12
560 Organic Chemistry Mircea IovuCarboxyl and other functional
groups containing compounds 561
12
CARBOXYL AND OTHER FUNCTIONAL GROUPS CONTAINING COMPOUNDS
Substituting one or more hydrogen atoms of an acid with a
functional group (-Cl,-OH, C=O), mixed functional compounds results
having the carboxyl group properties as well as properties of the
second functional group, but also new properties, according to the
mixed functional group.
The carbon atom that bonds the functional group is labelled with
(, (, (, (...
12.1. HALOGENATED ACIDS
12.1.1. PREPARATION
1) (-Halogenated acids XE "(-Halogenated acids" may be obtained
by direct halogenation of acids, under photochemical, thermal or
catalytic conditions. For example, acetic acid yields a mixture of
mono-, di- and trichloracetic acids, depending on the reagents
molar ratio:
Monochloroacetic Dicloroacetic Trichloroacetic
acid acid
acid
Direct halogenation of the acetic acid homologs leads to a
mixture of (,(,(-halogenated acids. In order to obtain only
(-halogenated acids, the acid must be transformed into its acid
halide, using PCl3, for example, followed by direct halogenation of
the halide, which occurs in ( position (10.2.4.3.).
Monochloroacetic acid XE "Monochloroacetic acid" may also be
obtained by heating trichlorethene with 70% sulfuric acid:
(-Halogenated acids may be transformed into other (-substituted
derivatives; for example, reaction with an aqueous basic solution
leads to (-hydroxy acids, XE "(-hydroxy acids," while reaction with
amines leads to (-aminoacids.
2) (-Halogenated acids XE "(-Halogenated acids" are obtained by
addition of halogenated acids to (,(-unsaturated acids. The halogen
atom adds to the farthest carbon atom toward the carboxyl group,
for example:
Addition of halogens to unsaturated carboxylic acids yields
dihalogenated acids.
3) Aromatic halogenated acids XE "Aromatic halogenated acids"
are obtained by electrophilic substitution reactions. For example,
bromination of benzoic acid occurs at high temperature, in presence
of an iron catalyst and leads to m-bromobenzoic acid, because
carboxyl group is a second order substituent. o- and p Halobenzoic
acids are obtained by oxidation of their corresponding halogenated
toluenes.
12.1.2. PROPERTIES
Most of the halogenated acids are solid compounds, with low
melting points. Short-chain terms are water soluble.
Presence of a halogen atom in the molecule of a carboxylic acid
determines increase of the acidity constant (table 12.1) due to the
electron withdrawing effect (-I), which facilitates proton release
(4.4.2.).
TABLE 12.1
Acidity constants of some chlorinated acids
AcidFormulaKa (10-5
Acetic acidCH3 -COOH 1.82
Cloroacetic acidClCH2 -COOH155
Dicloroacetic acidCl2CH -COOH 5100
Tricloroacetic acidCl3C-COOH 120000
Propionic acidCH3 -CH2 -COOH 1.34
(-Cloropropionic acidCH3 -CHCl COOH147
(-Cloropropionic acidClCH2 -CH2 -COOH 8.2
The acidity constant value increases with the increase in the
number of halogen atoms in the molecule and decreases with the
increase in the distance toward the carboxyl group.
The halogen presence facilitates decarboxylation of the acid. In
turn, the carboxyl group makes the carbon halogen bond more labile,
especially in ( position. Thus, (-halogenated acids easily undergo
hydrolysis and transform into (-hydroxy acids:
Lactic acid XE "Lactic acid" The carboxylate ions of
-halogenated acids undergo an elimination-decarboxylation reaction.
It is required that the carboxylate ion and the bromine atom to be
anticoplanare.
12.1.3. MAIN MEMBERS
Monocloroacetic acid, ClCH2-COOH, which is the most important
halogenated acid, is a hygroscopic, cristalline compound (mp 61
0C). It serves to synthesis of medicines like blues, indigo and
2,4-diclorophenoxyacetic acid, used as herbicide.
