· Web viewUnit II: Alkaloids and Proteins Structural elucidation and total synthesis of morphine. Peptides and their synthesis (Synthesis of tripeptide using amino acids - Glycine,

ORGANIC CHEM – IV FOR PG - 2019

ORGANIC CHEMISTRY -IVFOR PG

( MADRAS UNIVERSITY )

BY

Dr. C.SEBASTIAN ANTONY SELVANASST. PROFESSOR OF CHEMISTRY

R. V. GOVT.ARTS COLLEGECHENGALPATTU

94440401152019

Dr. C.SEBASTIAN, AP/ CHEM, R. V. GOVT. ARTS COLLEGE, CHENGALPATTU . MOB: 9444040115 Page 1


FOURTH SEMESTER

Course Components/Title of the paper

Inst.

Hours/

week

Credits

Exam

Hours

MARKS

CIA EXT TOTAL

Core Paper XII : Organic Chemistry-IV 6 4 3 25 75 100

Core Paper XIII: Inorganic Chemistry-IV 6 4 3 25 75 100

Core Paper XIV: Physical Chemistry-IV 6 4 3 25 75 100

Core Paper XV: Physical Chemistry practical-II* 6 4 6 40 60 100

Elective Paper-V: Dissertation & Viva Voce exam. 6 3 6 40 60 100

Soft Skill -IV -- 2 3 40 60 100

*Practical examinations to be conducted at the end of the academic year.



Semester IV

Core Paper - XII – Organic Chemistry – IV (90 Hours)

Unit I: Bio-Organic chemistry

Synthesis of Pyrimidines and purines.

Structure and role of nucleic acids.

DNA and RNA - Genetic code.

Biosynthesis of cholesterol, phenanthrene alkaloids and bile acids.

Unit II: Alkaloids and Proteins

Structural elucidation and total synthesis of morphine.

Peptides and their synthesis (Synthesis of tripeptide using amino acids - Glycine, Alanine, Lysine, Cysteine, Glutamic acid, Arginine).Merrified synthesis, Determination of primary, secondary and tertiary structure of proteins.

Unit III: Modern synthetic methodology

Application of synthetic methodology for the synthesis of simple cyclic and acyclic target molecules -synthesis of cubane, 5 - hexenoicacid , bicyclo (4, 1, 0) heptane-2-one.,trans 9-methyl-1- decalone ,longifolene and onocerin. Concept of Synthones, synthetic equivalents and intermediates. Formation of C-C and C=C bonds. Reversal carbonyl polarity – Umpolung addition.

Unit IV: Retrosynthetic analysis, Protection and Deprotection

Retro synthetic analysis and synthesis of simple organic molecules such as 1,2, 1,3, 1,4 and 1,5 dicarbonyl compounds both acylic and cyclic. Formation of 3, 4, 5 and 6 membered cyclic compounds - Baldwin's rules. Use of standard reactions, like Grignard reactions, Robinson annulations. Protection and deprotection of functional groups (R-OH, RCHO, R-CO-R, R-NH2 and R-COOH). Use of PTC (Phase-transfer catalyst) and Crown ethers in organic synthesis.

Unit V: Novel reagents in organic synthesis:-

Synthesis and applications of Organolithium, Organomagnesium, Organozinc and Organo Copper and Gilman reagents. Modern synthetic methods: metal mediated C-C coupling reactions: Mechanism and synthetic applications of Heck, Stille, Suznki, Negishi, Sonogashira, McMurray, Metathesis and Carbonylation reactions. Green reactions and reagents.



UNIT I: BIO-ORGANIC CHEMISTRY

1. Synthesis of Pyrimidines and purines.

2. Structure and role of nucleic acids.

3. DNA

4. RNA

5. Genetic code.

6. Biosynthesis of cholesterol,

7. Biosynthesis of phenanthrene alkaloids

8. Biosynthesis of bile acids.

18SYNTHESIS OF PYRIMIDINES AND PURINES







thymin

cytosin



Uracil



28STRUCTURE AND ROLE OF NUCLEIC ACIDS.

NUCLEIC ACIDS

Nucleic acids are the principal genetic materials of living organisms. They gained their name

because they are acidic and were first identified in nuclei. They are the major component of chromosomes

present in nucleus.

Nucleic acid = purine + pyrimidine + sugar + H3PO4

Nucleosides:

These are glycosides formed between one of the bases and ribose or deoxy ribose. They are named as follows

1. Adenine + ribose = adenosine

2. Guanine+ ribose = guanosine

3. Uracil + ribose = uridine

4. Cytosine + ribose =cytidine



5. Thymine + ribose =thymidine

When the sugar is deoxy ribose they are named as deoxy adenosine and so on.

The linkage between base and sugar involves N1 in pyrimidine or N9 in purine with

C1 of sugar.

Nucleotides:

These are sugar phosphate esters of nucleosides. Those nucleoides , whose sugar is ribose are called

ribonucleotids and those having 2- deoxy ribose sugar is called deoxy ribo nucleotides.

There two types of nuceic acids . they are

1. Deoxy Ribonuceic acid ( DNA)

2. Ribo Nuceic Acid( RNA)

38 DNA -Deoxy Ribonuceic acid

Structure of DNA: (Watson and Crick model)

Watson-Crick Structure of DNA. Deoxyribonucleic Acid (DNA) is a double-stranded, helical molecule. It

consists of two sugar-phosphate backbones on the outside, held together by hydrogen bonds between pairs

of nitrogenous bases on the inside.

Watson and Crick (nobel prize in 1953 ) proposed a model of DNA according to which

1. DNA is made up of three units namely sugar( pentose), bases( purine and pyrimidine) and

phosphoric acid.

2. It is in the form of two long polynucleotide chains twisted around a central axis and form a

double helix..

3. The outsides of the helix are formed by the pentose – phosphate back bones

4. The pentose present in DNA is 2- deoxy ribose whose structure is



( there is no oxygen in second carbon and hence the name)

5. The pentose – phosphate groups in the two chains run in opposite directions. i.e one chain runs with

its phosphatediester bonds advancing in the 3→ 5 direction whereas the other in 5→3 direction

6. Two types of bases have been identified in DNA. They are

1.Pyrimidine bases( thymin,and cytosine)

Pyrimidine is an aromatic six membered ring that contains two nitrogen atoms at position 1 and 3

2.Purine bases( adenine and guanine):

Purine molecule is viewed as a pyrimidine fused with an imidazole. Imidazole is a five membered

ring containing two nitrogen atoms at positions 1 and 3.

purine (pyrimidine + imidazole)



8.The phosphate group of one nucleotide is attached to the pentose part of next nucleotide The term Nucleotides refers the phosphoric esters of nucleosides where nucleosides are glycosides

of purine or pyrimidine.

Sugar + base( purine or pyrimidine) → nucleosides

Nucleosides + H3PO4 → nucleotides

Nucleotides → poly nucleotides( nucleic acids)

9. The C1 of the pentose is attached to N1 of the pyrimidine or N9 of the purine.

10. The purine bases( adenine and guanine), pyrimidine bases(thymin and cytosine)

are stacked in the inner position, with the phosphate outside.

11. The purine and pyrimidine bases are facing inward toward each other and bonded by H- bonds and thus

holding the strands together.

12. The bases, pair in a specific manner .

13. Every base pair consists of a purine on one strand and a pyrimidine on the other.

14. The possible combination is between adenine and thymine (A-T, or T-A) and guanine and cytosine(G-C, or

C-G) .

15. Two hydrogen bonds are connecting the A-T base pair while three hydrogen bonds are connecting G-C pair.

16. The base pairs A-T, T-A, C-G, and G-C linking the two poly nucleotide chains are said to be complementary

base pairs. This complementarities is known as pase- pair rule or Chargaff’s rule.



17. The width of the double helix is 20 Ao.

18. Each turn of the helix is 34 Ao ( equivalents of 10 nucleotides arranged linearly).

19. Each successive nucleotides turns 36 0 in the horizontal plane.



48 RNA - RIBO NUCLEIC ACID

1. It is a polymer of purine and pyrimidine ribonucleotiodes linked together by 3’,5,-phospho di-ester bridges.

2. The sugar moiety in RNA is ribose.

3. The pentose ribose has a free hydroxyl group in position 2’.

4. It contains uracil instead of thymine, along with cytosine , adenine and guanine.

5. In regions where purine – pyrimidine pairing takes place adenine pairs with uracil and guanine with cytosine.

6. All normal chains start with either adenine or guanine.

7. It exists as single- stranded molecule rather than double-stranded helical molecule.

8. Since it is single stranded , its guanine content does not necessarily equal to its cytosine content and its adenine

content does not equal to its uracil content.

9. The molecule is unbranched.

10. It contains 60 - 60,000 nucleotides.

11. The single strand RNA is folded upon itself either entirely or in certain regions.

12. In the folded region the bases the bases are complementry and joined by H- bonds.

13. In the unfolded region the base have no complements.

14. Due to this RNA is not having the purine-pyrimidine equalities as in DNA.

TYPES OF RNA:

There are three classes of RNA. They are



1.Ribosomal-RNA ( r- RNA)

It consists of 80 % of total RNA and these are found in ribosomes and hence the name r-RNA. It

may be short compact rod,or a compact coil or an extended strand.

2.Messenger RNA( m-RNA)

This carries information for protein synthesis from DNA(genes) to the sites of protein

formation(ribosome). It is always single stranded. In mRNA no base pairing takes place. The sequence of

bases in mRNA molecule is complementary to the bases that constitute the genetic code



3.Transfer RNA( t-RNA) or soluble RNA(s-RNA)

It is the smallest RNA which contains 15- 80 nucleotides. It transfers the amino acids in the process of

protein synthesis and hence the name.It has clover leaf structure. It has 4 recognition sites.

1.Amino acid attachment site.

In this site amino acids are attached which terminates in CCA

2.Ribosomal recognition site (T-loop)

3. Anticodon site:

It consists of 3 bases which forms the anti codon.

4.Amino acid activating enzyme recognition site(DiHydro Uridine loop).



Nucleic acids:

These are formed from nucleotides. Nucleotides join by phosphodiester bonds between the 3 and 5

positions of ribosyl moieties.

FUNCTIONS OF NUCLEIC ACIDS:

1.DNA replication:

DNA makes exact copy of itself. This process is known as replication. This results in the formation of

two molecules of DNA , consisting of one old ( parental) and one new ( daughter) chain.

This involves the following stages.

1. Unwinding of the parental double helix:



The two strands separate by breaking the H- bonds. Each single strand (called primer) has now an exposed

row of bases ,that serves as a template.

2. The template strand, dictates the sequence in which the free bases are arranged.

3. The bonds are made between the complementary base pairs( A-T, T-A,G-C,C-G)

and thus a complementary chain to the template is formed. For example, if a segment

of the template has the arrangement ATTGCCA , the newly synthesised chain will be

TAACGGT.

4. As each strand produces its complementary strand , the two newly formed strands combine into a DNA

molecule identical to the original.

58 GENETIC CODE ( CODON)

Genetic code or codon: It is the hereditary unit which contains three bases which corresponds to single specific amino acid For example AAA- Lysine, GGG – glycine

anticodon The complementary set of bases is called anticodon . For example anticodon for AAA is TTT

Genetic code: The genetic code is composed of words formed by a sequence of nucleotide bases and a sequence of amino acids. Each word in the code is composed of three nucleotide bases. This genetic words are called codons.

The codons are found in messenger RNA. The four nucleotide bases A,G,T,C and U are used to form three base codons.Therefore 43 = 64 different combinations of bases are formed. 61 of 64 codons code for 20 amino acids and the remaining three( UAG,UGAand UAA) are non sense codons or termination codons, which do not code any amino acid.

For example CAU codes for histidine, AUG for methionine.For a specific codon, only a specific amino acid will be incorporated with few exceptions.If one of these codons appears in an m-RNA sequence,it signals the complete synthesis of the peptide chain.

GENETIC CODE (TRIPLET CODE)



Phe – Phenyl alanine Ser - Serine Tyr – Tyrosine Cys - Cystine



Leu – Leucine Pro - Proline His – Histidine Arg - ArginineLle – Iso leucine Thr- Threonine Asn – Aspartamine Ser - SerineMet – Methionine Ala – Alanine Lys - Lysine Gly - GlycineVal - Valine Asp – Aspartamic

Glu- Glutathione Stop - nonsense codons – which does take any amino acid.

68BIOSYNTHESIS OF CHOLESTEROL,

:

1.HMG-CoA formation and conversion to mevalonate

2. Conversion of mevalonate to isoprenoid precursors

3. Synthesis of squalene and its conversion to lanosterol

4. Conversion of lanosterol to cholesterol


http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/cholesterol.htm#lanchol

http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/cholesterol.htm#prenyl

http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/cholesterol.htm#isopent

http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/cholesterol.htm#hmgcoa












BIO – SYNTESIS OF CHOLESTEROL

1. SYNTESIS OF MEVELONIC ACID:

II. SYNTHESIS OF GERANIAL PHOSPHATE





78 BIOSYNTHESIS OF PHENANTHRENE ALKALOIDS

phenanthrene alkaloids are codeine and morphine . Papaver somniferum L. contains the phenanthrene

alkaloids . the biosynthetic sequence is

tyrosine -->norlaudanosoline --> reticuline --> salutaridine --> salutaridinol-I -->thebaine --> codeine -->

morphine in Papaver somniferum



88BIOSYNTHESIS OF BILE ACIDS.

Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Primary bile

acids are those synthesized by the liver. Secondary bile acids result from bacterial actions in the colon.

In humans, taurocholic acid and glycocholic acid (derivatives of cholic acid) and taurochenodeoxycholic

acid and glycochenodeoxycholic acid (derivatives of chenodeoxycholic acid) are the major bile acids in bile

Production

Bile acid synthesis occurs in liver cells which synthesize primary bile acids (cholic acid and chenodeoxycholic

acid in humans) via cytochrome P450-mediated oxidation of cholesterol in a multi-step process.

The rate-limiting step in synthesis is the addition of a hydroxyl group on position 7 of the steroid nucleus by

the enzyme cholesterol 7 alpha-hydroxylase.

.

When these bile salts are secreted into the lumen of the intestine, bacterial partial dehydroxylation and removal

of the glycine and taurine groups forms the secondary bile acids, deoxycholic acid and lithocholic acid.

Cholic acid is converted into deoxycholic acid and chenodeoxycholic acid into lithocholic acid.

Structure and synthesis The structures of the principal human bile acids

Cholic acid Glycocholic acid


https://en.wikipedia.org/wiki/Glycocholic_acid

https://en.wikipedia.org/wiki/Cholic_acid

https://en.wikipedia.org/wiki/Lithocholic_acid

https://en.wikipedia.org/wiki/Deoxycholic_acid

https://en.wikipedia.org/wiki/CYP7A1

https://en.wikipedia.org/wiki/Rate-limiting_step

https://en.wikipedia.org/wiki/Cholesterol

https://en.wikipedia.org/wiki/Cytochrome_P450

https://en.wikipedia.org/wiki/Chenodeoxycholic_acid



https://en.wikipedia.org/wiki/Hepatocyte


https://en.wikipedia.org/wiki/Glycochenodeoxycholic_acid

https://en.wikipedia.org/wiki/Taurochenodeoxycholic_acid



https://en.wikipedia.org/wiki/Glycocholic_acid

https://en.wikipedia.org/wiki/Taurocholic_acid

https://en.wikipedia.org/wiki/Colon_(anatomy)

https://en.wikipedia.org/wiki/Bile

https://en.wikipedia.org/wiki/Acid

https://en.wikipedia.org/wiki/Steroid

https://en.wikipedia.org/wiki/File:Cholic_acid.png

https://en.wikipedia.org/wiki/File:Glycocholic_acid.png


Taurocholic acid Deoxycholic acid

Chenodeoxycholic acid Glycochenodeoxycholic acid

Taurochenodeoxycholic acid Lithocholic acid

Bile Acid Synthesis and Utilization

The major pathway for the synthesis of the bile acids is initiated via hydroxylation of cholesterol at the 7 position via the action of cholesterol 7α-hydroxylase (CYP7A1) which is an ER localized enzyme. CYP7A1 is a member of the cytochrome P450 family of metabolic enzymes.

The pathway initiated by CYP7A1 is referred to as the "classic" or "neutral" pathway of bile acid synthesis.

There is an alternative pathway that involves hydroxylation of cholesterol at the 27 position by the mitochondrial enzyme sterol 27-hydroxylase (CYP27A1).

This alternative pathway is referred to as the "acidic" pathway of bile acid synthesis.

The bile acid intermediates generated via the action of CYP27A1 are subsequently hydroxylated on the 7 position by oxysterol 7α-hydroxylase (CYP7B1).


https://en.wikipedia.org/wiki/Lithocholic_acid


https://en.wikipedia.org/wiki/Glycochenodeoxycholic_acid


https://en.wikipedia.org/wiki/Deoxycholic_acid

https://en.wikipedia.org/wiki/Taurocholic_acid

https://en.wikipedia.org/wiki/File:Taurocholic_acid.png

https://en.wikipedia.org/wiki/File:Deoxycholic_acid.png

https://en.wikipedia.org/wiki/File:Chenodeoxycholic_acid.png

https://en.wikipedia.org/wiki/File:Glycochenodeoxycholic_acid.png

https://en.wikipedia.org/wiki/File:Taurochenodeoxycholic_acid.png

https://en.wikipedia.org/wiki/File:Lithocholic_acid_acsv.svg

https://en.wikipedia.org/wiki/File:Steroid_numbering.png


The hydroxyl group on cholesterol at the 3 position is in the β-orientation and must be epimerized to the α-orientation during the synthesis of the bile acids.

This epimerization is initiated by conversion of the 3β-hydroxyl to a 3-oxo group catalyzed by 3β-hydroxy-Δ5 -C27-steroid oxidoreductase (HSD3B7).

Following the action of HSD3B7 the bile acid intermediates can proceed via two pathways whose end products are chenodeoxycholic acid (CDCA) and cholic acid (CA).

The distribution of these two bile acids is determined by the activity of sterol 12α-hydroxylase (CYP8B1).



Synthesis of the 2 primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA). The reaction catalyzed by the 7α-hydroxylase (CYP7A1) is the rate limiting step in bile acid synthesis. Expression of CYP7A1 occurs only in the liver. Conversion of 7α-hydroxycholesterol to the bile acids requires several steps not shown in detail in this image. Only the relevant co-factors needed for the synthesis steps are shown. Sterol 12α-hydroxylase (CYB8B1) controls the synthesis of cholic acid and as such is under tight transcriptional control (see text).

The most abundant bile acids in human bile are chenodeoxycholic acid (45%) and cholic acid (31%). These are referred to as the primary bile acids. Before the primary bile acids are secreted into the canalicular lumen they are conjugated via an amide bond at the terminal carboxyl group with either of the amino acids glycine or taurine. These conjugation reactions yield glycoconjugates and tauroconjugates, respectively. This conjugation process increases the amphipathic nature of the bile acids making them more easily secretable as well as less cytotoxic. The conjugated bile acids are the major solutes in human bile.

Structure of the conjugated cholic acids



UNIT IIALKALOIDS AND PROTEINS

1..Structural elucidation and total synthesis of morphine.

2. Peptides and their synthesis

3. Synthesis of tripeptide using amino acids

4. Glycine,

5. Alanine,

6. Lysine,

7. Cysteine,

8. Glutamic acid,

9. Arginine

10..Merrified synthesis

11.Determination of primary, secondary and tertiary structure of proteins.



111Structural elucidation and total synthesis of morphine.

STRUCTURAL ELUCIDATION OF MORPHINE

1. Molecular formula

Molecular formula of morphin was found to be C17 H19 O3N

2. Nature of N atom

a. It adds with one molecule of methyl iodide to form quaternary ammonium salt

b. *Hoffmann degradation proves the Nitrogen atom is in the ring

c. ** Herzig mayer method proves the presence of NCH3 group

From the amount of silver iodide formed , the number of methyl groups can be determined.

This shows that the Nitrogen atom in morphine is tertiory

3. Nature of oxygen atom:

a. When acetylated and benzoylated morphin yields diacetyl or dibenzoyl derivative indicating that morphine

contains two hydroxyl group.

This shows that morphin two contains 2 OH groups



b. It is soluble in NaOH to give monosodium salt which is reconverted in to morphine by passing CO 2 through

it

c. With ferric chloride it gives violet colour

These facts reveal that one of the two OH groups is phenolic

d. When morphine is treated with HCl it gives mono halo derivative. This reaction is characteristics of alcohols.

e. On oxidation with chromic acid the methyl derivative of morphin (codeine) yields ketone.

These reactions show that the hydroxyl group in morphine is secondary alcoholic in nature.

f. From the unreactivity of third oxygen atom and the degradation product of morphine , one can draw the

conclusion that the third oxygen atom of morphine is present as ether linkage

4. Presence of double bond:

When morphine is reduced catalytically in the presence of palladium it takes up one molecule of

hydrogen suggesting that it contains one double bond.

5. Presence of phenanthrene nucleus.

When morphine is distilled with zinc dust. It yields phenanthrene along with other

products ,suggesting that morphine may contain a phenanthrene nucleus.

6. Presence of cyclic tertiory base system:

When subjected to * exhaustive methylation morphine yields a compound of formula which contains

one more CH2 than morphine itself and the nitrogen atom remains intact .

This shows that morphine has cyclic tertiory amine system.

Had morphine been possesses an acyclic t – amine system , then the product obtained would posses lesser

number of carbon atoms and there also loss of Nitrogen atom.

7. Position of three oxygen atoms:



The structure of morphenol shows that , of the three O-atoms in morphine , one at C3 and the other ether

linkage between C4 andC5.

When treated with acetic anhydride codinone gives 4,6,- dihydroxy- 3- methoxy phenanthrene.

The hydroxyl group in the 6 th position might have been produced from the oxygen at 6 th position. Therefore

3 rd oxygen should be at C6. Thus , the positions of oxygen atoms in morphine are as follows.

1. One :phenolic at C3

2. Second :Ether linkage between C4 and C5

3. Third: secondary alcoholic at C6 of the phenanthrene nucleus

8.Presence of N-CH3 group:

When morphine is methylated followed by addition of methyl iodide yields codeine methiodide. This

when boiled with NaOH gives α – methyl morphimethine. This on heating with acetic anhydride yields a

mixture of ethanoldimethylamine and methyl morphol The formation of ethanoldimethylamine shows the

presence of N-CH3 group:



This is confirmed by the evidence that codeine when subjected to **VonBraun degradation adds on one

Nitrogen atom but loses three Hydrogen-atoms.

This result can be interpreted by saying that there occurs the conversion of NCH3 into NCN and so it follows

that morphine contain NCH3 group.

9. Presence of (CH3) NCH2CH2 – group

1.Hoffmann exhaustive methylation of methylated morphin(Codeine) yields methyl morphol and

ethanoldimethylamine

This shows the presence of (CH3) NCH2CH2 – group

10 .Point of linkage of

Nitrogen end

Codeine on oxidation by CrO3 ,followed by exhaustive methylation and acetolysis yields methoxy diacetoxy

phenanthrene which on oxidation gives methoxy monoacetoxy phenanthrene

There is a

loss of an acetyl group in the oxidation of Methoxy diacetoxyphenthrene



This shows that

1. one of the acetoxy group in the reactant must be present either at C9 or at C10

2. since the acetoxy group is inserted via ketonic group, the keto group and hence the hydroxyl group must be

present either at C9 or at C10

And thus nitrogen containing group must be linked either at C9 or at C10

3. On the basis of steric consideration the attachment at C9 is most probable.the partial structure is

b. Carbon - end:

The side chain having nitrogen atom is eliminated during aromatization. This indicates that the carbon end

of side chain must be located at an angular position , so that its extrusion from that position should take

place during aromatization.

Out of two such possible positions C13 and C14 , the former is selected because this only explain the

rearrangement of thebaine to thebinine



11. Position of double bond:

Double bond is placed between C7and C8

MORPHIN SYNTHESIS

(Nme reacions involved:1. Micheal addition 2. Diels Alder 3. WK 4. Openauer]

1. Protection by benzoyl chloride:

2,6- napthalenediol 2- benzoyl -6- hydroxyl napthalene

2. Nitrosiation

2- benzoyl -5-nitroso -6- hydroxyl napthalene

3. Reduction by Pd/C

4. Conversion in to quinone

2- benzoyl -5,6- napthoquinone

5.Reduction



6. Protection

7.Partial Deprotection

8,9,10 ( nitrosation, reduction, conversion to quinone)

11. Micheal addition

( error in the str no double bond)

12. Hydrolysis



13. Diels Alder reaction

14. Hydrolysis and condensation

15.Wulf – Kishner reduction[ for aromatic ketone]

16. N- methylation

17.Reduction

18.Hydration



19.Partial hydrolysis

20.Oppanauer oxidation

21.Protection and Bromination

22. Deprotection

23.Dehalogenation and reduction



24. Protection, bromination and condensation

25. Deprotection

26. Dehalogenation and reduction

Codeine



27. Demethylation

211PEPTIDES AND THEIR SYNTHESIS

SYNTHESIS OF TRIPEPTIDE USING AMINO ACIDS - GLYCINE, ALANINE, LYSINE, CYSTEINE, GLUTAMIC ACID, ARGININE



A tripeptide is a peptide consisting of three amino acids joined by peptide bonds. The exact nature and

function of proteins is determined by the amino acids present and the order they occur. ... The

other tripeptides can have different orders:glycine-alanine-glycine, glycine-glycine-alanine, and alanine-

glycine-glycine.

