

CHCl2NO2

NO2

HOH

CHONO2

NO2

7.5.6.9.

COOH

NO2

SOCl2

COCl

NO2

C6H6

AlCl 3

COPh

NO2

7.5.6.10.

Cl

OC6H6

AlCl 3

O

Zn(Hg)

HCl

7.5.6.11.

OH K2Cr2O7 O KCN

H+OH

CN

HOH

H+OH

COOH

7.5.6.12.

COOHPCl5

COClPhH

COPhEtMgBr OH

EtPh

7.5.6.13.

A: B: C: D: E:

D<A<C<B<F<E

O

H3C OF:

H3C

O

O

O

OH

H

7.5.6.14.

OHOMe

KOH

OHOMe

Ac2O

OAcOMe

K2Cr2O7

OAcOMe

CHO

HOH

OHOMe

CHO

7.5.6.15.

152

BrPPh3

PPh3 BrC4H9Li

PPh3

PhCHO Ph

PhCH2BrPPh3 PhCH2PPh3Br

C4H9LiPhCH=PPh3

O Ph

BrPPh3 PPh3Br

C4H9LiPPh3

CHO

a)

b)

Br PPh3PPh3Br C4H9Li PPh3 O

7.5.6.16.

O

O 1. PhMgBr

2. HOH, H+ Ph O

OHH+, ∆

-H2O Ph O O

Ph+a)

O 1) NaBH4

2) HOH, H+

OH H2SO4, ∆ NBS Br 1. PPh3

2. BuLiPPh3

O

b)

O Cl2, H+ O

Cl

KOH, EtOH

∆

OHOH, H+

O

OH

H2CrO4O

O

c)

7.5.6.17.

7.6.9.1.

OHH2CrO4

O

HBr

BrMg, ether

MgBr2) HOH, H+

O1) OH

a)

Ob)Br2, H+

O

Br

tBuOK

∆O


NCl

Cl

NC

NCN

NaNH2 NCOOEt

EtOH

H2SO4

a)

N

O

C6H5MgBr

N

OH

N

OOCCH2CH3

CH3CH2COClb)

7.6.9.2.

K

CH2=CH-CH2Br CNCN

H2O

H2SO4 CONH2

7.6.9.3.

OOH O

OH2N

C2H2

NaNH2

ClCONH2

7.6.9.4.

CNCOOH CN

-CO2

∆

Br2 CNBr

H2O CONH2

Br

7.6.9.5.

B

7.6.9.6.

C < F < A < D < B < E

7.6.9.7.

E < B < A < D < C

7.6.9.8.

A: benzene; B: toluene; C: o-nitrotoluene; C’: p-nitrotoluene; E: o-nitrobenzyl chloride; E’: p-nitrobenzyl chloride

154

7.6.9.9.

Ph

O

Ph

NC OHHCN H2O

Ph

HOOC OH

-CO2 Ph

OH

-H2O Ph

7.6.9.10.

a: methyl chloride; B: toluene; b: chlorine; C: benzyl chloride; D: benzyl cyanide

7.6.9.11.

E < C < A < D < B

7.6.9.12.

COOEtEtOOC EtONa iPrBr H2O

-CO2

COOEtEtOOCCOOEtEtOOC COOHHOOC

COOH

H2SO4 BrBr

CNCN

Br2OH KCN

H2O

COOHCOOH

-H2OO

O

O

7.6.9.13.

all of them

7.6.9.14.

A, B, E

7.6.9.15.

A, B, D

7.6.9.16.

B, C

7.6.9.17.

A, E


7.6.9.18.

A, B, D, E

7.6.9.19.

a) with NaHCO3

b) with ethanol

c) with NaOH and heating

d) NaHCO3 and heating

e) AgNO3

7.6.9.20.

COOEtEtOOC NaOEt BrBr

COOEtEtOOC

Na

BrEtOOC

COOEt

NaOEt

BrEtOOC

COOEt

NaCOOEtEtOOC

1.NaOH

2. H+, ∆

HOOC

7.6.9.21.

CH3CH2COOHLAH

CH3CH2CH2OHPBr 3 CH3CH2CH2Br

COOEtEtOOC

Na EtOOC

COOEt

1.NaOH

2. H+, ∆HOOC

7.6.9.22.

156

7.6.9.23.

7.6.9.24.

HOCl KCN

HOCN HOH, H+

HOCOOH

Br Mg MgBr 1. CO2

HOH, H+

COOH

a)

b)

7.7.7.1.


7.7.7.2.

O

OHO

HOHO

HOH2C

Ac2O

pyridine

O

OAcO

AcOAcO

AcOH2C

H Ac

O

OMeO

HOHO

HOH2C

H

CH3I, Ag2O

MeOH

O

OMeO

MeOMeO

MeOH2C

Me

H

OMe

H

CH2OH

OH H

H OHO HIO4

H

OMe

H

CH2OH

O O

O

OMe

H

H

CH2OH

OH H

H OHO HIO4

OMe

H

H

CH2OH

O O

O

a)

b)

c)

d)

7.7.7.3.

COOHH OH

CH3

7.7.7.4.