12.2. HYDROXY ACIDS
Depending on the radical nature that bonds the two functional
groups, namely carboxy and hydroxy groups, we may distinguish
hydroxy-acids XE "hydroxy-acids" and phenoxy-acids XE
"phenoxy-acids" .
According to the number of the functional groups, we can
distinguish polyhydroxy-monocarboxylic acids and
monohydroxypolycarboxylic acids.
12.2.1. PREPARATION
1) (-Hydroxy acids XE "(-Hydroxy acids" may be obtained by
hydrolysis of (-halogenated acids or aldehyde cyanohydrines: XE
"aldehyde cyanohydrines\:"
For example:
Benzaldehyde
Mandelonitril XE "Mandelonitril" Mandelic acid XE "Mandelic
acid" Treatment of aminoacids with nitrous acid:
Aminoacetic acid XE "Aminoacetic acid"
Glycolic acid XE "Glycolic acid" (Glycocol XE "Glycocol" )
2) (-hydroxy acids XE "(-hydroxy acids" may be obtained by
addition of hydrogen cyanide to epoxides and hydrolysis of the
resulted nitriles.
Moreover, (-hydroxy acids can be obtained by (-halogenated
esters condensation with ketones or aldehydes, in presence of zinc
or magnesium. Reformatsky reaction XE "Reformatsky reaction" :
50 75%
If using aldehydes (R = H), linear hydroxy acids result.
Aldehydes are more reactive than ketones. The halogenated esters
reactivity decreases as follows: I > Br > Cl.
3) ( and (-hydroxy acids XE "( and (-hydroxy acids" may be
obtained by ( and (-halogenated acids hydrolysis.
12.2.2. PROPERTIES
Most of the hydroxy acids are cristalline compounds, very
soluble in water. They can not undergo distillation at normal
pressure, because they decompose. They are stronger acids than the
unsubstituted acids having the same number of carbon atoms.
They undergo reactions of the carboxyl and hydroxyl groups.
However, water elimination depends on the mutual position of the
two functional groups in the molecule.
(-Hydroxy acids eliminate water intermolecularly, by simply
heating, yieldig cyclic esters, called lactides XE "lactides" .
Heating with mineral acids leads to elimination of formic acid
XE "formic acid" .
(-Hydroxy acids dehydrate intramolecularly by heating to yield
(,(-unsaturated acids XE "(,(-unsaturated acids" .
( or (-hydroxy acids also eliminates easily water
intramolecularly yielding cyclic esters called lactones XE
"lactones" .
-Hydroxyvaleric acid XE "-Hydroyivaleric acid"
-Valerolactone XE "-Valerolactone"
The reaction is acid catalysed and occurs similar to
esterification, for example:
-valerolactone XE "-valerolactone" Lactones are hydrolysed, like
esters, by aqueous basic solutions, while under acid conditions (
or (-lactones may form, eventually.
Lots of lactones occur naturally. For example, vitamine C XE
"vitamine C" (19.3.5.) is a (-lactone.
12.2.3. MAIN MEMBERS
Glycolic acid XE "Glycolic acid" (hydroxyacetic acid XE
"hydroxyacetic acid" ) CH2OH-COOH, occurs in unripe grapes, vine
leafs and other plants. It also occurs at monochloroacetic acid
hydrolysis or by reaction between CH2O and CO, in presence of a
mineral acid (H2SO4 or HCl) at 300 - 900 atm and 160 200 0C. In
presence of HF, the reaction takes place at 20 60 0C. It is a
cristalline solid (mp 80 0C), soluble in water, alcohol and ether.
It serves to adhesives industry, biodegradable polymers industry,
detergents and metals pickling industry.