Examples of tripeptides are:]



Eisenin (pGlu-Gln-Ala-OH) is a peptide with immunological activity that is isolated from the Japanese

marine alga, Eisenia bicyclis, which more commonly is known as, Arame

GHK-Cu (glycyl-L-histidyl-L-lysine) is a human copper binding peptide with wound healing and skin

remodeling activity, which is used in anti-aging cosmetics and more commonly referred to as copper

peptide

Glutathione (γ-L-Glutamyl-L-cysteinylglycine) is an important antioxidant in animal cells

Isoleucine-proline-proline (IPP) found in milk products, acts as an ACE inhibitor

Leupeptin (N-acetyl-L-leucyl-L-leucyl-L-argininal) is a protease inhibitor that also acts as an inhibitor

of calpain

Melanostatin (prolyl-leucyl-glycinamide) is a peptide hormone produced in the hypothalamus that inhibits

the release of melanocyte-stimulating hormone (MSH)

Ophthalmic acid (L-γ-glutamyl-L-α-aminobutyryl-glycine) is an analogue of glutathione isolated

from crystalline lens

Norophthalmic acid (y-glutamyl-alanyl-glycine) is an analogue of glutathione (L-cysteine replaced by L-

alanine) isolated from crystalline lens

Thyrotropin-releasing hormone (TRH, thyroliberin or protirelin) (L-pyroglutamyl-L-histidinyl-L-

prolinamide) is a peptide hormone that stimulates the release of thyroid-stimulating

hormone and prolactin by the anterior pituitary

ACV (δ-(L-α-aminoadipyl)-L-Cys-D-Val) is a key precursor in penicillin and cephalosporin biosyntheses.


https://en.wikipedia.org/wiki/Cephalosporin

https://en.wikipedia.org/wiki/Penicillin

https://en.wikipedia.org/wiki/Anterior_pituitary

https://en.wikipedia.org/wiki/Prolactin

https://en.wikipedia.org/wiki/Thyroid-stimulating_hormone

https://en.wikipedia.org/wiki/Thyroid-stimulating_hormone

https://en.wikipedia.org/wiki/Peptide_hormone

https://en.wikipedia.org/wiki/Thyrotropin-releasing_hormone

https://en.wikipedia.org/wiki/Crystalline_lens

https://en.wikipedia.org/w/index.php?title=Norophthalmic_acid&action=edit&redlink=1

https://en.wikipedia.org/wiki/Lens_(anatomy)

https://en.wikipedia.org/wiki/Ophthalmic_acid

https://en.wikipedia.org/wiki/Melanocyte-stimulating_hormone

https://en.wikipedia.org/wiki/Hypothalamus

https://en.wikipedia.org/wiki/Melanostatin

https://en.wikipedia.org/wiki/Calpain

https://en.wikipedia.org/wiki/Protease_inhibitor_(biology)

https://en.wikipedia.org/wiki/Leupeptin

https://en.wikipedia.org/wiki/Lactotripeptides

https://en.wikipedia.org/w/index.php?title=Isoleucine-proline-proline&action=edit&redlink=1

https://en.wikipedia.org/wiki/Glutathione

https://en.wikipedia.org/wiki/Copper_peptide_GHK-Cu



https://en.wikipedia.org/wiki/Arame

https://en.wikipedia.org/w/index.php?title=Eisenin&action=edit&redlink=1




SYNTHESIS OF TRIPEPTIDE USING AMINO ACIDS LYSINE, CYSTEINE, GLUTAMIC ACID, ARGININE



311SYNTHESIS OF TRIPEPTIDE USING AMINO ACIDS

411 GLYCINE,

511 ALANINE,

611 LYSINE,

711 CYSTEINE,

811GLUTAMIC ACID,

911ARGININE

1011 .MERRIFIED SYNTHESIS

Merrifield Solid-Phase Peptide Synthesis

It is a synthesis of peptides and small proteins in which the resinous polymer supported amino acid and

succeeding peptide repeatedly reacts with N-protected amino acids followed by deprotection until the desired

peptide or protein is assembled


https://i2.wp.com/assets.en.chem-station.com/uploads/2014/02/merrifieldspps.png?fit=530,185&ssl=1


Characteristics

A protein consists of one peptide folded in a particular way, or several peptides folded together. Such

peptides are synthesised very rapidly within living cells, but until recently could only be artificially synthesised

in very long, slow processes that had poor yields and gave impure products. Solid phase peptide synthesis

(SPPS), developed by R. B. Merrifield, was a major breakthrough allowing for the chemical synthesis of

peptides and small proteins. SPPS results in high yields of pure products and works more quickly than classical

synthesis (liquid-phase peptide synthesis, LPPS).

The advantages of this method are very considerable. Through the replacement of a complicated isolation

procedure for each intermediate product with a simple washing procedure much time is saved. In addition, it

has proven possible to increase the yield in each individual step to 99.5% or better, a result which cannot be

attained using conventional synthetic approaches. In the example given above the final overall yield would

thus be increased from 0.003% to 61%. Finally, this method is also suitable for automation and automatic

peptide synthesizers are now commercially available.

SPPS methodology has brought about a revolution in peptide and protein chemistry and thousands of different

peptides have now been synthesized using this approach. In addition, this methodology is a completely new

approach to organic synthesis. It has created new possibilities in the research fields of peptide-protein

chemistry and nucleic acid chemistry It has greatly stimulated progress in biochemistry, molecular biology,

pharmacology and medicine. It is also of great practical importance, both for the development of new drugs

and for gene technology.



1111DETERMINATION OF PRIMARY, SECONDARY AND TERTIARY STRUCTURE OF

PROTEINS.



STRUCTURE OF PROTEIN

A.PRIMARY SRTUCTURE OF PROTEINS

The primary structure of protein is referred to the number, nature and sequence of amino acids along the peptide chain. The various steps for establishing the primary structure of proteins are as follows.

1.Isolation and purification of protein:

Protein is isolated from tissue material at controlled pH using buffer solutions and it is purified by electrophoresis, chromatography, dialysis etc.

2. Determination of number of peptide chains:

The next step is to ascertain , weather the protein consists of a single peptide chain or composed of many sub units. If it is as latter, then the sub units are separated and analysed.

3. Determination of amino acid composition:

The protein is completely hydrolysed into its constituent amino acids and then

a. Their nature and amounts are determined. b. From the relative amount of each of the amino acid present, the empirical formula can be deduced.c. The molecular weight is also determined by physical method.

4. End group analysis:

Each polypeptide has two different ends namely N- terminal end and C- terminal end. The N- terminal end contains a free amino group ( NH2) and the C-terminal end contains a free carboxyl group(COOH).

A Determination of C- terminal amino acid.

1. Hydrazinolysis

In this method, the protein is heated with anhydrous hydrazine at 100 0 C when all the amino acids ,except the C-terminal one, are converted in to amino acid hydrazide. The products obtained are allowed to pass on a column of cation exchange resin. When eluted , the hydrazides are retained on the resin whereas the free amino acid is eluted and can be identified

......NHCHR1CONHCHR2CONHCHR3COOH + N2H4

100 OC→ -.....H2NCHR1CONHNH2 +H2NCHR2CONHNH2+H2NCHR3COOH



2. Reduction method.

In this method , the protein is reduced with lithium borohydride or lithium aluminium hydride. This converts the free terminal carboxyl group to a primary alcohol group. The reduced product , on hydrolysis, yields a mixture of amino acids and an amino alcohol. The amino acid is separated and identified by paper chromatography.

......NHCHR1CONHCHR2CONHCHR3COOH LiBH 4→

-......NHCHR1CONHCHR2CONHCHR3CH2OH

.--> -.....H2NCHR1CONHNH2 + H2NCHR2CONHNH2 + H2NCHR3CH2OH

Amino alcohol

B. Determination of N-terminal amino acid.

1. Sanger method(DNP method)

In this method 1-Flouro-2,4- dinitro benzene(FDNB) is treated with the amino acid in bicarbonate –buffered aqueous ethanol.. The terminal α- amino group reacts with FDNB to form N-(2,4- dinitrophenyl) peptide. The latter compound on hydrolysis with acid yields DNP –amino acid and a mixture of amino acids. As the DNP -amino acids are brilliantly coloured, they may be identified by TLC. It can be quantitatively determined by their absorbance at 360 nm.

2. Phenylthiohydantoin( Edman) method:

The first step is the addition reaction of phenylisothiocyanate with the protein to form the phenylthiocarbamyl peptide(PTC – peptide). The latter compound is cleaved in the presence of acetic acid to give a thiazolinone intermediate and the liberation of the remainder of the peptide intact. The thiazolinone is hydrolysed by dil.HCl, to the phenyl thio carbamyl amino acid( PTC – amino acid) which is then hydrolysed to form the phenylthiohydantoin derivative of the amino acid(PTH-aminoacid). The PTH- amino acids are extracted with organic solvents and identified by comparison with Standards using paper, column or TLC. This series of reactions may be written as follows:

6.Determination of the sequence of amino acids:



SECONDARY STRUCTURE PF PROTEINS: The secondary structure of protein is concerned with 3D arrangement of poly peptide chain. Thus it

deals with the conformation of peptide chain . The secondary structure may be ∝ - helix or β - helix.

1.∝-helix

According to Pauling and Cray, the ∝- helix is a spiral arrangement of poly peptide chain , winding

around a central axis.

In this helix, every peptide carbonyl oxygen is hydrogen bonded with the amide hydrogen of the fourth

amino acid residue.. This hydrogen bond prevents free rotation and so the helix is rigid and cylindrical in

shape, and capable of stretching and bending. The side chains of the amino acids are pointed away from the

helical axis.



The ∝– helix may be left or right handed but the right handed helix is more stable. There are either 3.7 or

5.1 amino acid residues in one complete turn of the helix, with a distance parallel to the helical axis of 5.4 A.

The diameter of the helix has been found to be 10 A.

The exception are proline, valine and isoleucine . They do not fit into the helix due to ring and bulky side

chain. Such acids are called helix breaker.



TERTIARY STRUCTURE

Tertiary structure of protein refers to the orientation of side chains in the folded molecule. This

structure involves hydrogen bonding, ionic, chemical, and hydro phobic bonds. These forces maintain coiling

and folding in a definite manner, thus giving rise to highly specific internal structure of the protein.

1.Hydrogen bonds:

These are formed between two amino acids , one of which contains a OH group , like tyrosine while the

other contains COOH group as in glutamic acid.

2.Ionic bond:

These are formed between amino acid side groups which are capable of ionising to form electrically

charged species. In these bonds R group s with unlike charges like NH3 + of lysine and COO - of glutamic acid

would be attracted to each other whereas groups having similar charges would repel each other.

3.Hydrophobic (non polar) bonds:

These are formed between hydrocarbon like side chain ( between two methyl or two phenyl groups).

These are present in the interior of protein molecules where less water is present.





QUATERNARY STRUCTURE

Proteins which consists of more than one poly peptide chain , such as haemoglobin are said to posses

Quaternary structure. Proteins having this type of structure are said to be oligomeric and the individual poly

peptide chains are known as promoters or sub units.

Each of these sub units is characterised by its own secondary and tertiary structure. The sub units may

or may not be identical. Some examples showing quaternary structure are





1.Haemoglobin:

2.Lactic dehydrogenase





UNIT III

MODERN SYNTHETIC METHODOLOGYApplication of synthetic methodology for the synthesis of simple cyclic and acyclic target

molecules synthesis of

1. Cubane,

2. 5- Hexenoicacid ,

3. Bicyclo (4, 1, 0) Heptane-2-One.

4. Trans 9-Methyl-1- Decalone ,

5. Longifolene

6. Onocerin.

7. Concept Of Synthones, Synthetic Equivalents And Intermediates.

8. Formation Of C-C And C=C Bonds.

9. Reversal Carbonyl Polarity

10. Umpolung Addition.



110 CUBANE,

Cubane (C8H8) is a synthetic hydrocarbon molecule that consists of eight carbon atoms arranged at the corners

of a cube, with one hydrogen atom attached to each carbon atom. cubane is one of the member of

the prismanes.

.SYNTHESIS:

1.2-bromocyclopentadienone undergoes a spontaneous Diels-Alder dimerization, to form 2

For the subsequent steps to succeed, only the endo isomer is useful, and this is the predominant isomer formed

in this reaction.

Both carbonyl groups are protected as acetals with ethylene glycol and p-toluenesulfonic acid in benzene;

one acetal is then selectively deprotected with aqueous hydrochloric acid to 3.

In the next step, the endo isomer 3 (with both alkene groups in close proximity) forms the cage-like isomer 4 in

a photochemical [2+2] cycloaddition.

The bromoketone group is converted to ring-contracted carboxylic acid 5 in a Favorskii

rearrangement with potassium hydroxide.

Next, the thermal decarboxylation takes place through the acid chloride (with thionyl chloride) and the tert-

butyl perester 6 (with tert-butyl hydroperoxide and pyridine) to 7;

afterward, the acetal is once more removed in 8.