158

H OH

CHOCH2OH

7.7.7.5.

erythrose

CH2OH

HO H

CHO

OHH

CHO

H OH

CH2OH

H OH

CHO

OHH

CH2OH

OHH

CH2OH

H OH

CHO

HHO

CHO

HO H

CH2OH

HO H

CHO

HHO

CH2OH

HHO

CH2OH

H OH

CHO

OHH

CHO

H OH

CH2OH

HO H

CHO

OHH

CH2OH

HHO

HO

CHO

HHO

C

HO

C

H

CHO

HHO

H

threose

enantiomer enantiomer

diastereomer

8.1.3.

A: benzene; B: bromobenzene; C: phenylmagnesium bromide; D: benzoic acid

8.1.4.

CH3

NH2

HNO2

CH3

N2+

KI

CH3

I

CuCN

CH3

N2+

CH3

CN

H2O

H+

CH3

COOH∆

8.1.5.

formic acid, acetic acid, propionic acid, isobutanoic acid


8.1.6.

COOH1. LiAlH4

2. HOHOH HBr Br

Mg, éter

MgBr1. CO2

2. HOH, H+COOH

8.2.3.

a) 2-chloroethanol; b) p-nitrobenzyl alcohol; c) glycerine

8.2.4.

a) 1-phenyl-2-propanol, 3-phenyl-1-propanol, 1-phenyl-1-propanolb) p-nitrobenzyl al-cohol, benzylalcohol, p-hydroxybenzyl alcoholc) 3-buten-1-ol, 2-buten-1-old) trans-2-methylcyclopentanol, 1-methylcyclopentanole) methanol, benzyl alcohol

8.2.5.

H+Cl

Cl

Cl+a)

b)

OH

H+

OH2

-H2O H-

H-

8.2.6.

O

O

O

AlCl 3

COOH

O

Zn(Hg)

HCl

COOH SOCl2 COCl

AlCl 3

O

Pd/H2

OH

H2SO4

8.2.7.

OH Na ONa EtBr O

160

OHNa

ONa

Br

8.2.8.

8.3.3.

a) 3-phenyl-2-butanol (erythro); b) 3-phenyl-2-butanol (threo); c) trans-2-methylcyclo-hexanol (e,e)

8.3.4.

a) p-nitrobenzyl alcohol, benzyl alcohol, p-methylbenzyl alcoholb) β-phenylethyl alco-hol, benzyl alcohol, α-phenylethyl alcohol

8.3.5.

OH H+ OH2

-H2OBr Br

Br+

HOH+

H2O-H2O

8.3.6.

OHHOH

H+

8.4.3.

NBS

Br

1. Me3N

NMe3

2. AgOH

HO

∆

8.4.4.

OH HBr

OH HBr

Br

no reaction

a)

b)


CHBr3/KOtBu Br

Br

H

H

KMnO4/H+ HOOCHOOC

Br

Br

H

H

H2/Ni HOOCHOOC

H

H

8.4.5.

COOH KOH H2SO4COOHBr O

OLiAlH 4

HOOH

8.5.3.

NO2 NO2

SO3H

H2SO4 NaOH

NO2

SO3Na

H2

NH2

SO3Na

HCl

NH2

SO3H

NaOH∆

NH2

ONa

HCl

NH2

OH

CO2, K2CO3

NH2

OHCOOK

HCl

NH2

OHCOOH

8.5.4.

OHCH2OH

OH

CH2OH

A: B: C:

OHCH2OCOCH3 D:

OBzCH2OCOCH3

8.6.4.

Cl

NO2

OEt

NO2

EtOK Fe, HCOOH

OEt

NH2

Ac2O

OEt

NHAc

8.6.5.

162

CH3

NH2

AcCl

CH3

NHAc

HNO3

H2SO4

CH3

NHAcNO2

H2O

H+

CH3

NH2

NO2

CH3

NO2

H2

HNO2

CH3

N2+

NO2

H3PO2

CH3

NO2

8.6.6.

COOH SOCl2COCl CONMe2Me2NH 1. LiAlH 4

2. H2O, H+

N

8.6.7.

CH3

NH2 (CH3CO)2O

CH3

NHAc HNO3/H2SO4

CH3

NHAc

NO2

H2O/KOH

CH3

NH2

NO2

HNO3/H2SO4CH3

NHAc

O2N

HNO3/H2SO4

CH3

NH3NO3

8.6.8.

CH3

NH2

CH3

NHAc

AcCl

-HCl

KMnO4

COOH

NHAc

H2O

-CH3COOH

COOH

NH2

8.7.3.

NK

O

O

Br COOEt

COOEt

N

O

O

COOEt

COOEt

1. NaOEt

Br2.

N

O

O

COOEtCOOEt

1.HOH, H+

2. ∆

COOH

NH2

8.8.3.


a) 2,4,6-trinitro- > 2,4-dinitro- > p-chloronitro- > m-chloronitro- > chlorobenzeneb) tol-uene > benzene > chlorobenzene > nitrobenzenec) allyl > primary > vinyld) toluene > p-bromotoluene > bromobenzene > 1,4-dibromobenzenee) benzyl chloride > ethyl chloride > chlorobenzene

8.8.4.

OHOH ClCH2COCl

POCl3

OHOH

OCl

CH3NH2

OHOH

ONHMe

H2

OHOH

HONHMe

8.8.5.