Lactic acid XE "Lactic acid" ((-hydroxypropanoic acid XE
"(-hydroxypropanoic acid" ), CH3-CH(OH)-COOH, has am asymmetrical
carbon atom and, thus, occurs as two optical isomers (dextrogir,
levogir) and a racemic. The racemic lactic acid XE "racemic lactic
acid" occurs in sour milk, as a result of fermentation of milk
sugar, namely lactose XE "lactose" , by enzymes produced by
Bacillus lactis acidi XE "Bacillus lactis acidi" bacteria. Lactic
acid is mainly obtained by synthesis as secondary product of
acrylonitrile fabrication process (discovered by Wislicenus, 1863)
starting from acetaldehyde XE "acetaldehyde" and hydrogen cyanide
XE "hydrogen cyanide" .
CH3CHO + HCN CH3CHOHCN
CH3CHOHCN + 2 H2O + HCl CH3CHOHCOOH + NH4Cl
It serves to pharmaceutical, food and textile industry as well
as in therapeutics.
Malic acid XE "Malic acid" (monohydroxysuccinic acid XE
"monohydroxysuccinic acid" ) HOOC-*CH(OH)-CH2-COOH occurs in unripe
fruits, mainly in apples and grapes. It has an asymmetrical carbon
atom, therefore it exhibits optical isomerism XE "optical
isomerism" .
It may be obtained by water addition to fumaric and maleic acid,
at temperature of 2000C or at lower temperatures, but in presence
of sodium or sulfuric acid.
Fumaric acid hydration XE "Fumaric acid hydration" (but not
maleic acid XE "maleic acid" ) can also be catalysed by an enzyme,
namely fumarase XE "fumarase" , when only L-malic acid XE "L-malic
acid" occurs (13.6). This is one example of enzymes
stereospecificity XE "enzymes stereospecificity" .
Tartric acid XE "Tartric acid" , (2,3-dihydroxysuccinic acid XE
"2,3-dihydroxysuccinic acid" ) HOOC-*CHOH-*CHOH-COOH, is a
dihydroxydicarboxylic acid, which occurs in fruits as free acid or
salts. Large quantities deposit from wine, as potassium acid salt,
which is slightly soluble in diluted alcohol.
It may also be obtained by oxidation of maleic or fumaric acids
with potassium permanganate, when two isomers, a racemic and an
inactive form (which can not be split in enantiomers) result. It
serves as acidifying agent in food industry.
Citric acid XE "Citric acid" is a monohydro- xytricarboxylic
acid that occurs in lemons (up to 10%), oranges, raspberry,
cramberries and other fruits as free acid or potassium acid salt.
It forms by sugar oxidative degradation in animal cells.
It is industrially obtained by citric fermentation of glucose
and zaccharose, using bacteria (Citromyces XE "Citromyces" ) or
moulds (Penicillium sau Aspergillus).
80 g of acid result from fermentation of 100 g of glucose after
9 days. Today, sugar-beet molasses is used for fermentation. The
annual world turnover is more than 100000 t.
It may be obtained by reaction between 1,3-dichloroacetone XE
"1,3-dichloroacetone" and hydrogen cyanide, followed by hydrolysis
of the resulted cyanhydrine. The chlorinated hydroxyacid is treated
with potassium cyanide and, finally, the resulted nitrile is
hydrolysed to yield the acid.
Citric acid crystallises with a water molecule that is lost by
heating at 800C; the anhydrous acid melts at 1530C. It is water and
alcohol soluble.
Citric acid serves to preparation of pharmaceuticals, limonades
and candies, as well as in cosmetic industry, to obtain acidic
astringent lotions and to monitor the shampoos pH.
12.3. PROSTAGLANDINS
Prostaglandins XE "Prostaglandins" are cyclic, unsaturated,
polyoxygenated, 20-carbon hydroxycarboxylic acids, which derive
from the hypothetic acid (prostanoic
acid) having the following conformation:
The chain bearing the carboxyl group is, conventionally, (
oriented, being placed under the cyclopentae ring plane. All
prostaglandins have an oxygen at C9 (as hydroxyl or carbonyl), a
hydroxyl at C15 (in () and a double bond at C13 ((13).