A second Favorskii rearrangement gives 9,

and finally another decarboxylation gives, via 10, cubane (11).


https://en.wikipedia.org/wiki/Pyridine

https://en.wikipedia.org/wiki/Tert-Butyl_hydroperoxide

https://en.wikipedia.org/wiki/Perester

https://en.wikipedia.org/wiki/Tert-butyl

https://en.wikipedia.org/wiki/Tert-butyl

https://en.wikipedia.org/wiki/Thionyl_chloride

https://en.wikipedia.org/wiki/Acid_chloride

https://en.wikipedia.org/wiki/Decarboxylation

https://en.wikipedia.org/wiki/Potassium_hydroxide

https://en.wikipedia.org/wiki/Favorskii_rearrangement

https://en.wikipedia.org/wiki/Favorskii_rearrangement

https://en.wikipedia.org/wiki/Carboxylic_acid

https://en.wikipedia.org/wiki/Haloketone

https://en.wikipedia.org/wiki/Cycloaddition

https://en.wikipedia.org/wiki/Photochemical

https://en.wikipedia.org/wiki/Alkene

https://en.wikipedia.org/wiki/Hydrochloric_acid

https://en.wikipedia.org/wiki/Benzene

https://en.wikipedia.org/wiki/P-Toluenesulfonic_acid

https://en.wikipedia.org/wiki/Ethylene_glycol

https://en.wikipedia.org/wiki/Acetal

https://en.wikipedia.org/wiki/Protecting_group

https://en.wikipedia.org/wiki/Endo-exo_isomerism

https://en.wikipedia.org/wiki/Diels-Alder_reaction

https://en.wikipedia.org/wiki/Prismanes

https://en.wikipedia.org/wiki/Hydrogen

https://en.wikipedia.org/wiki/Cube_(geometry)

https://en.wikipedia.org/wiki/Atom

https://en.wikipedia.org/wiki/Carbon

https://en.wikipedia.org/wiki/Molecule

https://en.wikipedia.org/wiki/Hydrocarbon


Cubane



PHILIP EATON SYNTHESIS of cubane1. WOHL ZEIGLER REACTION

2. bromination

3. Diels – Alder reaction

4. PROTECTION

5. Partial deprotection

6.



7. FAVAROSKEY REARRANGEMENT

8.

9.





2

10 SYNTHESIS OF 5- HEXENOICACID ,

310BICYCLO (4, 1, 0) HEPTANE-2-ONE.

410TRANS 9-METHYL-1- DECALONE ,

5 - hexenoicacid

BICYCLO (4.1, 0) HEPTAN-2-ONE

A convenient and efficient phosphine-catalyzed sequential annulation domino reaction between dienic sulfones

and MBH carbonates has been developed. In the presence of 20 mol% of tris(4-fluorophenyl)phosphine,

functionalized bicyclo[4.1.0]heptenes were prepared in excellent yields and stereoselectivities under mild



conditions.

TRANS 9-METHYL-1- DECALONE

510LONGIFOLENE

LONGIFOLINE

Longifolene was isolated, from Pinus longifolia

Chemically, longifolene is a tricyclic sesquiterpene.

. SYNTHESIS OF LONGIFOLINE


https://en.wikipedia.org/wiki/Terpene




Corey’S SYNTHESIS of longifoline 1. Protection

2. WITTIG REACTION

3. HYDROXYLATION

4. PARTIAL PROTECTIO

5. RING EXPANSION

6. DEPROTECTION



7. MICHEAL ADDITION

8. C-METHYLATION

9. PROTECTION

10. REDUCTION

11. DE PROTECTION and WULF – KISNER REDUCTION



12. OXIDATION

13. C- METHYLATION

14. DEHYDRATION

NOTE



Wittig reaction

The Wittig reaction or Wittig olefination is a chemical reaction of an aldehyde or ketone with a triphenyl phosphonium ylide (often called a Wittig reagent) to give an alkene and triphenylphosphine oxide.[1][2]

The Wittig reaction was discovered in 1954 by Georg Wittig, for which he was awarded the Nobel Prize in Chemistry in 1979. It is widely used in organic synthesis for the preparation of alkenes.[3][4][5] It should not be confused with the Wittig rearrangement.

The Wittig Reaction allows the preparation of an alkene by the reaction of an aldehyde or ketone with the ylide generated from a phosphonium salt.

610ONOCERIN.


https://en.wikipedia.org/wiki/File:Wittig_Reaktion.svg


ONOCERINE



Note:

BIRCH REDUCTION It converts aromatic compounds having a benzenoid ring into a product, 1,4-

cyclohexadienes, in which two hydrogen atoms have been attached on opposite ends

of the molecule.

It is the organic reduction of aromatic rings in

liquid ammonia with sodium, lithium or potassium and an alcohol, such

as ethanol and tert -butanol .

This reaction is quite unlike catalytic hydrogenation, which usually reduces the

aromatic ring all the way to a cyclohexane.

Also the use of tert-butyl alcohol has become common. The reaction is widely used in

synthetic organic chemistry.


https://en.wikipedia.org/wiki/Cyclohexane

https://en.wikipedia.org/wiki/Hydrogenation

https://en.wikipedia.org/wiki/Catalytic

https://en.wikipedia.org/wiki/Tert-Butanol

https://en.wikipedia.org/wiki/Ethanol

https://en.wikipedia.org/wiki/Alcohol

https://en.wikipedia.org/wiki/Potassium

https://en.wikipedia.org/wiki/Lithium

https://en.wikipedia.org/wiki/Sodium

https://en.wikipedia.org/wiki/Ammonia

https://en.wikipedia.org/wiki/Aromatic_ring

https://en.wikipedia.org/wiki/Organic_reduction

https://en.wikipedia.org/wiki/1,4-Cyclohexadiene

https://en.wikipedia.org/wiki/1,4-Cyclohexadiene

https://en.wikipedia.org/wiki/Benzenoid#Ring_formula

https://en.wikipedia.org/wiki/Aromaticity


The Barbier–Wieland degradation The Barbier–Wieland degradation is a procedure for shortening the carbon chain of a carboxylic acid by one carbon.

It only works when the carbon adjacent to the carboxyl is a simple methylene bridge (an aliphatic carbon with no substituents).

The reaction sequence involves conversion of the carboxyl and alpha carbon into an alkene, which is then cleaved by oxidation to convert the former alpha position into a carboxyl itself.[1][2


https://en.wikipedia.org/wiki/Barbier%E2%80%93Wieland_degradation#cite_note-2

https://en.wikipedia.org/wiki/Barbier%E2%80%93Wieland_degradation#cite_note-1

https://en.wikipedia.org/wiki/Oxidation

https://en.wikipedia.org/wiki/Bond_cleavage

https://en.wikipedia.org/wiki/Alkene

https://en.wikipedia.org/wiki/Alpha_carbon

https://en.wikipedia.org/wiki/Substituent

https://en.wikipedia.org/wiki/Aliphatic

https://en.wikipedia.org/wiki/Methylene_bridge

https://en.wikipedia.org/wiki/Methylene_bridge

https://en.wikipedia.org/wiki/Carboxylic_acid

https://en.wikipedia.org/wiki/Carbon_chain


710 CONCEPT OF SYNTHONES, SYNTHETIC EQUIVALENTS AND

INTERMEDIATES.

810FORMATION OF C-C AND C=C BONDS.

910REVERSAL CARBONYL POLARITY

1010 UMPOLUNG ADDITION



UNIT IVRETROSYNTHETIC ANALYSIS,

PROTECTION AND DEPROTECTIONRetro synthetic analysis and synthesis of simple organic molecules such as

1. 1,2,

2. 1,3,

3. 1,4 and

4. 1,5 dicarbonyl compounds both acylic and cyclic.

5. Formation of 3, 4, 5 and 6 membered cyclic compounds –

6. Baldwin's rules.

7. Use of standard reactions, like Grignard reactions,

8. Robinson annulations.

9. Protection and deprotection of functional groups

10. (R-OH,

11. RCHO,

12. R-CO-R,

13. R-NH2



14. R-COOH).

15. Use of PTC (Phase-transfer catalyst)

16. Crown ethers in organic synthesis

RETRO SYNTHETIC ANALYSIS AND SYNTHESIS OF SIMPLE ORGANIC MOLECULES SUCH AS

116RETRO SYNTHETIC ANALYSIS 1,2,

216RETRO SYNTHETIC ANALYSIS 1,3,

316 RETRO SYNTHETIC ANALYSIS 1,4

416RETRO SYNTHETIC ANALYSIS 1,5 DICARBONYL COMPOUNDS BOTH ACYLIC AND

CYCLIC.

516 FORMATION OF 3, 4, 5 AND 6 MEMBERED CYCLIC COMPOUNDS –

RETRO SYNTHESIS

1. DEFINITION

Retro synthesis is a technique, for planning the synthesis of organic compounds backwards,

by starting at the product, and taking steps with simple available starting materials.

Product starting material synthesis

The symbol stands for disconnection.

2.DISCONNECTION and SYNTHONS

Disconnection is the step to break the specific bonds of the product , to identify the reagent which

can be selected for the synthesis.



The broken pieces are called SYNTHONS. It is denoted by the symbol “ “

A --- B A + + B – or A - + B+

A + ,B – , A -, B+ are called synthons.

Two types of synthons are known

1. Nucleophilic synthons

R –(alkyl), R- (aryl), R-C = C –

2. Electrophilic synthons

R +(alkyl), R+ (aryl) R-CH = CH +, R-C = C + RC=O, HC=O, + COOH, .CH2OH,

.CHOHR,

.CR2OH,

.CH2CH2 OH,

.CH2CH2 COR,

.CH2CH2 COR

.CH2CH2 CO2R,

Rules to be followed during disconnections:

1. Adjacent to functional group

2. Between α –β to the functional group

3. Betweenβ – γ to the functional group

4. Adjacent to the branching point

5. If there are two functional groups not separated by more than 3 carbons, disconnect between the

functional group.

6. If the compound contains C=C then disconnect this bond.

4. SYNTHETIC EQUIVALENCE:

These are the actual reagents which carry the functions of synthons. There may be more

than one synthetic equivalence , for any synthon

SYNTHONS SYNTHETIC EQUIVALENCE



1

R - RMgX, RLi , RCu, R2Cd, R2Cu Li

2 R C- C- RC=CNa, RC=CMgX, RC=CLi, RC=CCu,

3 R+ RCl, RBr, RI

4 RCH=CH +

RCH=CHBr

Problem 1: Devise a synthetic route for 1- phenyl butan-2ol : Ph-CH2CHOHCH2CH3

ANALYSIS:

1.Writing the possible disconnections for the required end product.

Disconnection of the 1,2 –bond or 1,3-bond ( those flanking the functional group gives four pairs of synthons, as follows Ph-CH2 CHOHCH2CH3 Ph-CH2

+ +

- CHOHCH2CH3

Ph-CH2 - +

+ CHOHCH2CH3

Ph-CH2CHOH CH2CH3 Ph-CH2 +CHOH + - CH2CH3

Ph-CH2CHOH - + +CH2CH3

2. Recognising the synthetic equivalents

The synthetic equivalent for Ph-CH2 +

is PhCH2Br,



The synthetic equivalent for Ph-CH2 - is PhCH2MgBr

The synthetic equivalent for - CH2CH3 is CH3CH2MgBr The synthetic equivalent for + CH2CH3 is CH3CH2Br

3. Choosing the recognisable synthons:

Among the above four synthons , the recognised synthons are + CHOHCH2CH3 whose synthetic equivalent is

Propanol + H+ Ph-CH2

+CHOH whose synthetic equivalent is Phenyl ethanol Ph CH2CHO

SYNTHESIS:

In the above case, Grignard reagent is the easiest to make and it reacts satisfactorily with an aldehyde, So two synthetic routes have emerged to the given compound

FUNCTIONAL GROUP INTERCONVERSION( FGI)

Changing the functional groups in to other groups which can be disconnected.

Example: Aromatic acid can be made by oxidation of methyl group.

Amino group can be made by reduction of nitro groups.

ANALYSIS:



SYNTHESIS:

Disconnection of nitro group is easy because nitration of toluene occurs easily.

DISCONNECTION OF ALCOHOLS

(One group C-C disconnection)

1. Alcohol can be dis connected at the C-C bond next to Oxygen atom.

2. This requires the reagents for the carbanion synthon R –

3. Simple carbanions are never found in reactions. So we need reagents in which carbon is



joined to more electro positive atom such as metal

4. The most popular metals are Li and Mg.

5. Butyl lithium is commercially available.

6. Other Lithium can be made from it by exchange

7. Direct reaction between metal and alkyl halide

8. Grignard reagents are made directly from alkyl halide and Mg.

9. Therefore Grignard reagent, aldehydes and ketones are the synthetic equivalence.

ANALYSIS:

Synthetic equivalence are Grignard reagent and ketone

SYNTHESIS:

RETRO DIELS ALDER SYNTHESIS

It is one of the most important reactions in synthesis because

1. It makes two C-C bonds in one step.

2. It is regio selective and stereo selective.



3. It is stereo specific ( cis reagent gives cis product and trans gives trans product)

4. It is Pericyclic cyclo addition between conjugated diene and congucated alkene forming a

cyclohexene.

