Esters
Esters
Esters
Chemo-selectivity In Reactions
Esterification And Their Preparation
(Esters)
By
Ahmed Ragab Ismail
Tarek Mohamed farghly
Ayman Abd El-Maksoud
To
Department of Chemistry
Faculty of science,
Al-Azhar University. Asyut Branch
Prof :Doctor By
Abu-Bakr Abd El-Hady
1
Indroduction
ester, any of a class of organic compounds that react with water to
produce alcohols and organic or inorganic acids. Esters derived from carboxylic
acids are the most common. The term ester was introduced in the first half of the
19th century by German chemist Leopold Gmelin.
Carboxylic acid esters, formula RCOOR′ (R and R′ are any organic combining
groups), are commonly prepared by reaction of carboxylic acids and alcohols in the
presence of hydrochloric acid or sulfuric acid, a process called esterification. In the
reaction the hydroxyl group (OH) of the carboxylic acid is replaced by the alkoxy
group (R′O) of the alcohol
2
the soaps can become sticky or dissolve, causing damage to the painting.
Carboxylic acid esters of low molecular weight are colourless, volatile liquids with
pleasant odours, slightly soluble in water. Many are responsible for the fragrance
and flavour of flowers and fruits; for example, isopentyl acetate is present
in bananas, methyl salicylate in wintergreen, and ethyl butyrate in pineapples.
These and other volatile esters with characteristic odours are used
in synthetic flavours, perfumes, and cosmetics. Certain volatile esters are used as
solvents for lacquers, paints, and varnishes; for this purpose, large quantities of
ethyl acetate and butyl acetate are commercially produced. Waxes secreted by
animals and plants are esters formed from long-chain carboxylic acids and long-
chain alcohols. Fats and oils are esters of long-chain carboxylic acids and glycerol.
Liquid esters of low volatility serve as softening agents for resins and plastics.
Esters also include many industrially important polymers. Polymethyl methacrylate
is a glass substitute sold under the names Lucite and Plexiglas; polyethylene
terephthalate is used as a film (Mylar) and as textile fibres sold as Terylene, Fortrel,
and Dacron.
Esters are also formed from alcohols and such inorganic acids as sulfuric,
phosphoric, and nitric acids. Nitrate esters (e.g., glyceryl trinitrate, or nitroglycerin)
are explosive. Phosphate esters are biologically important (nucleic acids belong to
this group) and are used widely in industry as solvents, plasticizers, flame
retardants, gasoline and oil additives, and insecticides.
Esters of sulfuric and sulfurous acids are used in the manufacture of dyes and
pharmaceuticals. Dimethyl sulfate, the best-known ester of sulfuric acid, is a
dangerous poison.
3
List of ester odorants
Many esters have distinctive fruit-like odors, and many occur naturally in the essential oils of plants. This
has also led to their common use in artificial flavorings and fragrances which aim to mimic those odors
Ethyl acetate nail polish remover, model paint, model airplane glue, pears
4
Ethyl hexanoate pineapple, waxy-green banana
4
Ethyl cinnamate cinnamon
5
Linalyl acetate lavender, sage
6
Nonyl caprylate orange
7
The esters and their smells
As you know, there are synthetic substances that are added to food to increase its smell and
taste. These are what we know as artificial essences. Well, within this type of substances
there is a chemical species that stands out for the variety of pleasant odors that they present,
so they are widely used as flavors, I speak of the esters.
In the following image we can observe how with the simple substitution of the R' group or the
quantity of carbon atoms in the acid group the aroma of the resulting compound changes.
8
Preparation
Esterification is the general name for a chemical reaction in which two reactants
(typically an alcohol and an acid) form an ester as the reaction product. Esters are
common in organic chemistry and biological materials, and often have a pleasant
characteristic, fruity odor. This leads to their extensive use in
the fragrance and flavor industry. Ester bonds are also found in many polymers.