More classes of prostanoic containing compounds can be
distinguished and they are denoted by letters A, B, C etc. There
are known 6 primary prostaglandins and 8 secondary prostaglandins
which derive from prostaglandin E.
Prostaglandins A and B have, for example, a OH group at C19.
Prostaglandins differ by position and number of the double bonds,
for example, (13-trans, (13-trans-(5-cis,
(13-trans-(5-cis-(17-cis.
Prostaglandins result by biosynthesis starting from fatty acids,
which occur in membranes phospholipids as esters with glycerol or
cholesterol.
The first step of prostaglandins formation is release of the
fatty acids, which is catalysed by a phospholipidase.
SHAPE \* MERGEFORMAT
The arachidonic acid XE "arachidonic acid" is oxidised by
molecular oxygen (in presence of cyclooxygenase XE "cyclooxygenase"
) to an endoperoxide, which yields various prostaglandins, as shown
above.
Leukotriene A is an intermediate in the biosynthesis of
leukotriene C. Transformation of A in C involves addition of
glutathione (a tripeptide, 15.1.5) to the oxirane. A results from
the attack of the nucleophilic sulfur atom of the glutathione.
Leukotriene C is known as a slow-reacting substance involved in the
anaphylactic shock.
Thromboxane instantenously clots the blood.
Prostaglandins occur in accessory sex organs, namely in ovaries,
and in small quantities in almost all tissues. They are extracted
from animal prostate glands and a Carribean coral named Plexaura
homomalla XE "Plexaura homomalla" , which contains 2-3%
prostaglandins.
Prostaglandins act similar to hormones on various biological
functions; for instance they inhibit aggregation of platelets,
lower blood pressure, stimulate uterine contractions, relax or
contract bronchial muscle etc.
12.4. CARBOXY PHENOLS
12.4.1. PREPARATION
Carboxy phenols XE "Carboxy phenols" may be devided in two
groups depending on whether the carboxyl group is bonded or not to
the aromatic ring.
Carboxy phenols (with the carboxyl directly bonded to the
aromatic ring) can be obtained starting from hydroxyl containing
compounds or carboxyl containing compounds.
p-aminobenzoic acid XE "p-aminobenzoic acid" p-hydroxybenzoic
acid XE "hydroxybenzoic acid" 1) Reaction of aromatic aminoacids XE
"aromatic aminoacids" with nitrous acid XE "nitrous acid" yields as
intermediate a diazonium salt XE "diazonium salt" , which is
decomposed by water to the corresponding carboxy phenol.:
2) The alkaline fusion of aromatic sulfonic acids XE "alkaline
fusion of aromatic sulfonic acids" , such as sulfobenzoic acid,
occurs with replacement of the sulfone group with the hydroxyl
group (sodium salt, 8.4.1. ).
3) Reaction between anhydrous alkaline phenoxides and carbon
dioxide (Kolbe-Schmitt reaction XE "Kolbe-Schmitt reaction"
8.4.4.3.).
Among the arylaliphatic acids bearing the phenol hydroxyl group,
we can mention the o-hydroxycynnamic acids, which occur as two
cis-trans isomers (10.6.)
12.4.2. PROPERTIES
Carboxy phenols are cristalline compounds, slightly soluble in
cold water, but soluble in hot water, alcohol and ether. They
exhibit both carboxylic acid and phenols properties.
The hydroxyl group exhibits a -IS and +ES effect and influence
the ionisation constant value, which depends on the mutual position
of the hydroxyl and carboxyl groups (table 12.2.). The hydroxyl
group in orto position exhibits a stronger effect, due to formation
of a kelate which enhance p-( conjugation of the carboxyl group and
facilitates the proton release (the acidity constant is higher than
benzoic acid constant).