ANALYSIS:

SYNTHESIS:

Problem 2 Devise a synthetic route for Pentadecane – 4- one CH3 (CH2 )10 CO (CH2 )2 CH3

RETRO SYNTHETIC ANALYSIS AND SYNTHESIS OF1,3, DICARBONYL COMPOUNDS



1. ACYLIC

Problem 2 Devise a synthetic route for PhCOCH2COCH3 ( 1,3-ketone)

ANALYSIS:1.Writing the possible disconnections for the required end product

2. Recognising the synthetic equivalents

PhCOCH3 and CH3COOEt are the synthetic equivalent

cyclic

616BALDWIN'S RULES.

BALDWIN'S RULES

Baldwin's rules are a series of guidelines outlining the relative favorability’s of ring closure reactions

in alicyclic compounds.



The rules classify ring closures in three ways:

the number of atoms in the newly formed ring into exo and endo ring closures, depending whether the bond broken during the ring closure is inside

(endo) or outside (exo) the ring that is being formed

into tet, trig and dig geometry of the atom being attacked, depending on whether this electrophilic carbon

is tetrahedral (sp 3 hybridised), trigonal (sp 2 hybridised) or digonal (sp hybridised).

Thus, a ring closure reaction could be classified as, for example, a 5-exo-trig.

Baldwin discovered that orbital overlap requirements for the formation of bonds favour only certain

combinations of ring size and the exo/endo/dig/trig/tet parameters.

Baldwin dis/favoured ring closures

3 4 5 6 7

type exoen

dexo end exo end exo

en

dexo end

tet ✓ ✓ ✓ ✗ ✓ ✗ ✓ ✗

trig ✓ ✗ ✓ ✗ ✓ ✗ ✓ ✓ ✓ ✓

dig ✗ ✓ ✗ ✓ ✓ ✓ ✓ ✓ ✓ ✓

The rules apply when the nucleophile can attack the bond in question in an ideal angle. These angles are 180°

for exo-tet reactions, 109° for exo-trig reaction and 120° for endo-dig reactions.

Applications[edit]


https://en.wikipedia.org/wiki/File:Baldwinregel2.png


In one study, seven-membered rings were constructed in a tandem 5-exo-dig addition reaction / Claisen

rearrangement:[5]

A 6-endo-dig pattern was observed in an allene - alkyne 1,2-addition / Nazarov cyclization tandem

catalysed by a gold compound:[6]

A 5-endo-dig ring closing reaction was part of a synthesis of (+)-Preussin:[7]

Rules for enolates[edit]

Baldwin's rules also apply to aldol cyclizations involving enolates:[8][9]


https://en.wikipedia.org/wiki/File:5-exo-dig-reaction.png

https://en.wikipedia.org/wiki/File:6-endo-dig-reactionR_(1).png

https://en.wikipedia.org/wiki/File:Preussin_cyclization.png


The rules are the following:[10]

Dis/favored ring closures for enolates

enolendo enolexo

type 3 4 5 6 7 3 4 5 6 7

exo-tet ✗ ✗ ✗ ✓ ✓ ✓ ✓ ✓ ✓ ✓

exo-trig ✗ ✗ ✗ ✓ ✓ ✓ ✓ ✓ ✓ ✓

Exceptions[edit]

These rules are based on empirical evidence and numerous "exceptions" are known Examples

include:

cyclisations of cations

reactions involving third-row atoms, such as sulfur

716USE OF STANDARD REACTIONS, LIKE GRIGNARD REACTIONS,


https://en.wikipedia.org/wiki/File:Baldwin_rules_enolates.png


816 ROBINSON ANNULATIONS.

Robinson annulationThe Robinson annulation is a chemical reaction used in organic chemistry for ring formation. It was discovered by Robert Robinson in 1935 as a method to create a six membered ring by forming three new carbon–carbon bonds.[1] The method uses a ketone and a methyl vinyl ketone to form an α,β-unsaturated ketone in a cyclohexane ring by a Michael addition followed by an aldol condensation. This procedure is one of the key methods to form fused ring systems.

Formation of cyclohexenone and derivatives are important in chemistry for their application to the synthesis of many natural products and other interesting organic compounds such as antibiotics and steroids.[2] Specifically, the synthesis of cortisone is completed through the use of the Robinson annulation.[3]

The initial paper on the Robinson annulation was published by William Rapson and Robert Robinson while Rapson studied at Oxford with Professor Robinson. Prior to their work, cyclohexenone syntheses were not derived from the α,β-unsaturated ketone component. Initial approaches coupled the methyl vinyl ketone with a naphthol to give a naphtholoxide, but this procedure was not sufficient to form the desired cyclohexenone. This was attributed to unsuitable conditions of the reaction.[1]

Robinson and Rapson found in 1935 that the interaction between cyclohexanone and α,β-unsaturated ketone afforded the desired cyclohexenone. It remains one of the key methods for the construction of six membered ring compounds. Since it is so widely used, there are many aspects of the reaction that have been investigated such as variations of the substrates and reaction conditions as discussed in the scope and variations section. [4] Robert Robinson won the Nobel Prize for Chemistry in 1947 for his contribution to the study of alkaloids. [5]

Reaction mechanism[edit]

The original procedure of the Robinson annulation begins with the nucleophilic attack of a ketone in a Michael reaction on a vinyl ketone to produce the intermediate Michael adduct. Subsequent aldol type ring closure leads to the keto alcohol, which is then followed by dehydration to produce the annulation product.

In the Michael reaction, the ketone, labeled A in the diagram below, is deprotonated by a base to form an enolate nucleophile which attacks the electron acceptor as we can see in step B. This acceptor is generally an α,β-unsaturated ketone, although aldehydes, acid derivatives and similar compounds can work as well (see scope). The aldol condensation is an intramolecular process that creates the namesake ring of the Robinson annulation product going from step C through to step F.


https://en.wikipedia.org/wiki/File:Reaction_Scheme_for_Robinson_Annulation.svg


Note: in the above reaction scheme, the elimination in the final step to produce the cyclohexenone is incorrectly shown as a bimolecular elimination (E2). The elimination of the hydroxy group occurs by an E1CB mechanism .

In order to avoid a reaction between the original enolate and the cyclohexenone product, the initial Michael adduct, labeled C, is often isolated first and then cyclized to give the desired octalone, labeled F, in a separate step. [6]

Stereochemistry[edit]Studies have been completed on the formation of the hydroxy ketones in the Robinson annulation reaction scheme. The trans compound is favored due to antiperiplanar effects of the final aldol condensation in kinetically controlled reactions. It has also been found though that the cyclization can proceed in synclinal orientation. The figure below shows the three possible stereochemical pathways, assuming a chair transition state. [7]

It has been postulated that the difference in the formation of these transition states and their corresponding products is due to solvent interactions. Scanio found that changing the solvent of the reaction from dioxane to DMSO gives different stereochemistry in step D above. This suggests that the presence of protic or aprotic solvents gives rise to different transition states.[8]

Mechanistic Classification[edit]

Generalised Tandem Michael-aldol reaction

Robinson annulation is one notable example of a wider class of chemical transformations termed Tandem Michael-aldol reactions, that sequentially combine Michael addition and aldol reaction into a single reaction. As is the case with Robinson annulation, Michael addition usually happens first to tether the two reactants together, then aldol


https://en.wikipedia.org/wiki/File:Full_Mechanism.png

https://en.wikipedia.org/wiki/File:Stereochemical_Possibilities_of_Robinson_Annulation.png

https://en.wikipedia.org/wiki/File:22_fig._1.png


reaction proceeds intramolecularly to generate the ring system in the product. Usually five- or six-membered rings are generated.

Asymmetric Robinson annulation[edit]Asymmetric synthesis of Robinson annulation products most often involve the use of a proline catalyst. Studies report the use of L-proline as well as several other chiral amines for use as catalysts during both steps of the Robinson annulation reaction.[13] The advantages of using the optically active proline catalysis is that they are stereoselective with enantiomeric excesses of 60–70%.[14]

Organocatalytic tandem Michael-aldol reaction for the one-pot synthesis of chiral thiochromenes

Wang, et al[15] reported the one-pot synthesis of chiral thiochromenes via such an organocatalytic Robinson annulation.

Applications to synthesis[edit]

The Wieland–Miescher ketone is the Robinson annulation product of 2-methyl-1,3-cyclohexanedione and methyl vinyl ketone. This compound is used in the syntheses of many steroids possessing important biological properties and can be made enantiopure using proline catalysis.[14]

F. Dean Toste and co-workers[16] have used Robinson annulation in the total synthesis of (+)-Fawcettimine, a tetracyclic Lycopodium alkaloid that has potential application to inhibiting the acetylcholine esterase.

916PROTECTION AND DEPROTECTION OF FUNCTIONAL GROUPS

In many preparations of delicate organic compounds, some specific parts of their molecules cannot survive the

required reagents or chemical environments. Then, these parts, or groups, must be protected. For

example, lithium aluminium hydride is a highly reactive but useful reagent capable of

reducing esters to alcohols. It will always react with carbonyl groups, and this cannot be discouraged by any


https://en.wikipedia.org/wiki/File:22_fig._3.png

https://en.wikipedia.org/wiki/File:Example_of_Proline_Catalysts.png

https://en.wikipedia.org/wiki/File:Wieland%E2%80%93Miescher_ketone.svg


means. When a reduction of an ester is required in the presence of a carbonyl, the attack of the hydride on the

carbonyl has to be prevented. For example, the carbonyl is converted into an acetal, which does not react with

hydrides. The acetal is then called a protecting group for the carbonyl. After the step involving the hydride is

complete, the acetal is removed (by reacting it with an aqueous acid), giving back the original carbonyl. This

step is called deprotection

Acetal protection of a ketone during reduction of an ester, vs. reduction to a diol when unprotected.

1016 PROTECTION OF R-OH,

1. PROTECTION OF ALCOHOLS:

1. As ethers: Alcohols are protected as methyl and ethyl ethers.

Application: in carbohydrate chemistry,


https://en.wikipedia.org/wiki/File:Acetal-protection-example.png


These are readily formed but not easily removed so Lewis acid such as BCl3 can be used to

cleave methyl ethers.

Benzyl and trityl( triphenyl methyl) ethers are formed by treatment of alcohol with appropriate halide

in presence of base.. The hydroxyl group can be regenerated by hydrogenolysis or in the case of trityl ether,

by mild acid treatment.

During reactions involving organometalic compounds, alcohols are protected as

Tetrahydropyranyl ethers are formed from the alcohol and 2,3-dihydropyran under acid

catalysis. The alcohol is regenerated with dil. H2SO4.

2. As esters:

During nitration, oxidation and formation of acid chloride, OH groups are protected as esters. Aetates ,

and trifluoro acetates are formed by treating the alcohol with appropriate anhydride or acid chloride in the presence of

base. The alcohol is regenerated by treatment with base.

Protection of alcohols:

1. Acetyl (Ac) – Removed by acid or base (see Acetoxy group).

2. Benzoyl (Bz) – Removed by acid or base, more stable than Ac group.

3. Benzyl (Bn) – Removed by hydrogenolysis. Bn group is widely used in sugar and nucleoside chemistry.

4. β-Methoxyethoxymethyl ether (MEM) – Removed by acid.



5. Dimethoxytrityl, [bis-(4-methoxyphenyl)phenylmethyl] (DMT) – Removed by weak acid. DMT group is widely used for protection of 5'-hydroxy group in nucleosides, particularly in oligonucleotide synthesis.

6. Methoxymethyl ether (MOM) – Removed by acid.

7. Methoxytrityl [(4-methoxyphenyl)diphenylmethyl] (MMT) – Removed by acid and hydrogenolysis.

8. p -Methoxybenzyl ether (PMB) – Removed by acid, hydrogenolysis, or oxidation.

9. Methylthiomethyl ether – Removed by acid.

10. Pivaloyl (Piv) – Removed by acid, base or reductant agents. It is substantially more stable than other acyl protecting groups.

11. Tetrahydropyranyl (THP) – Removed by acid.

12.Tetrahydrofuran (THF) - Removed by acid.

13.Trityl (triphenylmethyl, Tr) – Removed by acid and hydrogenolysis.

14. Silyl ether (most popular ones include trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-iso-propylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers) – Removed by acid or fluoride ion. (such as NaF, TBAF (tetra- n -butylammonium fluoride , HF-Py, or HF-NEt3)). TBDMS and TOM groups are used for protection of 2'-hydroxy function in nucleosides, particularly in oligonucleotide synthesis.