OHH

R-2-butanol

TsClOTs

H NH3

NH2

H

S-2-butilamin

8.8.6.

a) SN2; b) SN1

8.8.7.

8.8.8.

OH

Me

TsCl OTs

Me

t-BuOK

Me

H

E2

8.9.3.

a) benzene, toluene, p-xylene, m-xylene, mesityleneb) nitrobenzene, bromobenzene, benzene, toluenec) acetophenone, benzene, acetanilide, anilined) phthalic acid, p-methylbenzoic acid, toluene, p-xylenee) 2,4-dinitrochlorobenzene, p-chloronitroben-zene, chlorobenzenef) 2,4-dinitrochlorobenzene, 2,4-dinitrophenolg) m-dinitrobenzene, 2,4-dinitrotoluene

8.9.4.

R-2-butanolTsCl OTs HOH (SN2)

OH

164

OMeNO2

Cl

Me

NO2

MeO2N

NO2

O2NNO2

NO2

NO2 NO2 NO2

O

ONO2

O

O

NO2 OHNO2

OH

NO2

a) b) c) d)

e) f)

8.9.5.

NaHCO3, SNA

8.9.6.

Br

SO3/H2SO4

Br

NO2

Br2/FeBr3

CH3

AcCl/AlCl 3

SO3H

Br

SO3H

+

CH3 O

CH3

CH3

CH3O

+

NO2

Br

a)

b)

c)

CH3O

AcCl/AlCl 3

COOEt

Cl2/FeCl3

NHCH3

HCl

CH3O

O

CH3

COOEt

Cl

NH2CH3 Cl

d)

e)

f)


NHCOCH3

CH2=CH2/HCl

AlCl 3

NHCOCH3

+

NHCOCH3

g)

8.9.7.

OH

CH3CH2COCl

AlCl 3

OH O

Zn(Hg)

HCl

OH

OH

NaOH

ONa

CO2

∆

OHCOO

H+

OHCOOH

8.9.8.

HNO3/H2SO4

NO2

Cl2/FeCl3

NO2

1) Fe, HCl

2) NaOH

NH2

Cl Cla)

Cl

O

AlCl 3

OZn/Hg

HClb)

CHCl3AlCl 3

c)

NO2

HNO3/H2SO4 1) Fe, HCl

2) NaOH

NH2

Br2 felesleg

NH2

Br Br

Br

NaNO2

HCl

N2

Br Br

Br

Cl

HOH∆

OHBr Br

Br

d)

166

8.10.1.

Cl

NH2

Cl2

OMe

NO2

MeCl/ AlCl 3

NH2

Cl

Cl

NH2

Cl Cl

OMeMe

NO2

OMe

NO2

Me

8.10.2.

N

I

O

Nu

NO

E+

8.10.3.

Br 1. Mg2. H2O

MgBr

HCHO

CH2OH

MeCHO

Me

aceton

MeHOMe

NO2+

BrNO2

NO2

HO-

OHNO2

NO2

allil bromid1. CO22. H+

COOH

NaNH2/NH3

a) b)

HOMgBr

c)

MgBr

d) e)

Br

MgBr

f)

MgBr

g)

Br

h)

NH2

8.10.4.


a) CH2=C-CH2-OH

Br

b)

Br

CH2NH2

c)

OMeCl

NO2

MgBr

Cl

d) e)

CH2Br

BrCl

f)

CH2Cl

Br

g) h)

CF3

BrNaNH2

CF3

NH2

CF3

H2N

NH3

CF3

H2N

8.10.5.

Br

OH

CH3

AlCl 3

Cl

AlCl 3

Cl

AlCl 3

Cl

AlCl 3

Cl

Br Br

+

OH OH

+

CH3 CH3

+

a)

b)

c)

d)

b > c > d > a

8.10.6.

168

NH2

Cl Cl2

OMe

NO2

MeCl, AlCl 3

OHN

HNO3/H2SO4

NH2

Cl

Cl

NH2

ClCl+

OMe

NO2

H3C

OMe

NO2

CH3

+

OHN

NO2

OHN

NO2+

a)

b)

c)

8.10.7.

NH2

3Br2

NH2

Br Br

Br

NaNO2/HCl

0 °C

N2

Br Br

Br

Cl

H3PO2Br Br

Br

8.11.3.

Cl2 (AlCl 3) Mg CO2

HCl

PCl5C6H6 (AlCl 3)

Cl MgCl COOMgCl

COOHCOCl

Ph Ph

O

8.11.4.


8.11.5.

COOEtiPrOH/H2SO4

∆COOiPr

COOEt CH2OHLiAlH 4

COOEt C6H5CH2ONa COOCH2C6H5

COOEtC6H5MgBr

Ph

OHPh

e)

f)

g)

h)

8.12.3.

170

HNO3 + H2SO4

NO2

Cl2/FeCl3

NO2

Cl

Cl2/AlCl 3

Cl

HNO3 + H2SO4

Cl

NO2

Br2/FeBr3

Br

HNO3 + H2SO4

Br

NO2

Br2/FeBr 3

Br

NO2

Br

CH3

Tl(OOCCF3)3

CH3

Tl(OOCCF3)2

KI

CH3

I

CH3

Br2/FeBr3

CH3

Br

Mg

CH3

MgBr

CH3COCH3

CH3

CH3C CH3

OH

a)

b)

c)

d)

e)

8.12.4.