9
(4) Transesterification
Transesterification, which involves changing one ester into another one, is widely
practiced:
RCO2R' + CH3OH → RCO2CH3 + R'OH
Like the hydrolysation, transesterification is catalysed by acids and bases. The
reaction is widely used for degrading triglycerides, e.g. in the production of fatty
acid esters and alcohols. Poly(ethylene terephthalate) is produced by the
transesterification of dimethyl terephthalate and ethylene glycol:[14]
10
Chemoselectivity between amines and alcohols
Because of the much higher reactivity of the amino group and higher thermodynamic stability of
amides vs. esters, the selective O-acylation of hydroxy groups is not a trivial task. As a result, the
common strategy for the selective acylation of hydroxy groups in the presence of an amino group
4
involves the protection of the amino group by its conversion into the corresponding ester or carbamate,
followed by the acylation of the hydroxy functionality and final selective N-deprotection. Nevertheless,
several methods for direct acylation of aliphatic hydroxy groups in the presence of an unprotected
alkyl amino function were suggested. A few attempts for select- ive O-acylation that were undertaken use
a highly acidic media to ensure the protonation of aliphatic amino groups. This approach is similar to the
5
acid catalyzed esterification of amino acids that proceed with a complete chemoselectivity but in the
presence of a large excess of the alcohol. However, as in the case of amino alcohols even the presence
of a substantial excess of acid does not fully prevent acylation of amino groups. The most convenient O-
acylation of amino alcohols (eqn. (1)) involves the reaction of a two-fold excess of acyl chlorides with
hydrochlorides of amino alcohols in an acetonitrile–benzene mixture. Isolated yields were from low to
moderate (up to 58%)
6
and highly solvent dependent.
(1)
For compounds possessing aromatic amino groups obtaining a selective O-acylation is simpler,
especially in the case of very unreactive hydroxy substituted aromatic amines. In the example seen in
7
eqn. (2), hydroxy substituted aminoquinones can be selectively O-acylated with basic catalysis owing
both to very low nucleophilicity of aminoquinones and easy deprotonation of aromatic hydroxy groups.
11
11
Similarly, due to the ease of deprotonation, the selective acylation of acidic phenols and formation of
corresponding active esters can be carried out in the presence of aromatic amino groups. The reaction
8
(eqn. (3)) proceeds through carbodiimide couplings and provides only low to moderate yields. These low
yields however may also be attributed to difficulties in isolation of active esters possessing a primary or
secondary amino group rather than the lack of intrinsic chemoselectivity.
(3)
A high selectivity towards the acylation of phenolic hydroxy groups in amino phenols was achieved using
9
N-methyl-N- nitroso-p-nitrobenzamide (eqn. (4)). Acylation of amino phenols with p-nitrobenzoyl chloride
produced exclusively products of N-acylation.
(4)
Similarly to eqn. (4), selective O-acylation of p-aminophenol can also be achieved using bipyridyl esters as
10
acyl transfer reagents in the presence of a large excess of CsF (eqn. (5)). This method also provides a
substantial selectivity towards the acylation of aliphatic primary hydroxy group vs. aromatic amino
groups, although with a substantial amount of diacyl- ation product.
12
12
While no explanations of this dependence of the chemo- selectivity (eqns. (4) and (5)) have been provided,
it should be mentioned that both N-methyl-N-nitroso and bipyridynyl leaving groups are potentially capable
of concerted proton transfer through a 6-centered non-planar transition state shown on eqn. (6). Such a
11
concerted proton transfer could
(7)
13
13
Chemoselectivity between thiols and alcohols
Selective O- or S-acylation of mercapto alcohols is synthetically important but there are not many examples
in the literature. The most common example of selective O-acylation involves acid catalyzed esterifications
of thiol-substituted carboxylic acids. In the presence of a large excess of an alcohol, all these reactions,
like the one shown on eqn. (8), proceed with complete chemoselectivity, thus producing corresponding
13
mercapto esters without any S-acylation products.
(8)
Acid catalyzed esterification could also be used with equimolar amounts of alcohols or mercapto alcohols.