15. Methyl Ethers – Cleavage is by TMSI in dichloromethane or acetonitrile or chloroform. An alternative method to cleave methyl ethers is BBr3 in DCM

16. Ethoxyethyl ethers (EE) – Cleavage more trivial than simple ethers e.g. 1N hydrochloric acid

1116 PROTECTION OF RCHO,

1216 PROTECTION OF R-CO-R,

2. PROTECTION OF ALDEHYDES AND KETONES

Aldehydes and ketones are protected as acetal or ketal derived from ethylene glycol.



When acid sensitive compounds are used the monothio ketal is the better protecting group. It is introduced by

zinc chloride catalysed reaction with mercapto ethanol.

Application :

Deprotection:

The aldehyde group is regenerated by treatment with Raney nickel.

Carbonyl protecting groups[



Protection of carbonyl groups:

1. Acetals and Ketals – Removed by acid. Normally, the cleavage of acyclic acetals is easier than of cyclic acetals.

2. Acylals – Removed by Lewis acids.

3. Dithianes – Removed by metal salts or oxidizing agents.

1316 PROTECTION OF R-NH2

These are protected as trityl ( triphenyl methyl ) group. This derivative is formed by base catalysed

substitution of trityl chloride by the amino group.

It is removed by mild acid treatment.

Application:

It is used in peptide synthesis.

Amines are also protected by acetylation when moderate stability under acidic condition is required.

Amines are protected as benzyloxy carbonyl group by treating with benzyl chloroformate

This is removed by hydrogenolysis

Protection of amines:

1. Carbobenzyloxy (Cbz) group – Removed by hydrogenolysis

2. p -Methoxybenzyl carbonyl (Moz or MeOZ) group – Removed by hydrogenolysis, more labile than Cbz



3. tert -Butyloxycarbonyl (BOC) group (common in solid phase peptide synthesis) – Removed by concentrated strong acid (such as HCl or CF3COOH), or by heating to >80 °C.

4. 9-Fluorenylmethyloxycarbonyl (FMOC) group (Common in solid phase peptide synthesis) – Removed by base, such as piperidine

5. Acetyl (Ac) group is common in oligonucleotide synthesis for protection of N4 in cytosine and N6 in adenine nucleic bases and is removed by treatment with a base, most often, with aqueous or gaseous ammonia or methylamine. Ac is too stable to be readily removed from aliphatic amides.

6. Benzoyl (Bz) group is common in oligonucleotide synthesis for protection of N4 in cytosine and N6 in adenine nucleic bases and is removed by treatment with a base, most often with aqueous or gaseous ammonia or methylamine. Bz is too stable to be readily removed from aliphatic amides.

7. Benzyl (Bn) group – Removed by hydrogenolysis

8. Carbamate group – Removed by acid and mild heating.

9. p -Methoxybenzyl (PMB) – Removed by hydrogenolysis, more labile than benzyl

10. 3,4-Dimethoxybenzyl (DMPM) – Removed by hydrogenolysis, more labile than p-methoxybenzyl

11. p -methoxyphenyl (PMP) group – Removed by ammonium cerium(IV) nitrate (CAN)

12. Tosyl (Ts) group – Removed by concentrated acid (HBr, H2SO4) & strong reducing agents (sodium in liquid ammonia or sodium naphthalenide)

13.Troc (trichloroethyl chloroformate ) group – Removed by Zn insertion in the presence of acetic acid

14. Other Sulfonamides (Nosyl & Nps) groups – Removed by samarium iodide, tributyltin hydride [2]

1416 PROTECTION OF R-COOH

Carboxylic acids are protected as esters. Methyl and ethyl esters are frequently used.

but strongly acidic and basic condition is required for their removal. both benzyl and t-butyl esters are used in

peptide synthesis.

Protection of acid by formation of t- butyl ester

Application:

t-butyl esters are used in peptide synthesis.



De protection:

t- butyl esters can be removed by mild acid treatment.

Protection of acid by formation of trichloroethyl ester

De protection: for β , β , β – trichloro ethyl esters , de protection involves a zinc reduced elimination

reaction.

Protection of carboxylic acids:

1. Methyl esters – Removed by acid or base.

2. Benzyl esters – Removed by hydrogenolysis.

3. tert -Butyl esters – Removed by acid, base and some reductants.

4. Esters of 2,6-disubstituted phenols (e.g. 2,6-dimethylphenol, 2,6-diisopropylphenol, 2,6-di- tert -butylphenol ) – Removed at room temperature by DBU-catalyzed methanolysis under high-pressure conditions.[3]

5. Silyl esters – Removed by acid, base and organometallic reagents.

6. Orthoesters – Removed by mild aqueous acid to form ester, which is removed according to ester properties.



17. Oxazoline – Removed by strong hot acid (pH < 1, T > 100 °C) or alkali (pH > 12, T > 100 °C), but not e.g. LiAlH4, organolithium reagents or Grignard (organomagnesium) reagentsProtecting group

.

1516 USE OF PTC (PHASE-TRANSFER CATALYST)

a phase-transfer catalyst or PTC is acatalyst that facilitates the migration of a reactant from one phase into

anotherphase where reaction occurs. Phase-transfer catalysis is a special form of heterogeneous catalysis.

In nucleophilic substitution reactions, the substrate is insoluble in water and other polar solvents while the nucleophile ( anion) is soluble in water but not in organic solvents.

In such a case, when two reactants are brought together, their concentration in the same phase are too low for the reaction to occur. Therefore we must choose a solvent that dissolves both species.

A catalyst used to carry the nucleophile , from the aqueous phase to the organic phase is called phase transfer catalyst. Such reaction is called phase transfer catalysis.

The various phase transfer catalysts are

1. Quarternary ammonium salts or phosphonium salts.

Consider the reaction RX + NaCN -- RCN + NaX

In the above reaction the CN ion cannot cross the interface between the two phases. Because sodium ion is solvated with water . without sodium CN can not cross the barrier , because it would destroy the electrical neutrality of each phase.

But when quaternary ammonium salt is added , the R4N – or R4P +, ions are poorly solvated in water and prefer organic solvents and three equilibrium are set up.



The Q ions cross the interface and carry the anion with them.

At the beginning, the anion present is CN-. This gets carried into organic phase ( eq -1) where it reacts with RCl to produce the RCN and Cl - . the Cl - then gets carried in to the aqueous phase( eq-2). The eq-3 takes place entirely in the aqueous phase, and allows QCN to be regenerated.

2. Crown ethers and cryptands:Theses are able to surround certain cations. In effect, salt like KCN is converted in to new salt where the anion is more attracted by organic solvents.

3. Pyridyl sulphoxide4. 4. TDA-1 ( tris ( 3,6 dioxaheptyl) amine.



5.



. POLYMER SUPPORT IN SYNTHESIS

Polymers are used as support in organic synthesis. Mainly in poly peptide synthesis. Merrifield adopted this technique for the synthesis of poly peptides and the polymer is called Merrifield resin.

It is the co polymer of styrene and divinyl benzene in which some aromatic rings are chloromethylated and nitrated.

1. t- butyloxy carbonyl derivative of the C- terminal aminoacid ( (CH3) 3COCONHCHRCOOH is heated with the resin in the presence of triethyl amine. A benzyl ester derivative would be formed. ( CH 3) 3COCONHCHRCOOCH3 Ph -resin

2. Then the N- acyl group is removed by acid hydrolysis to yield a product. NH2CHRCOOCH3 Ph -resin

3. This product is coupled with N- acyl amino acid using DCC ( N,N- dicyclohexylcarbodimide) C6H11N:C:C6NH11

By following the procedure the polypeptide chain is extended.

1616 CROWN ETHERS IN ORGANIC SYNTHESIS

UNIT V: NOVEL REAGENTS IN ORGANIC SYNTHESIS:-

1. Synthesis and applications of Organolithium,

2. Organomagnesium,

3. Organozinc

4. Organo Copper

5. Gilman reagents.

6. Modern synthetic methods: metal mediated C-C coupling reactions:



7. Mechanism and synthetic applications of Heck,

8. Stille,

9. Suznki,

10. Negishi,

11. Sonogashira,

12. McMurray,

13. Metathesis

14. Carbonylation reactions

15. . Green reactions and reagents.

Gilman reagent

General structure of a Gilman reagent

A Gilman reagent is a lithium and copper (diorganocopper) reagent compound, R2CuLi, where R is

an alkyl or aryl. These reagents are useful because, unlike related Grignard reagents and organolithium

reagents, they react with organic halides to replace the halide group with an R group (the Corey-House

reaction). Such displacement reactions allow for the synthesis of complex products from simple building

blocks.[1]


https://en.wikipedia.org/wiki/Gilman_reagent#cite_note-1

https://en.wikipedia.org/wiki/Corey%E2%80%93House_synthesis

https://en.wikipedia.org/wiki/Corey%E2%80%93House_synthesis

https://en.wikipedia.org/wiki/Halides

https://en.wikipedia.org/wiki/Halide

https://en.wikipedia.org/wiki/Organic_halide

https://en.wikipedia.org/wiki/Organolithium_reagent

https://en.wikipedia.org/wiki/Organolithium_reagent

https://en.wikipedia.org/wiki/Grignard_reagent

https://en.wikipedia.org/wiki/Aryl

https://en.wikipedia.org/wiki/Alkyl

https://en.wikipedia.org/wiki/Reagent

https://en.wikipedia.org/wiki/Organocopper_compound

https://en.wikipedia.org/wiki/Copper

https://en.wikipedia.org/wiki/Lithium

https://en.wikipedia.org/wiki/File:Gilman_reagent2.gif


Generalized chemical reaction showing Gilman reagent reacting with organic halide to form products

and showing Cu(III) reaction intermediate

These reagents were discovered by Henry Gilman and coworkers.[2] Lithium dimethylcopper (CH3)2CuLi can

be prepared by adding copper(I) iodide to methyllithium in tetrahydrofuran at −78 °C. In the reaction depicted

below,[3] the Gilman reagent is a methylating reagent reacting with an alkyne in a conjugate addition, and the

negative charge is trapped in a nucleophilic acyl substitution with the ester group forming a cyclic enone.

Structure[edit]

Lithium dimethylcuprate exists as a dimer in diethyl ether forming an 8-membered ring. Similarly, lithium

diphenylcuprate crystallizes as a dimeric etherate, [{Li(OEt2)}(CuPh2)]2.[4]

If the Li+ ions is complexed with the crown ether 12-crown-4, the resulting diorganylcuprate anions adopt a

linear coordination geometry at copper.[5]

19Heck reaction



https://en.wikipedia.org/wiki/Coordination_geometry

https://en.wikipedia.org/wiki/12-crown-4

https://en.wikipedia.org/wiki/Crown_ether


https://en.wikipedia.org/wiki/Diethyl_ether

https://en.wikipedia.org/wiki/Dimer_(chemistry)

https://en.wikipedia.org/w/index.php?title=Gilman_reagent&action=edit&section=1

https://en.wikipedia.org/wiki/Enone

https://en.wikipedia.org/wiki/Ester

https://en.wikipedia.org/wiki/Nucleophilic_acyl_substitution

https://en.wikipedia.org/wiki/Conjugate_addition

https://en.wikipedia.org/wiki/Alkyne


https://en.wikipedia.org/wiki/Tetrahydrofuran

https://en.wikipedia.org/wiki/Methyllithium

https://en.wikipedia.org/wiki/Copper(I)_iodide


https://en.wikipedia.org/wiki/Henry_Gilman

https://en.wikipedia.org/wiki/Reaction_intermediate

https://en.wikipedia.org/wiki/Organic_halide

https://en.wikipedia.org/wiki/Chemical_reaction

https://en.wikipedia.org/wiki/File:Gilman_reaction_example.png

https://en.wikipedia.org/wiki/File:Lithium-diphenylcuprate-dietherate-dimer-from-xtal-3D-sticks-C.png

https://en.wikipedia.org/wiki/File:Lithium-diphenylcuprate-etherate-dimer-from-xtal-2D-skeletal.png


The Heck reaction (also called the Mizoroki-Heck reaction)[1] is the chemical reaction of an

unsaturated halide (or triflate) with an alkene in the presence of a base and a palladium catalyst (or

palladium nanomaterial-based catalyst) to form a substituted alkene.

The Heck reaction allows one to do substitution reactions on planar sp2-hybridized carbon atoms.

The Heck reaction

The reaction is performed in the presence of an organopalladium catalyst. The halide (Br, Cl)[4] or triflate is

an aryl, benzyl, or vinyl compound and the alkene contains at least one hydrogen and is often electron-deficient

such as acrylate ester or an acrylonitrile.The catalyst can

be tetrakis(triphenylphosphine)palladium(0), palladium chloride or palladium(II) acetate.

The ligand is triphenylphosphine, PHOX or BINAP. The base is triethylamine, potassium carbonate or sodium

acetate.


The catalytic cycle for the Heck reaction involves a series of transformations around the palladium catalyst.