TABLE 12.2
The acidity constants of some monohydroxybenzoic
acidsAcidCondensed structural formulaKa x 10-5
o-hydroxybenzoic XE "o-hydroxybenzoic" 10.6
m-hydroxybenzoic XE "m-hydroxybenzoic" 8.7
p-hydroxybenzoic XE "p-hydroxybenzoic" 2.85
Benzoic XE "Benzoic" 6.86
The hydroxyl group in para position exhibits a strong electron
donor effect which makes difficult the proton release and thus the
acidity constant is lower than benzoic acid constant.
Hydroxybenzoic acids form salts like C6H4(OH)(COONa) in reaction
with alkaline carbonates, while with alkaline hydroxides they form
salts like C6H4(ONa)(COONa).
Carboxy phenols decompose at heating loosing carbon dioxide and
yielding phenols.
Reaction with alcohols, at heating, in presence of mineral
acids, leads to esterification of the carboxyl group.
Treatment with acetic anhydride leads to acylation of benzene
ring. Thus, is obtained, for example, acetylsalicylic acid.
Reaction between carboxy phenols and alkyl halides, in presence
of sodium hydroxide, leads to compounds bearing both ether and
ester groups.
Carboxy acids give the characteristic coloured solutions of
phenols when mixed with ferric chloride.
12.4.3. MAIN MEMBERS
The most important isomer of the hydroxybenzoic acid is the
o-hydroxybenzoic or salicylic acid XE "salicylic acid" .
Salicylic acid occurs naturally either as free acid or as methyl
ester in some ether oils. It is industrially obtained by
Kolbe-Schmitt synthesis XE "Kolbe-Schmitt synthesis" (8.4.4.3.). It
is a cristalline compound (mp 1570C) that undergoes
sublimation.
At slow heating, it reacts by itself yielding salicylsalicylic
acid XE "salicylsalicylic acid" , which undergoes decarboxylation
yielding phenyl salicylate XE "phenyl salicylate" , named salol XE
"salol" .
Salicylsalicylic acid
Salol
By heating, it undergoes further decarboxylation to yield
phenol.
If phosgen is used, the esterification of the carboxyl group in
a molecule with the hydroxyl group of another molecule takes place
yieding disalicyde XE "disalicyde" , which serves for therapeutic
purposes.
Salicylic acid is acetylated with acetic anhydride in presence
of various solvents (.
90%
The resulted acetylsalicylic acid XE "acetylsalicylic acid" is a
softer acid (Ka = 3.3 x 10-4) than salicylic acid (Ka = 10.6 x
10-5) due to the hydroxyl group protection, which allows its use as
medicine (aspirine).
Treatment of methyl salicylate with ammonia yields salicylamide
XE "salicylamide" (2-hydroxybenzamide).
It serves for the same purposes as acetylsalicylic acid, bu it
undergoes hydrolysis slower in organism and it is eliminated almost
entirely unchanged.
Unlike phenols and benzoic acid, salicylic acid may be
hydrogenated even using nascent hydrogen, resulted from reaction
between sodium and alcohol, without high pressure or catalysts. The
incomplete hydrogenation leads to a cyclic (-keto acid, which is
unstable in presence of water.
Reaction under alcohol conditions
Reaction in aqueous Sodium pimelate XE "Sodium pimelate"
mediumThe aromatic ring of the salicylic acid is activated by
the OH group, which directs the electrophilic substitution to orto
and para positions and is deactivated by the COOH group, which
directs the same substitution to meta positions (which coincides
with o- and p- toward the OH group). That is why, the electrophilic
attack can occur in positions 3 and 5 and it frequently occurs in
5, where there is no steric hindrance, such as for sulfonation,
nitration and couplings with diazoic comounds.
Salicylic acid is used for various synthesis and, due to its
antiseptic properties, it serves as food and beverages preserving
agent. In therapeutics, it serves to treat rheumatism as sodium
salt. The salt is also used as painkiller and antipyretic.
Acetylsalicyl phenyl ester XE "Acetylsalicyl phenyl ester" ,
salol XE "salol" , is used as antiseptic.