N2+ Cl OH

NN

OH

N2+ Cl OMe

NN

OMe

O2N

NO2 NO2O2N

8.12.7.

benzoic acid, 2-methylbenzoic acid, 2,3-dimethylbenzoic acid

8.12.8.


8.12.9.

CH3COOH CH3COOEtEtOHMeCOMe

EtONa O O

CH3COOHLAH

CH3CH2OHPBr3 CH3CH2Br

CH3COOEtNaOEt

CH3COCH2COOEtNaNH2

CH3CH2BrCH3COCHCOOEt

Et

HOH/H+

CH3COCHCOOHEt

∆CH3COCH2CH2CH3

8.13.3.

A: allyl chloride; B: allyl alcohol; C: 2-chloro-1,3-propanediol; D: glycerine

8.13.4.

CH3

I

CH3

HOH

CH3

OH

CH3

+OH

NaOH

340 °C

CH3

I

NaOH

250 °C

CH3

IHO

CH3

OH

8.13.5.

OO

NH3

LiAlH 4

OO

HOO

NH2

HOOH

OO HO

O

OEt

EtOHH+

a)

b)

c)

8.13.6.

HOOC

H

H

1. MeMgBr

2. CO2

HOH/H+

HCOOH

O KMnO4HOOC COOH

172

OH

HBr

Br

Mg

MgBr

CO2

COOH

EtOH/H+

COOEt

8.13.7.

methanol, n-propanol, sec-butanol, tert-butanol

8.13.8.

COOH MeOH

H+, ∆COOMe COOH1. NaOH

2. MeI

8.14.4.

CH3

OH

CH3

NH2

CH3

NO2

HCl

CH3

NH2*HCl

NaOH

CH3

NH2

NaOH

CH3

ONa

CH3

OH

CH3

NO2

HCl

8.14.5.

CH3CH3

NO2

CH3

NH2HNO3

H2SO4

H2 AcCl

CH3

NHAcBr2

CH3

NHAc

Br

HOHH+

CH3

NH2

Br

HONO

CH3

N2+

Br

H3PO2

CH3

Br

8.15.1.


MgBrHCHO

CH2OH

O CH2CH2OH

Br

Mg

8.15.2.

a) benzyl alcohol, phenol, benzoic acid, benzenesulfonic acidb) water, phenol, H2CO3, H2SO4c) m-cresol, phenol, m-bromophenol, m-nitrophenold) p-chlorophenol, 2,4-di-chlorophenol, 2,4,6-trichlorophenol

8.15.3.

n-PrOHKMnO4

COOHMeOH

H+ H+ COOMeBr2/P

COOMe

BrPPh3

DBU COOMe

PPh3

8.15.4.

Br

Mg

éter

MgBrO

OH

PBr3

Br

NaCN

CN

H2O/H2SO4

COOH

SOCl2

COCl

AlCl 3

O

H2/Ni

OH

H2SO4

8.15.5.

174

H3CCOOH

H

H

Br2/CCl4CH3

H Br

COOHH Br

CH3

Br H

COOHBr H

PhCOOH

OHH

∆ PhCOOH

H

H

COOHCH2OH

H∆

OO

a)

b)

c)

8.15.6.

NBS

Br

Br

KCN

CN

Br

HOH/H+

COOH

HO

H2/Ni

COOH

HO

CrO3

COOH

O

8.15.7.

Cl COOH1. NaOH

2. KCN NC COOHHOH, H+

∆HOOC COOH

8.16.3.

NO2

Cl H2N

NO2

HNHCOOH

NO2

NOHC

H2

NH2

NOHC

N

N

8.17.3.

COOH

ClNaCN

COOH

CNEtOH

H2SO4 COOEt

COOEt Et-Br

NaOEt COOEt

COOEt

EtEt H2N NH2

O

HN

NH

O

O

EtEt

ONaOEt

8.17.4.

CH3COOEtCH3COOEt

NaOEtCH3COCH2COOEt

HN NH2 N

NO

CH3

NNO

CH3

Me2SO4CH3


8.17.5.

HOOC

H3CO

N

N

COOH

8.17.6.

Cl

CN

CH3CH2COOEt

Cl

CN

Et

O CH2N2

Cl

CN

Et

OMe N

NH2N

Et

NH2

Cl

NH

NH2

H2N

8.18.6.

PhCH2CHONH3

PhCH2CH=NHHCN Ph

CN

NH2

H2O/H+/∆Ph

COOH

NH2

COOEt

COOEt

Br

NK

O

ON

O

O

COOEt

COOEt

1. NaOEt

2. PhCH2BrN

O

O

COOEt

COOEtCH2Ph

H2O/H+/∆Ph

COOH

NH2

a)

b)

8.19.3.

8.20.1.

O LAHOH H+ 1.O3

2. Zn, H2OCHOOHC

CHO PCl5 CHCl2 NaOEt HOH

H+, Hg2+

O

OHCrO3

AcOHO

HCl, ZnCl 2

ClMg

MgClOHO

H+

O

O

NaOAc

O

O

NaOHO

a)

b)

c)

d)

176

OEt

O ONaOEt

OEt

O O

Na-EtOHBr

OEt

O O

a)

b) Ph OEt

O ONaOEt

-EtOH Ph OEt

O O

NaMeI

Ph OEt

O OHOH, H+

∆ PhCOOH

O∆

-CO2 Ph

O

8.20.2.