The palladium(0) compound required in this cycle is generally prepared in situ from a palladium(II) precursor.[13][14]

For instance, palladium(II) acetate is reduced by triphenylphosphine to bis(triphenylphosphine)palladium(0)

(1) and triphenylphosphine is oxidized to triphenylphosphine oxide. Step A is an oxidative addition in which

palladium inserts itself in the aryl to bromide bond. Palladium then forms a π complex with the alkene (3) and

in step B the alkene inserts itself in the palladium - carbon bond in a syn addition step. Then follows a torsional

strain relieving rotation to the trans isomer (not shown) and step C is a beta-hydride elimination step with the

formation of a new palladium - alkene π complex (5). This complex is destroyed in the next step. The

palladium(0) compound is regenerated by reductive elimination of the palladium(II) compound by potassium

carbonate in the final step, D. In the course of the reaction the carbonate is stoichiometrically consumed and


https://en.wikipedia.org/wiki/File:Heck_Reaction_Scheme.png


palladium is truly a catalyst and used in catalytic amounts. A similar palladium cycle but with different scenes

and actors is observed in the Wacker process.

Heck Reaction Mechanism

29 STILLE REACTION


https://en.wikipedia.org/wiki/File:Heck_Reaction_Mechanism.svg


The Stille reaction, or the Migita-Kosugi-Stille coupling, involves the coupling of an organotin

compound (also known as organostannanes) with a variety of organic electrophiles via palladium-catalyzed

coupling reaction.

The first example of a palladium catalyzed coupling of aryl halides with organotin reagents

This process was expanded to the coupling of acyl chlorides with alkyl-tin reagents yielding

87% ketone product (B).[18]

Mechanism

The mechanism of the Stille reaction is one of the most extensively studied pathways for coupling reactions.[12]

[24] The basic catalytic cycle, as seen below, involves an oxidative addition of a halide or pseudohalide (2) to

a palladium catalyst (1), transmetalation of 3 with an organotin reagent (4), and reductive elimination of 5 to

yield the coupled product (7) and the regenerated palladium catalyst (1).[25]


https://en.wikipedia.org/wiki/Stille_reaction#cite_note-name11-25

https://en.wikipedia.org/wiki/Reductive_elimination

https://en.wikipedia.org/wiki/Organotin_chemistry

https://en.wikipedia.org/wiki/Transmetalation

https://en.wikipedia.org/wiki/Palladium_catalyst

https://en.wikipedia.org/wiki/Halide

https://en.wikipedia.org/wiki/Oxidative_addition

https://en.wikipedia.org/wiki/Catalytic_cycle



https://en.wikipedia.org/wiki/Coupling_reactions

https://en.wikipedia.org/wiki/Stille_reaction#cite_note-Kosugi77b-18

https://en.wikipedia.org/wiki/Ketone

https://en.wikipedia.org/wiki/Acyl_chlorides

https://en.wikipedia.org/wiki/Organotin_chemistry

https://en.wikipedia.org/wiki/Palladium-catalyzed_coupling_reactions

https://en.wikipedia.org/wiki/File:History_of_the_Stille_reaction_1.png

https://en.wikipedia.org/wiki/File:History_of_the_Stille_reaction_2.png


39Suznki


https://en.wikipedia.org/wiki/File:Catalytic_cycle_of_the_Stille_reaction.png


The Suzuki reaction is an organic reaction, coupling partners are a boronic acid and

an organohalide catalyzed by a palladium(0) complex. by the name Suzuki–Miyaura reaction and

is also referred to as the Suzuki coupling.

It is widely used to synthesize poly-olefins, styrenes, and substituted biphenyls.

a carbon-carbon single bond is formed by coupling an organoboron species (R1-BY2) with

a halide (R2-X) using a palladium catalyst and a base.


The mechanism of the Suzuki reaction is best viewed from the perspective of the palladium catalyst 1. The first step is the oxidative addition of palladium to the halide 2 to form the organopalladium species 3. Reaction with base gives intermediate 4, which via transmetalation [8] with the boron-ate complex 6 (produced by reaction of the boronic acid 5 with base) forms the organopalladium species 8. Reductive elimination of the desired product 9 restores the original palladium catalyst 1 which completes the catalytic cycle. The Suzuki coupling takes place in the presence of a base and for a long time the role of the base was never fully understood. The base was first believed to form a trialkyl borate (R3B-OR), in the case of a reaction of an trialkylborane (BR3) and alkoxide (−OR); this species could be considered as being more nucleophilic and then more reactive towards the palladium complex present in the transmetalation step.[9][10][11] Duc and coworkers investigated the role of the base in the reaction mechanism for the Suzuki coupling and they found that the base has three roles: Formation of the palladium complex [ArPd(OR)L2], formation of the trialkyl borate and the acceleration of the reductive elimination step by reaction of the alkoxide with the palladium complex. [9]



Oxidative addition[edit]In most cases the oxidative Addition is the rate determining step of the catalytic cycle.[12] During this step, the palladium catalyst is oxidized from palladium(0) to palladium(II). The palladium catalyst 1 is coupled with the alkyl halide 2 to yield an organopalladium complex 3. As seen in the diagram below, the oxidative addition step breaks the carbon-halogenbond where the palladium is now bound to both the halogen and the R group.


https://en.wikipedia.org/wiki/File:Suzuki_Coupling_Full_Mechanism_2.png

https://en.wikipedia.org/wiki/File:Suzuki_Coupling_Oxidative_Addition.png


Oxidative addition proceeds with retention of stereochemistry with vinyl halides, while giving inversion of stereochemistry with allylic and benzylic halides.[13] The oxidative addition initially forms the cis–palladium complex, which rapidly isomerizes to the trans-complex.[14]

The Suzuki Coupling occurs with retention of configuration on the double bonds for both the organoboron reagent or the halide.[15] However, the configuration of that double bond, cisor trans is determined by the cis-to-trans isomerization of the palladium complex in the oxidative addition step where the trans palladium complex is the predominant form. When the organoboron is attached to a double bond and it is coupled to an alkenyl halide the product is a diene as shown below.

Transmetalation[edit]Transmetalation is an organometallic reaction where ligands are transferred from one species to another. In the case of the Suzuki coupling the ligands are transferred from the organoboron species 6 to the palladium(II) complex 4 where the base that was added in the prior step is exchanged with the R1 substituent on the organoboron species to give the new palladium(II) complex 8. The exact mechanism of transmetalation for the Suzuki coupling remains to be discovered. The organoboron compounds do not undergo transmetalation in the absence of base and it is therefore widely believed that the role of the base is to activate the organoboron compound as well as facilitate the formation of R2-Pdll-OtBu from R2-Pdll-X.[12]


https://en.wikipedia.org/wiki/Suzuki_reaction#cite_note-Kurti_and_Czako-12

https://en.wikipedia.org/wiki/Ligands

https://en.wikipedia.org/wiki/Organometallic

https://en.wikipedia.org/w/index.php?title=Suzuki_reaction&action=edit&section=3

https://en.wikipedia.org/wiki/Stereochemistry

https://en.wikipedia.org/wiki/Sterochemistry

https://en.wikipedia.org/wiki/Suzuki_reaction#cite_note-Carey_and_Sundberg-15

https://en.wikipedia.org/wiki/Suzuki_reaction#cite_note-14

https://en.wikipedia.org/wiki/Isomerization

https://en.wikipedia.org/wiki/Cis_isomer


https://en.wikipedia.org/wiki/Benzylic

https://en.wikipedia.org/wiki/Allylic

https://en.wikipedia.org/wiki/Walden_inversion

https://en.wikipedia.org/wiki/Vinyl_halide

https://en.wikipedia.org/wiki/Stereochemistry

https://en.wikipedia.org/wiki/File:CisTrans_Palladium_Complex.png

https://en.wikipedia.org/wiki/File:Suzuki_Double_Bond_Three.png


Reductive elimination[The final step is the reductive elimination step where the palladium(II) complex (8) eliminates the product (9) and regenerates the palladium(0) catalyst(1). Using deuterium labelling, Ridgway et al. have shown the reductive elimination proceeds with retention of stereochemistry.[16]

Synthetic applications[edit]The Suzuki coupling has been frequently used in syntheses of complex compounds. [23][24] The Suzuki coupling has been used on a citronellal derivative for the synthesis of caparratriene, a natural product that is highly active against leukemia:[25]


https://en.wikipedia.org/wiki/Suzuki_reaction#cite_note-Vyvyan1999-25

https://en.wikipedia.org/w/index.php?title=Caparratriene&action=edit&redlink=1

https://en.wikipedia.org/wiki/Citronellal



https://en.wikipedia.org/w/index.php?title=Suzuki_reaction&action=edit&section=8


https://en.wikipedia.org/wiki/Deuterium_labelling

https://en.wikipedia.org/wiki/File:Suzuki_Coupling_Transmetalation.png

https://en.wikipedia.org/wiki/File:Suzuki_Coupling_Reductive_Elimination.png

https://en.wikipedia.org/wiki/File:Suzuki_coupling_capparatriene.tif


49Negishi COUPLING

The Negishi coupling is transition metal catalyzed cross-coupling reaction. The reaction couples organic

halides or triflates with organozinc compounds, forming carbon-carbon bonds (c-c) in the process.

A palladium (0) species is generally utilized as the metal catalyst, though nickel is sometimes used:

The leaving group X is usually chloride, bromide, or iodide, but triflate and acetyloxy groups are

feasible as well. X = Cl usually leads to slow reactions.

The organic residue R = alkenyl, aryl, allyl, alkynyl or propargyl.

The halide X' in the organozinc compound can be chloride, bromine or iodine and the organic

residue R1 is alkenyl, aryl, allyl, alkyl benzyl, homoallyl, and homopropargyl.

The metal M in the catalyst is nickel or palladium

The ligand L in the catalyst can be triphenylphosphine, dppe, BINAP or chiraphos


The reaction mechanism is thought to proceed via a standard Pd catalyzed cross-coupling pathway, starting

with a Pd(0) species, which is oxidized to Pd(II) in an oxidative addition step involving the organohalide

species.[5] This step proceeds with aryl, vinyl, alkynyl, and acyl halides, acetates, or triflates, with



substrates following standard oxidative addition relative rates (I>OTf>Br>>Cl).[6]

The actual mechanism of oxidative addition is unresolved, though there are two likely pathways. One

pathway is thought to proceed via an SN2 like mechanism resulting in inverted stereochemistry. The other

pathway proceeds via concerted addition and retains stereochemistry.

Though the additions are cis- the Pd(II) complex rapidly isomerizes to the trans- complex.[7]


https://en.wikipedia.org/wiki/File:Scheme2Catcycle.png

https://en.wikipedia.org/wiki/File:Scheme3oxadd.png

https://en.wikipedia.org/wiki/File:Scheme4cistrans.png


Next, the transmetalation step occurs where the organozinc reagent exchanges its organic substituent with

the halide in the Pd(II) complex, generating the trans- Pd(II) complex and a zinc halide salt. The

organozinc substrate can be aryl, vinyl, allyl, benzyl, homoallyl, or homopropargyl.[5] Transmetalation is

usually rate limiting and a complete mechanistic understanding of this step has not yet been reached

though several studies have shed light on this process. It was recently determined that alkylzinc species

must go on to form a higher-order zincate species prior to transmetalation whereas arylzinc species do not.[8] ZnXR and ZnR2 can both be used as reactive reagents, and Zn is known to prefer four coordinate

complexes, which means solvent coordinated Zn complexes, such as ZnXR(solvent) 2 cannot be ruled out a

priori. [9] Studies indicate competing equilibriums exist between cis- and trans- bis alkyl organopalladium

complexes, but that the only productive intermediate is the cis complex.[10] [11]

The last step in the catalytic pathway of the Negishi coupling is reductive elimination, which is thought to

proceed via a three coordinate transition state, yielding the coupled organic product and regenerating the

Pd(0) catalyst. For this step to occur, the aforementioned cis- alky organopalladium complex must be

formed.[12]


https://en.wikipedia.org/wiki/File:Scheme5redelim.png

https://en.wikipedia.org/wiki/File:Scheme6redelim2.png


59SONOGASHIRA REACTION

The Sonogashira reaction is a cross-coupling reaction used in organic synthesis to form carbon–carbon

bonds. It employs a palladium catalyst to form a carbon–carbon bond between a terminal alkyne and

an aryl or vinyl halide.[1]

Mechanism[edit]

Catalytic cycle for the Sonogashira reaction[5]

The palladium cycle[edit]

An inactive palladium PdII catalyst is activated by a reduction to the Pd0 compound. The active palladium catalyst is the 14 electron compound Pd0L2, complex A, which reacts with

the aryl or vinyl halide in an oxidative addition to produce a PdII intermediate, complex B. This step is believed to be the rate-limiting step of the reaction.


https://en.wikipedia.org/wiki/Rate-limiting_step

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Complex B reacts in a transmetallation with the copper acetylide, complex F, which is produced in the copper cycle, to give complex C, expelling the copper halide, complex G.

Both organic ligands are trans oriented and convert to cis in a trans-cis isomerization to produce complex D.

In the final step, complex D undergoes reductive elimination to produce the alkyne, with regeneration of the palladium catalyst.