Galic acid XE "Galic acid" , (3,4,5-trihydroxybenzoic acid XE
"3,4,5-trihydroxybenzoic acid" ) C6H2 (OH)3 COOH, occurs freely in
tea, oak bark and in gall doughnuts of the oak leafs. It occurs
mainly in tanins, from which it is obtained by acid or enzyme
hydrolysis.
It is slightly soluble in cold water, but soluble in hot water,
ether and alcohol. It crystallise with a water molecule, which is
lost at 1200C, while at 2220C it melts decomposing to carbon
dioxide and pirogallol.
Galic acid is a strong reducing agent; it reduces the Fehling
reagent under alkaline conditions and absorbs oxygen from air
(getting coloured in dark yellow).
Reaction with iron (III) chloride yields a dark blue solid,
which dissolves in excess of iron (III) chloride and forms a green
solution.
Galic acid may undergo a condensation reaction (similar to
salicylic acid) yielding an ester such as m-galoylgalic acid XE
"m-galoylgalic acid" , which has similar properties to natural
tanins.
Galic acid serves to preparation of pirogallol XE "pirogallol" ,
some inks and dyes. It is used as antiseptic and haemostatic.
Tanins XE "Tanins" are substances that yield, in reaction with
proteins and alkaloids, insoluble and unputrescible solids; for
this reason, they serve to tanning leathers. They form colloidal
solutions with water, with astringent taste; reaction with ferric
chloride yields a black or green colour that indicate presence of
phenols.
Natural tanins were devided in hydrolysible tanins XE
"hydrolysible tanins" and condensed tanins XE "condensed tanins"
.
The hydrolysible tanins are esters of galic acid with
monosacharides such as glucose. The condensed tanins are not esters
with sugars; C-C bonds occur between the component rings. That is
why, they decompose by melting with alkaline hydroxides. Dry
heating yields pirocatequine.
Tanins occur mainly in oak bark, birch, chestnut and pine spruce
bark as well as in some exotic trees; they are extracted by
treatment with water and concentration of the solutions till a
syrup consistency or dryness..
12.5. CARBOXY ALDEHYDES AND KETONES
Carboxy aldehydes and ketones XE "Carboxy aldehydes and ketones"
contain in their molecules a carboxyl and a carbonyl group. Their
properties depend on the two groups positions. The carbonyl group
position toward the carboxyl group is indicated by Greek leters: (,
(, (, ...
12.5.1. PREPARATION
The preparation methods depend on the positions of the carboxyl
and the carbonyl groups
There is only one (-aldo acid, namely the glyoxylic or
formylformic acid, HCO-COOH, which may be obtained by oxidation of
ethyleneglycol (8.2.4.) or by hydrolysis of dichloroacetic acid XE
"dichloroacetic acid" , at 1400C.
(-Keto acids may be prepared as follows:
1) Oxidation of (-hydroxy acids XE "Oxidation of (-hydroxy
acids" R-CHOH-COOH R-CO-COOH
2) Hydrolysis of keto nitriles XE "Hydrolysis of keto nitriles"
, which in turn can be obtained starting from their corresponding
acid chlorides or other parthways:
-Carbonyl acids are unstable and often can not be isolated. For
example, formylacetic acid easily decomposes:
HCO-CH2-COOH HCO-CH3 + CO2
Decarboxylation of -keto acids XE "Decarboxylation of -keto
acids" occurs in mild conditions. Formation of an intramolecular
bond allows a cyclic transition state which transforms into an
enol. The tautomer equilibrium leads to the most stable
product.
(-Keto acids esters are more stable. For example, ethyl
acetoacetate XE "ethyl acetoacetate" may be obtained by
condensation of ethyl acetat XE "ethyl acetat" e, in presence of
sodium ethoxide (when sodium acetylacetic ester results in 75%).
The resulted ethanol is removed by distillation.