Chemo- selective O-acetylation of mercaptoethanol with moderate (65%) yield was achieved in the
14
esterification with hetero- geneous yttria–zirconia-based Lewis acid catalyst. In general, proton and
Lewis acid catalyzed thioesterifications are disfavored by lower equilibrium constants between carboxylic
15
acids and thioesters as well as a higher energy transition state. Alternatively, selective S-acylation of
16
mercaptoethanol was obtained in carbodiimide coupling without acylation catalysts (eqn. (9)). As
indicated by the relative rates of thioesterific- ation, the origin of chemoselectivity in this reaction is the
acidity of the mercapto group resulting in the attack of the
thiolate anion on the intermediate symmetric anhydride.
(9)
Lipase catalyzed selective acylation of linear ω-mercapto alcohols produced the corresponding ω-
mercapto esters with high chemoselectivity through a transesterification of the ethyl ester used as a
17
solvent (eqn. (10)). At the same time, mercapto alcohols with secondary thiol and hydroxy groups were
found to possess extremely low transesterification rates. The chemoselectivity of these reactions is
probably enzyme-specific as lipase catalyzed thioesterifications have also been
14 (10)
14
Chemoselectivity between phenols and alcohols
The most commonly used acylation reagents, like acyl halides and anhydrides, often provide comparable
rates for the acyl- ation of phenols and alcohols. Several acylation methods for the acylation of vanilinol
19
were checked. . Reactions of symmetric and mixed anhydrides and acyl chlorides in the presence of
pyridine or triethylamine/DMAP were found to be non-selective. In reactions of a carboxylic
acid/carbodiimide/ DMAP system with polyfunctional substrates, there are also rather similar rates for the
19
formation of alkyl and aryl esters. Low selectivity of the acylation was also observed in reactions with
20
acetic anhydride with Cu(OTf )2 as a catalyst.
(11)
15
15
Lewis acid catalyzed esterification provided excellent selectivity between alcohols and phenols. Hafnium
chloride was found to be a highly efficient reaction for the selective esterification of the aliphatic hydroxy
22
group of p-(3-hydroxy- propyl)phenol with more than 99 : 1 selectivity. The high attributed to the
6
generally lower basicity and nucleophilicity of the oxygen atom in phenols (Kb of phenol is about 10
times
lower than that of methanol). This is true for reactions involving neutral molecules like protic and Lewis
acid-catalyzed
16
16
esterifications while the presence of basic catalysis can radically alter the chemosel ectivity.
A complete selectivity between alcohol and phenol function- alities was obtained in the catalyzed
transesterification of alkenyl esters shown in eqn. (13). This method necessitates the use of a large excess
of alkenyl esters but provides essentially neutral reaction conditions. This method tolerates a variety of
23
sensitive functional groups, making it highly useful for acylation of highly functionalized molecules. The
24
suggested mechanism involves the formation of the four-membered chelate complex of distannoxane
catalyst with an alcohol followed by the acyl transfer on the three-coordinated oxygen atom through the
transition state seen of eqn. (13). Although no reasons for the observed complete chemoselectivity were
suggested, it is probably related to the geometry of the transition state. Both the stability of the four-
membered chelate complex and the reactivity of the remaining lone pair on the three-coordinated oxygen
atom should be higher for alcohols than for phenols.
(13)
Complete ionization of both hydroxy functions with BuLi followed by the acylation of the resulting salt with
1 eq. of enol ester shown in eqn. (14) was used for discrimination between aliphatic and aromatic
25
hydroxyls.
(14)
17
17
Carboxylic acids possessing strong electron withdrawing groups like ROC(O), (EtO) P(O), or RSO in the α
were found to be capable of efficient and chemoselective acylations of primary, secondary, and position
tertiary alcohols in the absence of any acylation catalysts. This reaction (eqn. (15))
proceeds through ketene intermediates and shows a high select- ivity towards the acylation of aliphatic
hydroxy groups. Highly acidic phenols showed comparable reaction rates to alcohols but their acylation
16
can be suppressed using catalytic amounts of acids.