The copper cycle[edit]

It is suggested that the presence of base results in the formation of a pi-alkyne complex, complex E, which makes the terminal proton on the alkyne more acidic, leading to the formation of the copper acetylide, compound F.

Compound F continues to react with the palladium intermediate B, with regeneration of the copper halide, G.

Mechanistic studies suggest that these catalytic cycles represent the preferred reaction pathway, however there is debate about the exact identity of some intermediates, which may depend upon reaction conditions. For example, it has been shown that monoligated Pd0(PR3) complexes (B) can be formed when dealing with bulky phosphanes and have been suggested as possible catalytic species in coupling reactions. [7] In contrast, some results point to the formation of anionic palladium species, which would be the real catalysts instead of the coordinatively unsaturated Pd0L2. Generally seen in the presence of anions and halides, it is known that Pd0(PPh3)2 does not exist in solution when generated in the presence of halide anions because they coordinate the Pd0 center to form anionic species of the type [L2Pd0Cl]− which can participate in cross-coupling reactions.[8]

Catalysts[edit]

Typically, two catalysts are needed for this reaction: a zerovalent palladium complex and a halide salt of copper(I). Examples of such palladium catalysts include compounds in which palladium is ligated to phosphines (Pd(PPh3)4). A common derivative is Pd(PPh3)2Cl2, but bidentate ligand catalysts, such as Pd(dppe)Cl, Pd(dppp)Cl2, and Pd(dppf)Cl2 have also been used.[6] The drawback to such catalysts is the need for high loadings of palladium (up to 5 mol %), along with a larger amount of a copper co-catalyst.[6] PdII is often employed as a pre-catalyst since it exhibits greater stability than Pd0 over an extended period of time and can be stored under normal laboratory conditions for months.[9] The Pd II catalyst is reduced to Pd0 in the reaction mixture by either an amine, a phosphine ligand, or a reactant, allowing the reaction to proceed.[10] The oxidation of triphenylphosphine to triphenylphosphine oxide can also lead to the formation of Pd0 in situ when catalysts such as bis(triphenylphosphine)palladium(II) chloride are used.

Copper(I) salts, such as copper iodide, react with the terminal alkyne and produce a copper(I) acetylide, which acts as an activated species for the coupling reactions. Cu(I) is a co-catalyst in the reaction, and is used to increase the rate of the reaction.[5

69 MCMURRY REACTION


https://en.wikipedia.org/wiki/Sonogashira_coupling#cite_note-Recent_Advances-5

https://en.wikipedia.org/wiki/Bis(triphenylphosphine)palladium(II)_chloride

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https://en.wikipedia.org/wiki/Phosphine

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https://en.wikipedia.org/wiki/Dppf

https://en.wikipedia.org/wiki/Dppp

https://en.wikipedia.org/wiki/Dppe

https://en.wikipedia.org/wiki/Ligand

https://en.wikipedia.org/wiki/Bidentate

https://en.wikipedia.org/wiki/Ligand

https://en.wikipedia.org/wiki/Zerovalent


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https://en.wikipedia.org/wiki/Trans-cis_isomerization

https://en.wikipedia.org/wiki/Acetylide

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The McMurry reaction is an organic reaction in which two ketone or aldehyde groups are coupled to

an alkene using titanium chloride compound such as titanium(III) chloride and a reducing agent.[1] The reaction

is named after its co-discoverer, John E. McMurry. The McMurry reaction originally involved the use of a

mixture TiCl3 and LiAlH4, which produces the active reagent(s). Related species have been developed

involving the combination of TiCl3 or TiCl4 with various other reducing agents, including potassium, zinc,

and magnesium.[2][3] This reaction is related to the Pinacol coupling reaction which also proceeds by reductive

coupling of carbonyl compounds.



This reductive coupling can be viewed as involving two steps. First is the formation of a pinacolate (1,2-diolate) complex, a step which is equivalent to the pinacol coupling reaction. The second step is the deoxygenation of the pinacolate which yields the alkene, this second step exploits the oxophilicity of titanium.

A proposed mechanism when TiCl4and Zn(Cu) are used for the coupling of benzophenone, as proposed in a reference. [4] Note

that the mechanism may vary when different conditions are used.

Several mechanisms have been discussed for this reaction.[4] Low-valent titanium species induce coupling of the carbonyls by single electron transfer to the carbonyl groups. The required low-valent titanium species are generated via reduction, usually with zinc powder. This reaction is often performed in THF because it solubilizes intermediate complexes, facilitates the electron transfer steps, and is not reduced under the reaction conditions.


https://en.wikipedia.org/wiki/File:McMurry-Mechanism-Updated.png


The nature of low-valent titanium species formed is varied as the products formed by reduction of the precursor titanium halide complex will naturally depend upon both the solvent (most commonly THF or DME) and the reducing agent employed: typically, lithium aluminum hydride,zinc-copper couple, zinc dust, magnesium-mercury amalgam, magnesium, or alkali metals.[5] Bogdanovic and Bolte identified the nature and mode of action of the active species in some classical McMurry systems,[6] and an overview of proposed reaction mechanisms has been published.[4] It is of note that titanium dioxide is not generally a product of the coupling reaction. Although it is true that titanium dioxide is usually the eventual fate of titanium used in these reactions, it is generally formed upon the aqueous workup of the reaction mixture.[5]

79Metathesis

Olefin metathesis

Olefin metathesis is an organic reaction that entails the redistribution of fragments of alkenes (olefins) by the scission and regeneration of carbon-carbon double bonds.[1][2] Because of the relative simplicity of olefin metathesis, it often creates fewer undesired by-products and hazardous wastes than alternative organic reactions. For their elucidation of the reaction mechanism and their discovery of a variety of highly active catalysts, Yves Chauvin, Robert H. Grubbs, and Richard R. Schrock were collectively awarded the 2005 Nobel Prize in Chemistry.[3]

Catalysts[edit]

The reaction requires metal catalysts. Most commercially important processes employ heterogeneous catalysts, but well-defined homogeneous catalysts are also active. The heterogeneous catalysts are often prepared by in-situ activation of a metal halide using organoaluminium or organotin compounds, e.g. combining WCl6–EtOH–EtAlCl2. A typical catalyst support is alumina. Commercial catalysts are often based on molybdenum and ruthenium. Well-defined organometallic compounds have mainly been investigated for small scale reactions or academic research. The homogeneous catalysts are often classified as Schrock catalysts and Grubbs' catalysts. Schrock catalysts feature molybdenum(VI)- and tungsten(VI)-based centers supported by alkoxide and imido ligands.[4]


https://en.wikipedia.org/wiki/File:Metathesis.png

https://en.wikipedia.org/wiki/File:SchrockMetathesisCatalysts.png


Grubbs' catalysts, on the other hand, are ruthenium(II) carbenoid complexes. [5] Many variations of Grubbs' catalysts are known. Some have been modified with a chelatingisopropoxystyrene ligand to form the related Hoveyda–Grubbs catalyst.

Types of olefin metathesis processes[edit]

Some important classes of olefin metathesis include:

Cross metathesis (CM) Ring-opening metathesis (ROM) Ring-closing metathesis (RCM) Ring-opening metathesis polymerisation (ROMP) Acyclic diene metathesis (ADMET) Ethenolysis


Hérisson and Chauvin first proposed the widely accepted mechanism of transition metal alkene metathesis. [12] The direct [2+2] cycloaddition of two alkenes is formally symmetry forbidden and thus has a high activation energy. The Chauvin mechanism involves the [2+2] cycloaddition of an alkene double bond to a transition metal alkylidene to form a metallacyclobutane intermediate. The metallacyclobutane produced can then cycloeliminate to give either the original species or a new alkene and alkylidene. Interaction with the d-orbitals on the metal catalyst lowers the activation energy enough that the reaction can proceed rapidly at modest temperatures.


https://en.wikipedia.org/wiki/File:GrubbsMetathesisCatalysts.png


Like most chemical reactions, the metathesis pathway is driven by a thermodynamic imperative; that is, the final products are determined by the energetics of the possible products, with a distribution of products proportional to the exponential of their respective energy values. In olefin metathesis, however, this is especially relevant since all the possible products have similar energy values (all of them contain an olefin). Because of this the product mixture can be tuned by reaction conditions, such as gas pressure and substrate concentration. In some cases a given reaction can be run in either direction to near completion.

Cross metathesis and Ring-closing metathesis are often driven by the entropically favored evolution of ethylene or propylene, which are both gases. Because of this CM and RCM reactions often use alpha-olefins. The reverse reaction of CM of two alpha-olefins, ethenolysis, can be favored but requires high pressures of ethylene to increase ethylene concentration in solution. The reverse reaction of RCM, ring-opening metathesis, can likewise be favored by a large excess of an alpha-olefin, often styrene. Ring opening metathesis usually involves a strained alkene (often a norbornene) and the release of ring strain drives the reaction. Ring-closing metathesis,


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conversely, usually involves the formation of a five- or six-membered ring, which is energetically favorable; although these reactions tend to also evolve ethylene, as previously discussed. RCM has been used to close larger macrocycles, in which case the reaction may be kinetically controlled by running the reaction at extreme dilutions.[13] The same substrates that undergo RCM can undergo acyclic diene metathesis, with ADMET favored at high concentrations. The Thorpe–Ingold effect may also be exploited to improve both reaction rates and product selectivity.

Cross-metathesis is synthetically equivalent to (and has replaced) a procedure of ozonolysis of an alkene to two ketone fragments followed by the reaction of one of them with a Wittig reagent.

89Carbonylation reactions

CARBONYLATION

Carbonylation refers to reactions that introduce carbon monoxide into organic and inorganic substrates.

Carbon monoxide is abundantly available and conveniently reactive, so it is widely used as a reactant in

industrial chemistry. The term carbonylation also refers to oxidation of protein side chains.

Organic chemistry[edit]

Several industrially useful organic chemicals are prepared by carbonylations, which can be highly selective

reactions. Carbonylations produce organic carbonyls, i.e., compounds that contain the C=O functional

group such as aldehydes, carboxylic acids, and esters.[1][2] Carbonylations are the basis of two main types of

reactions, hydroformylation and Reppe Chemistry.

Hydroformylation[edit]

Hydroformylation entails the addition of both carbon monoxide and hydrogen to unsaturated organic

compounds, usually alkenes. The usual products are aldehydes:

RCH=CH2 + H2 + CO → RCH2CH2CHO

The reaction requires metal catalysts that bind the CO, the H2, and the alkene, allowing these substrates to

combine within its coordination sphere.

Decarbonylation[edit]

Many organic carbonyls undergo decarbonylation. A common transformation involves the conversion of

aldehydes to alkanes, usually catalyzed by metal complexes:[3]

RCHO → RH + CO



Reppe chemistry[edit]

Reppe Chemistry, named after Walter Reppe, entails addition of carbon monoxide and an acidic

hydrogen donor to the organic substrate. Large-scale applications of this type of carbonylation are

the Monsanto and Cativa processes, which convert methanol to acetic acid. Acetic anhydride is

prepared by a related carbonylation of methyl acetate.[4] In the related hydrocarboxylation and

hydroesterification, alkenes and alkynes are the substrates. This method is used in industry to

produce propionic acid from ethylene:

RCH=CH2 + H2O + CO → RCH2CH2CO2H

These reactions require metal catalysts, which bind and activate the CO. [5] In the industrial

synthesis of ibuprofen, a benzylic alcohol is converted to the corresponding carboxylic acid via a

Pd-catalyzed carbonylation:[1]

ArCH(CH3)OH + CO → ArCH(CH3)CO2H

Acrylic acid was once prepared by the hydrocarboxylation of acetylene but is now produced by

the oxidation of propene. The hydrocarboxylation of alkenes is a prominent example of Reppe

chemistry. In industry, propanoic acid is mainly produced by the hydrocarboxylation

of ethylene using nickel carbonyl as the catalyst:[1]

H2C=CH2 + H2O + CO → CH3CH2CO2H

Hydroesterification is like hydrocarboxylation, but uses alcohols instead of water.[6]

Other reactions[edit]

The Koch reaction (also the related Koch-Haaf reactions) entail the addition of CO to

unsaturated compounds in the presence of strong acids such as sulfuric acid. This method

is less frequently used in industry as are the metal-catalyzed reactions, described above.

The industrial synthesis of glycolic acid is achieved in this way:[7]

CH2O + CO + H2O → HOCH2CO2H

The conversion of isobutene to pivalic acid is also illustrative:

(CH3)2C=CH2 + H2O + CO → (CH3)3CCO2H



Unrelated to the Koch reaction, dimethyl carbonate and dimethyl oxalate are also

produced in industry from carbon monoxide.[1] These reactions require oxidants:

2 CH3OH + 1/2 O2 + CO → (CH3O)2CO + H2O

Alkyl, benzyl, vinyl, aryl, and allyl halides can also be carbonylated in the

presence carbon monoxide and suitable catalysts such as manganese, iron,

or nickel powders.[8]

.99 Green reactions and reagents


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