COOEtO 1. NaOEt

2. Br

COOEtO

1. NaOEt

2. MeI

COOEtO

HOH, H+

∆

O

a)

NC CN1. NaOEt

BrBr Br CN

CNNaOEt CN

CN

b)

COOEt

tBu

EtOOC COOEt1.

2. NaOEt3. HOH, H+

COOEt

tBu

CH(COOEt)2 HOH, H+

∆

COOH

tBu

COOHc)

8.21.1.

N

Cl

NaOEt/EtOH

N

OEt

SH3C

HNO3/Ac2O

SH3C

NO2

N

CH3

HCl

N

CH3

H

a)

b)

c)

N Br

NH3

∆ N NH2

d)


NH

EtMgBr

NMgBr

N

Br2

∆N

Br

N

PhLi

N

NH

HNO3/Ac2O

e)

f)

g)

h)NH

NO2

8.22.2.

NH2O

NH2

MeNH2

∆

HNO

HN

COOHNC

Ac2O

NO

NH

O

CN

NaOHNO

N

O

NH

HNO2NO

N

O

NHNOH

Zn, H2SO4

NO

N

O

NH2

NH2

HCOOHN

O N

O

NH2

NHCOHNaOHN

O N

O

N

HNMe2SO4N

O N

O

N

N

koffein

8.23.2.

OHH2CrO4 COOH

SOCl2 COCl

HBr

BrKCN

CN1. LiAlH 4

2. H2O, H+NH2

COCl

NH

O

8.23.3.

A, C

8.23.4.

C

8.23.5.

178

all are E isomers

Functional groups of organic compounds 179

FUNCTIONAL GROUPS OF ORGANIC COMPOUNDS

Name General structure

1. alkenes

R4

R3R1

R2

R1 = H, alkyl, aryl R2 = H, alkyl, aryl R3 = H, alkyl, aryl R4 = H, alkyl, aryl

2. alkynes R1 R2

R1 = H, alkyl, aryl R2 = H, alkyl, aryl

3. halogeno derivatives R X X = F, Cl, Br, I R = alkyl, aryl

4. alkyl chlorides R Cl R = alkyl

6. primary alcohols R OH R = alkyl, aryl

7. secondary alcohols R2

R1 OH

R1 = alkyl, aryl R2 = alkyl, aryl

8. tertiary alcohols R3

R1 OHR2

R1 = alkyl, aryl R2 = alkyl, aryl R3 = alkyl, aryl

9. phenols OH

aromatic or heteroaro-matic ring with OH sub-

stituent

10. ethers R1 OR2


11. peroxides R1 OO

R2


12. hydroperoxides RO

OH R = alkyl, aryl

13. thiols

(mercaptanes) R SH R = alkyl, aryl

180


14. thioethers

(sulfides) R1 SR2


15. disulfides R1 SS

R2


16. primary amines R NH2 R = alkyl, aryl

17. secondary amines R1

HN

R2


18. tertiary amines R1 N

R2

R3


19 quaternary ammo-

nium salts NR1

R4 R2 XR3

R1 = alkyl, aryl R2 = alkyl, aryl R3 = alkyl, aryl R4 = alkyl, aryl

20. N-oxides

R1 NR3

O

R2


21. hydrazines

R2

NNR4

R1 R3


22. aldehydes R H

O

R = H, alkyl, aryl

R1 NR3

R2

O

R1 NR3

O

R2



23. ketones R1 R2

O


24. imines

R1 R2

NR3

R1 = H, alkyl, aryl R2 = H, alkyl, aryl R3 = H, alkyl, aryl

25. hydrazones

R1 R2

NN

R4

R3


26. oximes

R1 R2

NOH


27. oxime-ethers

R1 R2

NOR3


R3 = alkyl, aryl

28. hemiacetals R1 R2

R3O OH


R3 = alkyl, aryl

29. acetals R1 R2

R3O OR4



30. enamines

N

R3

R5 R4

R1

R2

R1 = H, alkyl, aryl R2 = H, alkyl, aryl R3 = H, alkyl, aryl R4 = H, alkyl, aryl R5 = H, alkyl, aryl