Ester function can be prepared indirectly through the alkyl- ation of carboxylates. This alkylation usually
does not interfere with unprotected phenolic hydroxyls and can be used for the selective preparation of
alkyl esters. Alkylation of carboxylic acids through the Mitsunobu reaction (eqn. (16)) was found to be a
19
selective method for the preparation of polyphenolic esters.
(16)
18
18
Similarly, the alkylation of phenolic carboxylic acid with ethyl, isopropyl, and benzyl iodides using a CsF–
Celite catalyst was reported to proceed with high chemoselectivity giving the corresponding esters. This
method requires two-fold excesses of alkyl iodides and was not proven on more complicated alkyl
26
halides.
Enzymes were employed for the chemoselective discrimin- ation between phenolic and alcoholic hydroxyl
groups present in the same molecule. Selective acylation of 2- and 4-hydroxy- methylphenols was achieved
27
with Aspergillus niger lipase. A number of experiments with highly selective acylation of
28
hydroxymethylated phenolic compounds with vinyl acetate were conducted with lipases. In general, both
29 30
lipases and esterases (eqn. (17)) selectively catalyze acylation of aliphatic hydroxy groups.
(17)
Because of the substantially higher reactivity of aryl esters towards nucleophilic reagents, a selective
31
hydrolysis of polyesters could be applied for the selective preparation of aliphatic esters . Despite
extensive use in the past, the use of this method is not necessary as the difference in electronic properties
between alcohols and phenols is large enough to enable selective acylation.
19
19
Selective acylation of phenols
The large difference in the acidity between alcohols and phenols can be used for the selective acylation of phenols
in the presence of alcohols. In the presence of even weak bases the deproton- ation of the phenolic moiety tends to
be the main factor controlling the chemoselectivity of acylation. Reactions in the presence of bases produce
phenolate anions that can be efficiently and selectively acylated without touching the less acidic hydroxy groups
32
(eqn. (18)). This selectivity, however completely disappears in the presence of commonly used acylation
19
catalysts like DMAP and pyridine.
(18)
The addition of triethylamine was found to reverse the chemoselectivity in the acylation of phenolic alcohols by 3-
33
acyl-1,3-thiazolidine-2-thiones (eqn. (19)).
(19)
20
20
Acylation of phenols with carboxylic acid–carbodiimide systems (except carboxylic acids that are capable of
reacting through ketene intermediates) in the absence of acylation catalysts were found to proceed much faster
16
than the acylation of alcohols. Reaction rates rapidly increased with the acidity of the phenol. Even less acidic
phenols like p-methoxyphenol were acylated easily. The selective acylation of highly acidic phenols through
carbodiimide couplings was achieved in the presence of multiple aliphatic hydroxy groups (eqn. (20)) resulting in
34
the formation of the corresponding active esters
.
(20)
Selective acylation of a phenolic hydroxyl in the presence of a secondary hydroxy group was obtained by solid state
35
acetylation using acetylimidazole.
Monoacylation of polyols
Monoacylation of symmetric diols
Selective monoacylation of symmetric diols is substantially more complicated and the formation of a statistical
mixture of
mono- and diacylated products is frequent. For primary and secondary 1,2- and 1,3-diols selective monoacylation
36
with symmetric anhydrides is possible (eqn. (21)). The reaction proceeds through the formation of chelate metal
complexes with Lewis acid catalysts. Cerium, dysprosium, and ytterbium chlorides were checked with the latter
generally providing better results. The use of an excess of the symmetric anhydride is essential for the
reaction. The proposed mechanism of the acylation involves the coordination of both diol and symmetric anhydride
with a lanthanide cation followed by the intra- molecular transfer of the acyl group. The high chemoselectivity of
monoacylation is due to the higher stability of bidentate complexes of lanthanide catalysts with diols vs.
21
monodentate complexes of monoesters. This mechanism
37
is also supported by substantially higher acylation
rates of C2 symmetric diols vs. analogous meso diols.