This condensation, called Claisen condensation XE "Claisen
condensation" , occurs similar to aldol condensation, at the (
carbon toward the carbonyl group.
Synthesis of the acetylacetic acids esters may also take place
in presence of haloesters or haloketones. Using (-haloesters,
(-keto acids may be obtained:
The most important (-keto acid is levulic acid XE "levulic acid"
((-ketovaleric acid) which may be prepared from fructose XE
"fructose" (levulose XE "levulose" ) by boiling with concentrated
hydrogen chloride following a mechanism that has not been
completely elucidated yet:
12.5.2. PROPERTIES
(-Keto acids XE "(-Keto acids" undergo all the characteristic
reactions of carbonyl and carboxyl groups. They are more stable
than (-keto acids; their decomposition requires heating with
diluted sulfuric acid.
Heating with concentrated sulfuric acid leads to decarbonylation
of the carboxyl group XE "decarbonylation of the carboxyl group" ,
which was evidenced using labelled carbon atoms.
(-keto acids esters have particular properties beside those
arising from presence of the carboxyl and carbonyl groups. For
example, ethyl acetoacetate XE "ethyl acetoacetate"
CH3-CO-CH2-COOC2H5 behaves as an ester, yielding an acid under
hydrolysis, and as a ketone, undergoing reactions with
hydroxylamine XE "hydroxylamine" , phenylhydrazine XE
"phenylhydrazine" or hydrogen cyanide XE "hydrogen cyanide" to form
oxime XE "oxime" , phenylhydrasone XE "phenylhydrasone" and a
cyanohydrine XE "cyanohydrine" , respectively. Besides these, ethyl
acetoacetate XE "ethyl acetoacetate" undergoes reactions that are
not proper to esters and ketones. Thus, they react with iron(III)
chloride XE "iron(III) chloride" yielding a red colour like phenols
and decolour bromine water. Theses properties may be explained by
the two equilibrium tautomers of ethyl acetoacetate, as ketone and
enol.
92.5%
7.5%
When hydroxylamine XE "hydroxylamine" is added to the reaction
mixture, the keto form transforms into oxime XE "oxime" and the
equilibrium shifts toward this form, thus the entire ester
transforms into oxime. When bromine is used, the enol form is able
to react and the equilibrium shits toward replacement of the
reacted enol.
The reversible transformations of the two forms (keto and enol)
are very fast, therefore their separation is very difficult.
However, the ketone form was separated (de L. Knorr XE "Knorr"
1911) by crystallisation from an ether solution, at -78oC, while
the enol form was obtained from sodium acetylacetic ester,
suspended in burning oil, at -78oC, by treatment with hydrogen
chloride. In normal conditions, ethyl acetoacetate occurs as 7,5%
enol.
Treatment of acetylacetic ester (weakly acidic) with sodium
ethoxide yield a nucleophilic bidentate anion:
This may be alkylated to the methylene carbon using alkyl
halides:
Oxygen alkylation is achieved using diazomethane XE
"diazomethane" or ethyl ortho formate.
Fragmentation of (-keto esters XE "Fragmentation of (-keto
esters" . Heated with diluted acids or bases, (-keto esters undergo
hydrolysis yielding the corresponding alcohol and (-keto acid,
which is very unstable and suffers dercarboxylation. For example,
acetone can be obtained from acetylacetic ester. That is why, the
reaction is named keto fragmentation XE "keto fragmentation" .
Treatment of ethyl acetoacetate with concentrated alkalis leads
to a fragmentation, which corresponds to the reversible formation
reaction (Claisen condensation XE "Claisen condensation" ) starting
from ethyl acetate, yielding two acetic acid molecule (as salt).
That is why, the reaction is named acid fragmentaion XE "acid
fragmentaion" .
If instead of concentrated alkalis sodium ethoxide in ethanol is
used (catalyst), ethyl acetate forms as a result of the
fragmentation.
The homologs and derivatives of ethyl acetoacetate undergo
similar fragmentations.