182


31. enols

OH

R3R1

R2


32. enol ethers

OR4

R3R1

R2


R4 = alkyl, aryl

33. carboxylic acids R OH

O

R = H, alkyl, aryl

34. carboxylic acid salts R O M

O

R = H, alkyl, aryl

35. carboxylic esters R1 O

OR2

R1 = H, alkyl, aryl R2 = alkyl, aryl

36. lactones

O

O

cyclic esters

37. carboxylic acid am-

ides R1 N

OR2

R3


38. lactams

O

NR

cyclic carboxylic amides

R = H, alkyl, aryl



39. thiolactams

S

NR

cyclic thiocarboxylic am-ides

R = H, alkyl, aryl

40. hydrazides

R1 NN

R2

O R4

R3


41. carboxylic acid az-

ides R N

O

N N R = H, alkyl, aryl

42. hydroxamic acids R N

H

OOH

R = H, alkyl, aryl

43. amidines R1 N

NR3

R2

R4


44. nitriles

R C N R = H, alkyl, aryl

45. carboxylic acid hal-

ides R X

O

R = H, alkyl, aryl X = F, Cl, Br, I

46. carboxylic acid chlo-

rides R Cl

O

R = H, alkyl, aryl

47. carboxylic acid or-

thoesters R1 OR4

R2O OR3

R1 = H, alkyl, aryl R2 = alkyl, aryl R3 = alkyl, aryl R4 = alkyl, aryl

184


48. carboxylic acid anhy-

drides R1 O

O

R2

O


49. carboxylic acid im-

ides R1 N

O

R2

O

R3


50. urethanes

NR2

R1O

OR3


R3 = alkyl, aryl

51. carbamides NR2

R1O

NR3

R4


52. thiocarbamides NR2

R1S

NR3

R4


53. guanidines NR2

R1N

NR3

R4

R5


54. semicarbazides NR2

R1O

NR3

NR5

R4


55. azides R N N N R = alkyl, aryl



56. azo compounds


57. diazonium salts R N N N R = alkyl, aryl

58. isonitriles R N C R = alkyl, aryl

59. cyanates O C NR R = alkyl, aryl

60. isocyanates R N C O R = alkyl, aryl

61. thiocyanates S C NR R = alkyl, aryl

62. isothiocyanates R N C S R = alkyl, aryl

63. carbodiimides R1 N C N R2


64. nitroso compounds R N O R = alkyl, aryl

65. nitro compounds R NO

O

R = alkyl, aryl

66. nitrite esters O N OR R = alkyl, aryl

67. nitrate esters O NO

OR

R = alkyl, aryl

68. sulfonic acids R SO

OHO

R = alkyl, aryl

69. sulfonamides R1 SO

NO R3

R2

R1 = alkyl, aryl R2 = H, alkyl, aryl R3 = H, alkyl, aryl

R1

NN

R2

186


70. sulfonyl halides R SO

XO

R = alkyl, aryl X = F, Cl, Br, I

71. sulfones R1 SO

R2

O


72. sulfoxides R1 S

R2

O


73. phosphonic acids PO

R OHOH

R = alkyl, aryl

74. 1,2-amino alcohols

HO

R2 R3

NH2

R1 R4


75. α-hydroxy acids

OH

RO

OH

R = H, alkyl, aryl

76. α-amino acids

N

R1

R2

O

OH

R3


77. β-amino acids

R1

R2

O

OH

NR3

R4


Heterocylic skeletons 187

HETEROCYLIC SKELETONS

oxirane azetidine 2-azetidinone (β-lactam)

furan tetrahydrofuran

thiophen pyrrole pyrrolidine oxazole oxazolidine

isoxazole isoxazolidine thiazole thiazolidine isothiazole

isothiazolidine pyrazole pyrazolidine imidazole imidazolidine

O1

23

NH1

23

4 NH

O

1

23

4 O1

2

34

5

1

2

34

5O

S1

2

34

5NH

1

3

2

4

5

HN 1

3

2

4

5

N

O1

3

2

4

5

N

O1

3

2

4

5

H

NO1

3

2

4

5 NHO1

3

2

4

5

N

S1

3

2

4

5

HN

S1

3

2

4

5 NS1

3

2

4

5

NHS1

3

2

4

5 NNH

1

3

2

4

5 NHNH1

3

2

4

5

N

NH 1

3

2

4

5

N

NH 1

3

2

4

5

H

188

N N

O1

2

34

5

1H-1,2,3-triazole 1,3,4-oxadiazole 1,3,4-thiadiazole 1H-tetrazole 2H-pyran

4H-pyran tetrahydropyran pyridine piperidine 1,4-dioxane

pyridazine pyrimidine pyrazine piperazine 2H-1,2-oxazine

morpholine 2H-1,4-thiazine 1,3,5-triazine 1H-azepine azocine

N

NNH 1

3

2

4

5

N N

S1

3

2

4

5

N N

NNH 1

3

2

4

5

O1

2

3

4

5

6

6

5

4

3

2

1

O6

5

4

3

2

1

O6

5

4

3

2

1

N 6

5

4

3

21 N

H

6

5

4

3

2

1

O

O

6

5

4

3

2

1N

N 6

5

4

3

2

1N

N

6

5

4

3

2

1

N

N6

54

3

2

1

N

NH

H

NHO1

2

3

4

5

6

6

54

3

2

1

N

O

HN

S1

2

3

4

5

6 6

54

3

2

1

N

N

N

NH1

2

3

45

6

7N

1

2

3

45

6

7

8

NNH1

2

3

45

6

7

N

NH1

2

3

45

6

7

N

NH1

2

3

45

6

7 O1

2

34

5

6

7

Heterocylic skeletons 189

1H-1,2-diazepine 1H-1,3-diazepine 1H-1,4-diazepine benzofuran

indole isoindole indolizine indolizidine

benzimidazole quinoline isoquinoline 3,4-dihydro-2H-benzo[b]pyran

(chromane)