21
(21)
Similarly high chemoselectivity was obtained in the acylation of symmetric 1,3 and 1,4-diols with cerium(iii)
38
chloride. Monoesterification of diols possessing a larger distance between hydroxy groups requires a different
approach. Because of the substantial difference in hydrophilicity between diols and their monoesters,
monoacylation of 1,n-diols, ranging from 1,2-ethanediol to 1,16-hexadecanediol was achieved by trans-
esterification in ester/alkane mixtures catalyzed by strongly acidic ion-exchange resins (eqn. (22)). At 70–80%
conversions a good selectivity 20 : 1–15 : 1 was achieved after the optimization of ester–alkane ratio. The
selectivity decreases at higher conver- sions and different from the optimal ester–alkane ratio. The suggested
mechanism of the selectivity toward monoacylation is based on the formation of a strongly acidic aqueous layer on
the surface of ion-exchange resin beads. The preferential acylation of 1,n-diols is explained by their higher solubility
39
in the water layer where the transesterification proceeds.
(22)
A similar mechanism of selectivity was also proposed for the selective monoesterification of different 1,n-diols with
an ester–alkane mixture catalyzed by silica supported Ce(SO4)2 and NaHSO4 shown in eqn. (23). The selectivity is
in the 20 : 1 to 10 : 1 range for C2 to C16 diols at 75–90% conversions, and was particularly high when isopropyl
acetate was used as an acyl donor. Secondary diols can also be monoformylated by the
(23)
22
22
reaction with ethyl formate. Similar but lower selectivity was observed for the catalysis with unsupported
40
NaHSO4.
Another, but probably related, approach to monoesters of α,ω-diols involves the acylation of preadsorbed diols on
41
silica gel with acetyl chloride in refluxing cyclohexane (eqn. (24)). This method is remarkable because of the
practically quantitative chemoselectivity for primary diols up to 1,16- hexadecanediol. Secondary and benzylic diols
produced much lower selectivity.
(24
23
23
However, the steric bulk of acylating reagents does not always provide a substantially higher discrimination of primary vs.
33
secondary hydroxy groups. Pivaloyl chlorides and other derivatives of bulky pivalic acid were found to give a distri-
bution of acylation products on 1,5-hexanediol that is very similar to a simple acetylation. It is probable that direct acid-
catalyzed esterifications show more sensitivity towards the steric hindrance than the acylation of alcohols by other
carboxylic acid derivatives.
Probably the most efficient and practical method for the selective acylation of primary hydroxy groups involves the use of
46
acyl chlorides in combination with bulky amines such as diisopropylethylamine or 2,4,6-collidine (eqn. (26)). The use of
2,4,6-collidine was found to provide more consistent results—the chemoselectivity was beyond 94% for all tested acyl
chlorides (with the exception of Cl3COCl).
.
(26)
Distannoxane catalyzed transesterification of alkenyl esters was also found to possess a very high sensitivity towards steric
differences in alcohols (eqn. (27)). Reported examples showed almost complete absence of acylation of secondary hydroxy
47
groups in diols. The observed high sensitivity of the reaction towards the steric bulk of alcohols is probably related to the
reaction mechanism that involves the formation of the highly sterically crowded transition state shown in eqn. (13). This
method requires the use of a large excess of alkenyl ester.(27)
Reaction of methylene acetals of unsymmetric 1,3-diols with acetyl chloride proceeds with complete chemoselectivity from the less
48
hindered side as shown in eqn. (28). Acetals of unsymmetric 1,2-diols react with substantially lower (3 : 1) selectivity that can be
only marginally improved through the use of bulky pivaloyl chloride instead of AcCl.
(28)
24
24
An opposite chemoselectivity in the monoacylation of unsymmetric diols was achieved by the preliminary conversion of
diols into dibutylstannylene acetals followed by the acylation (eqn. (29)). The reason for the unusual chemoselectivity is the
reversibility of the opening of dibutylstannylene acetals on the first stage of the reaction. As a result, the major product a fter
the first stage is the secondary ester which is more thermo- dynamically stable as the most bulky chlorodibutyltin group is
attached to the less hindered primary position. The initial selectivity is in the range of 2–4 : 1 but the subsequent silylation or
49
acylation of the resultant stannyl monoesters provided much higher chemoselectivities.