(-Keto acids XE "(-Keto acids" undergo decarboxylation slower
than (-keto acids due to the longer distance between the carbonyl
and the carboxyl group, therefore they influence less to each
other.
Levulic acid undergo an intramolecular dehydration, yielding an
unsaturated lactone.
12.5.3. MAIN MEMBERS
Ethyl acetoacetate XE "Ethyl acetoacetate" (acetylacetic ester
XE "acetylacetic ester" ) CH3 -CO-CH2 -COOC2H5, is obtained by
condensation of ethyl acetate, in presence of sodium ethoxide. It
is a liquid (bp 181 0C) with a flower like odour. It serves to
various synthesis, especially for fenasone and aminofenasone
synthesis.
Pyruvic acid XE "Pyruvic acid" ((-ketopropanoic acid XE
"((-ketopropanoic acid" ) is a liquid (bp 13.60C) which decomposes
at its boiling point(. During storage, it undergoes a slow aldol
addition, which is faster in presence of hydrogen chloride,
yielding a ketolactone:
The presence of the carbonyl group makes the ionisation constant
of pyruvic acid higher than the propanoic acid constant.
Pyruvic acid may be obtained by distillation of tartaric acid XE
"tartaric acid" , in presence of strong dehydrating agents:
Stable enol
It may be also prepared by oxidation of lactic acid; reduction
with zinc and hydrogen chloride yields back the lactic acid. It is
a metabolit of the human organism and results from alcohol
fermentation (19.5.2.4.). It serves as intermediate in various
synthesis.
PROBLEMS
12.1. Give the IUPAC names for each of the following compounds:
ClCH2-COOH; Cl3C-COOH; CH2OH-COOH; CH3-CHOH-COOH; CH2OH-CH2-COOH;
CH2OH-CHOH-COOH; HOOC-CHCl-COOH; HOOC-CHOH-CH2-COOH;
HOOC-CHOH-CHOH-COOH; CH3-CO-COOH.
12.2. Write the structural formula of the following compounds
trivially named: glycol acid, lactic acid, malic acid, tartric
acid, citric acid, arachidonic acid, salycilic acid, salol, galic
acid, pyruvic acid, (-valerolactone and ethyl acetoacetate.
12.3. Which are the products of the keto and acid fragmentation
of ethyl 2-methyl-acetoacetate ?
12.4. Draw the ideal 1H NMR spectra of ethyl acetoacetate for
the keto and the enol form.
12.5. Identify the arachidonic acid skeleton within the
structural formulas of leukotriene A and prostaglandine 2.
12.6. Suggest a synthetic pathway of p-bromophenylacetic
acid.
12.7. Which is the transformation reaction of benzyl into a
hydroxy acid?
12.8. Which is the propanol transformation pathway into
2-hydroxybutanoic acid?
12.9. (8Z,11Z,14Z)-8,11,14-Icosatrienoic acid is converted by an
enzyme called soybean lipoxidase and molecular oxygen into
(8Z,11Z,13E)-15-hydroperoxy-8,11,13-icosatrienoic acid. Which are
the structural formulas for the two acids?
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( In the IVth cenrtuy, B.C. Hypocrat used to prescribe sage peal
extracts to treat fever; the main component of the extract was
salicylic acid. In 1835, the German chemist K. J. Lving discovered
salicylic acid in Spirea Ulmaria.
Salicylic acid was acetylated for the first time by Gerhardt, in
1853, using acetyl chloride. In the same period, it was used for
the first time by Felix Hofmann to treat his father rheumatism.
Since 1899 Bayer company offered it as commercial product named
aspirine (a from acetyl, spir from Spirea and in from the general
end given to vegetal originating compounds).
Annually, there is a world consumption of 45.000 tones.
( In biological media, decarboxylation of pyruvic acid to
ethanol and CO2 is a step of the alcohol fermentation. It occurs by
the aid of an enzyme called: pyruvate decarboxylase XE "pyruvate
decarboxylase" .
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