2H-quinolizine quinolizidine quinazoline quinoxaline

phthalazine 1,8-naphthiridine 7H-purine pteridine

NH

1

2

34

5

6

7

NH

12

34

5

6

7

N

1

2

345

6

7

8

N

1

2

345

6

7

8

N

N

H1

2

34

5

6

7

N1

2

3

45

6

7

8

N

1

2

3

45

6

7

8 1

2

3

45

6

7

8O

N

1

2

3

45

67

8

9

N

1

2

3

45

67

8

9N

N

1

2

3

45

6

7

8N

N

1

2

3

45

6

7

8

N

N

1

2

3

45

6

7

8

N N1

2

3

45

6

7

8

N

N

N

N

H1

2

34

56

7

8

9 N

N N

N

1

2

3

45

6

7

8

190

1H-1,4-benzodi-azepine

1H-2,3-benzodiaze-pine

penam cepham

xanthene acridine phenazine

phenothiazine 5H-dibenz[b,f]azepine β-carboline

N

N

H1 2

3

456

7

8

9N

N

12

3

456

7

8

9

N

S

O

1

2

34

5

6

N

S

O

1

2

3

45

6

7

1

2

3

45

6

7

8

9

10O

10

98

7

6

5 4

3

2

1

N

109

8

7

6 5 4

3

2

1N

N

109

8

7

6 5 4

3

2

1

S

NH

NH

1

2

34

56

7

8

910 11

abc d e

f

N

N

H1

2

345

6

7

8 9

Contents 191

CONTENTS

Preface ...................................................................................................................... 0 1. Common instruments and tools in the organic chemistry laboratory ............. 2 2. Laboratory notebook ........................................................................................... 8 3. Accident and fire prevention instructions in the organic chemistry laboratory 9 4. Fundamental operations in organic chemistry laboratory practicals ........... 11

4.1. Heating ........................................................................................................ 11 4.2. Cooling ........................................................................................................ 11 4.3. Filtration ...................................................................................................... 11 4.4. Washing ....................................................................................................... 12 4.5. Drying .......................................................................................................... 12

5. Purification of organic compounds .................................................................. 14

5.1. Distillation ................................................................................................... 14

5.1.1. Simple distillation .................................................................................. 14 5.1.2. Distillation under reduced pressure ....................................................... 15

5.2. Crystallization.............................................................................................. 16

5.2.1. Recrystallization .................................................................................... 16 5.2.2. Crystallization by acid-base precipitation .............................................. 17

5.3. Extraction .................................................................................................... 17 5.4. Chromatography .......................................................................................... 18

5.4.1. Column chromatography ....................................................................... 18

5.4.2. Thin-layer chromatography (TLC) ………………………… …….…20

6. Determination of the structures of organic compounds ................................. 21

6.1. Infrared (IR) spectroscopy ........................................................................... 21 6.2. Mass spectrometry (MS) ............................................................................. 22 6.3. Nuclear magnetic resonance (NMR) spectroscopy ..................................... 22

7. Reactivity of the functional groups of organic compounds ............................ 29

7.1. Hydrocarbons .............................................................................................. 29

7.1.1. Alkanes and cycloalkanes ...................................................................... 29 7.1.1.1. Reactions of alkanes with Br2 in the presence of UV light ................. 29 7.1.1.2. Spectroscopic characterization of alkanes .......................................... 29 7.1.2. Alkenes (olefins) .................................................................................... 30 7.1.2.1. Oxidation of olefins with KMnO4....................................................... 30 7.1.2.2. Addition of Br2 to an olefinic bond ..................................................... 30 7.1.2.3. Oxidation of alkenes with KMnO4 in acidic media ............................ 31 7.1.2.4. Spectroscopic identification of olefins ................................................ 31

192

7.1.3. Aromatic hydrocarbons .......................................................................... 32 7.1.3.1. Friedel-Crafts alkylation of aromatic hydrocarbons ........................... 32 7.1.3.2. Reactivity of the side-chain of aromatic hydrocarbons....................... 32 7.1.3.3. Spectroscopic characterization of aromatic hydrocarbons .................. 33 7.1.4. Problems and exercises .......................................................................... 33

7.2. Organohalogeno compounds ....................................................................... 36

7.2.1. Reactions of iodo, bromo and chloro compounds with alcoholic AgNO3

..................................................................................................................... …36 7.2.2. Reactions of bromo and chloro compounds with NaI ............................ 37 7.2.3. Spectroscopic characterization of halogeno compounds ....................... 37 7.2.4. Problems and exercises .......................................................................... 38

7.3. Hydroxy compounds ................................................................................... 42

Alcohols ........................................................................................................... 42 Enols ................................................................................................................ 42 Phenols ............................................................................................................. 42 7.3.1. Transformation of alcohols to halogeno compounds ............................. 43 7.3.2. Oxidation of alcohols with the Jones reagent ........................................ 43 7.3.3. Reactions of polyols with Cu(II)............................................................ 43 7.3.4. The iodoform test of ethanol .................................................................. 44 7.3.5. Spectroscopic characterization of alcohols ............................................ 44 7.3.6. Reactions of enols with Fe(III) .............................................................. 44 7.3.7. Reactions of enols with Cu(II) ............................................................... 45 7.3.8. Spectroscopic characterization of enols ................................................. 46 7.3.9. Reactions of phenols with Fe(III) .......................................................... 46 7.3.10. Bromination of phenols ....................................................................... 46 7.3.11. Synthesis of triarylmethane colorants from phenols ............................ 46 7.3.12. Spectroscopic characterization of phenols ........................................... 47 7.3.13. Problems and exercises ........................................................................ 48