(29)
Chemoselectivity can also be achieved through the Lewis acid assisted formation of chelate complexes with a neigh- boring group.
Only small (1–3 mol%) quantities of ytterbium triflate catalysts produce selective acylation of Taxol derivatives with acetic
50
anhydride giving >95% selectivity as shown in eqn. (30). Other lanthanide Lewis acids provided similarly high chemoselectivity
but substantially slower reaction rates. The reaction mechanism and chemoselectivity are probably common to other lanthanide
36,37
Lewis acid catalyzed acyl- ations and involve the formation of a cyclic transition state.
25
25
51
Formation of chelate complexes with copper salts was also used for the selective esterification of polyhydroxyanthra- quinones.
A substantial chemoselectivity between meta/para vs. ortho hydroxy groups in carbonyl-substituted polyphenols was achieved in
52
an enzymatic transesterification (eqn. (31)).
(31)
The difference in steric environment for secondary hydroxy groups can be substantial enough to ensure selective acylation in the
case where one of them is attached to a cyclic scaffold. Numerous examples of high chemoselectivity in acylations of this type of
56 53
substrates are known in the chemistry of natural products, especially carbohydrates and steroids.
Selective acylation of sterically and electronically similar hydroxy groups in non-symmetric diols and polyols can be efficiently
achieved using enzymatic methods. Despite the remarkable selectivity achieved in selected cases like mono- acylation of rather
54
similar primary hydroxy groups, as shown in eqn. (32), the prediction of chemoselectivity is somewhat complicated. A number of
55
enzymatic reactions have been reviewed.
Selective acylation of carbohydrates is a highly important application of chemoselective esterification. A number of methods
targeting both the selective acylation of primary vs. secondary as well as different secondary hydroxyls in partially protected
and non-protected carbohydrates have been developed. A substantial part of older accumulated experi- mental data before
56
1975 has been thoroughly reviewed. Most results in chemoselective esterification of carbohydrates, however, are not
56
general and are restricted for certain types of carbohydrates. Since the publication of the reviews, there has been a
substantial advance in the field of selective protection of carbohydrates involving enzymatically catalyzed trans-
57
esterification of enol, trifluoromethyl, and oxime esters. Enzymatic methods may provide selective acylations of primary
vs. secondary hydroxy groups and vice versa, as well as highly selective discrimination between different secondary
hydroxyls.
26
26
Monoesterification of symmetric dicarboxylic acids
Selective esterification of organic molecules possessing multiple acidic functionalities is an important process both in resea rch and
industry. Selective esterification of carboxylic groups in the presence of other acidic groups like -P(O)OH and SO3H is facile using
acid catalyzed esterifications, which provide exclusively esters of carboxylic acids. At the same time, selective monoesterification
of di- and polycarboxylic acids demands special methods.
27
27
Selective esterification of non-symmetric carboxylic acids
Numerous examples provide evidence that the conjugation of carboxylic groups with an aromatic ring or a double bond
results in a substantial decrease of esterification rates. A careful monitoring of the reaction progress enables the selective
60
preparation of monoesters in conditions of acidic catalysis. A complete discrimination between aromatic and aliphatic
carboxylic acids can be obtained in a biphasic esterification of a 1 : 1 carboxylic acid : alcohol mixture using fluoroalkyl-
44
distannoxane catalysts (eqn. (34)).
(34)
Similar considerations are behind a very high chemo- selectivity in the esterification of methyleneglutaric acid with MeOH
61
and iodine (eqn. (35)). A high selectivity between saturated and aromatic/α,β-unsaturated carboxylic acids and excellent
62
yields was achieved during the formation of methyl esters with CBr4/MeOH systems.
(35)
Opening of cyclic anhydrides possessing both types of carboxylic groups proceed in a similar way, producing selectively
63
monoesters (eqn. (36)).