7.4. Amines ......................................................................................................... 52

7.4.1. Reactions of amines with Cu(II) ............................................................ 52 7.4.2. Acylation of amines ............................................................................... 52 7.4.3. Schiff-base formation reaction of amines .............................................. 53 7.4.4. Reaction of aniline with Br2 ................................................................... 53 7.4.5. Spectroscopic characterization of amines .............................................. 54 7.4.6. Problems and exercises .......................................................................... 54

7.5. Carbonyl compounds (aldehydes and ketones) ........................................... 58

7.5.1. Identification of carbonyl compounds with 2,4-dinitrophenylhydrazine .................................................................................................................... ….58

Contents 193

7.5.2. Oxidation of carbonyl compounds ......................................................... 58 7.5.2.1. Oxidation with KMnO4 ....................................................................... 58 7.5.2.2. Oxidation with the Jones reagent ........................................................ 59 7.5.2.3. Oxidation with the Tollens reagent ..................................................... 59 7.5.2.4. The Fehling reaction ........................................................................... 59 7.5.2.5. The Benedict reaction ......................................................................... 60 7.5.3. Iodoform test of methyl ketones ............................................................ 60 7.5.4. Reactions of carbonyl compounds with Br2 ........................................... 60 7.5.5. Spectroscopic characterization of carbonyl compounds ........................ 61 7.5.6. Problems and exercises .......................................................................... 61

7.6. Carboxylic acids and carboxylic acid derivatives ....................................... 64

7.6.1. Ester formation of carboxylic acids ....................................................... 64 7.6.2. Hydrolysis of esters ............................................................................... 65 7.6.3. Hydrolysis of acid halides and acid anhydrides ..................................... 65 7.6.4. Formation of an amide (benzamide) from an acid chloride ................... 65 7.6.5. Hydroxamic acid complex formation .................................................... 66 7.6.6. Spectroscopic characterization of carboxylic acids ............................... 66 7.6.7. Spectroscopic characterization of esters ................................................ 66 7.6.8. Spectroscopic characterization of amides .............................................. 66 7.6.9. Problems and exercises .......................................................................... 67

7.7. Carbohydrates .............................................................................................. 71

7.7.1. The Molisch reaction of carbohydrates .................................................. 71 7.7.2. The Fehling reaction of mono- and disaccharides ................................. 71 7.7.3. The Tollens reaction of mono- and disaccharides ................................. 71 7.7.4. The Selivanov reaction of mono- and disaccharides ............................. 72 7.7.5. The Bial reaction of mono- and disaccharides ....................................... 72 7.7.6. Formation of osazones ........................................................................... 72 7.7.7. Problems and exercises .......................................................................... 73

8. Syntheses ............................................................................................................. 75

8.1. Benzoic acid ................................................................................................ 75

Problems and exercises .................................................................................... 76

8.2. Cyclohexanol ............................................................................................... 77


8.3. tert-Butyl chloride ....................................................................................... 80


8.4. 2,3-Dibromo-3-phenylpropanoic acid ......................................................... 82

194


8.5. Acetylsalicylic acid ..................................................................................... 85

Problems and exersices .................................................................................... 86

8.6. Acetanilide ................................................................................................... 87


8.7. N-Benzoylglycine (hippuric acid) ............................................................... 90


8.8. p-Toluenesulfonyl morpholide .................................................................... 92


8.9. 4-Nitroacetanilide ........................................................................................ 96


8.10. 4-Bromoacetanilide ................................................................................. 100

Problems and exercises .................................................................................. 101

8.11. Phenyl benzoate ....................................................................................... 104


8.12. Ethyl p-aminobenzoate (benzocaine) ...................................................... 107


8.13. Methyl salicylate ..................................................................................... 111


8.14. 3-Nitrobenzoic acid ................................................................................. 115


8.15. Phenylacetic acid ..................................................................................... 117


8.16. Benzimidazole ......................................................................................... 120

Problems and exercises: ................................................................................. 121

8.17. 3,5-Dimethylpyrazole .............................................................................. 122


8.18. 4-Benzylidene-2-methyloxazol-5-one ..................................................... 125


8.19. N-Benzylidene-3-nitroaniline .................................................................. 127


Contents 195

8.20. 5,5-Diethylbarbital ................................................................................... 129


8.21. 1-Phenyl-3-methyl-pyrazol-5-one ........................................................... 131


8.22. Isolation of caffeine ................................................................................. 133


8.23. Isolation of piperine ................................................................................. 135


References ............................................................................................................. 137 Answers to the problems ..................................................................................... 138 Functional groups of organic compounds .......................................................... 179 Heterocylic skeletons ........................................................................................... 187 Contents ................................................................................................................ 191

Documents

Practicals of Organic Chemistry - digit.bibl.u-szeged.hudigit.bibl.u-szeged.hu/eta/00000/00130/00130.pdf · dures are used for recrystallization, for distillation or when reactions