(36)
64
Similarly high chemoselectivity is also obtained in lipase catalyzed esterifications. The opposite selectivity has been very
recently described, although without details about reaction mechanism. Treatment of aromatic and α,β-unsaturated carb-
oxylic acids with primary, secondary, and tertiary alcohols in the presence of AlCl3/NaI produced esters in good yields while
no products of esterification of aliphatic carboxylic acids were found (eqn. (37)).
Selective esterification of non-symmetric carboxylic acids with two aliphatic carboxylic groups is more complicated and
28
28
formation of mixtures of two possible monoesters and diester can be expected in many cases. The influence of steric effects
on esterification rates of different carboxylic groups can be estimated on the grounds of data from esterification rates of
65
substituted monocarboxylic acids. In contrast to alcohols, the prediction of relative esterification rates of different
carboxylic groups is not simple because the steric volume both in the α and β positions to the carboxylic group were found
to influence the esterification rates. A large difference in esterification rates should be expected only in selected cases, for
example for acids possessing three substituents in the α-position. Even in this case the outcome is not completely
predictable.
A high degree of selectivity for the esterification of carb- oxylic acids with primary vs. tertiary substituents in the α-position
were observed by using biphasic esterification of a
44
1 : 1 carboxylic acid : alcohol mixture with fluoroalkyl dibutoxystannane catalysts. While direct competition results were
not present, in all experiments carboxylic acids possessing a quaternary carbon atom in the α-position consistently
showed a very low (<20%) yield of esters in the conditions providing >99.9% esterification yields for carboxylic acids like
PhCH2CH2COOH.
At the same time, formation of mixtures (5 : 1) was observed in the cleavage of the non-symmetric anhydride shown in
66
eqn. (38).
(38)
This difference in selectivity is similar to the one observed in the esterification of primary vs. secondary alcohols. Acid (protic
or Lewis) catalyzed esterification consistently showed substantially higher sensitivity towards steric factors than reactions of
various carboxylic acids derivatives in the con- ditions of basic catalysis.
Electronic factors and chelation substantially influence the esterification rates of carboxylic acids but their influence on the
chemoselectivity of esterification has not been systematically investigated. The importance of these factors on relative
esterification rates is evident from the chemoselectivity of esterification of aspartic and glutamic acid derivatives.
67
Alcoholysis of hydrobromides of l-aspartic acid anhydrides proceeds with a complete selectivity providing exclusively α-
esters (eqn. (39)) owing to the presence of a strong electron-withdrawing group in the α-position. Triethylamine- or pyridine-
catalyzed alcoholysis of a neutral N-benzyl- oxycarbonyl anhydride or diacid possessing a much weaker
29
29
electron-withdrawing (acylamino) group in the α position (eqn. (40)) resulted in a much lower or even opposite
68
chemoselectivity of the alcoholysis.
The opposite chemoselectivity of esterification can be easily achieved through the esterification of the corresponding copper
69
chelates of aspartic or glutamic acids. Boric acid was found to efficiently catalyze the esterification of α-hydroxy
carboxylic acids. The reaction involves the formation of the alkylboronate ester followed by the intramolecular transfer of the
alcohol to the chelated carboxylic group as shows the eqn. (41). Carboxylic acids that do not contain a hydroxy group in α
or β positions, including N-protected α-amino acids, do not undergo esterification under the reaction conditions. Malic acid
can be monoesterified with a reasonable regioselectivity but minor amounts of diester are also formed indicating that β-
hydroxy carboxylic acids can also be esterified by this method.
Relatively low selectivity based on different acidities could be obtained using the methylation of lithium salts of carboxylic
70
acids.
71
Existing kinetic data on the hydrolysis and alcoholysis rates of substituted esters can be exploited to estimate the
chemo- selectivity of selective hydrolysis of diesters or alcohololysis of cyclic anhydrides. According to these data, the
presence of a heteroatom (O, Hal) or another electron withdrawing (CN, CO) group in the α-position to the ester function
provide at least a 50 times increase in its hydrolysis rates.
Enzymatic methods were successfully applied for the selective monoesterification of dicarboxylic acids and are especially
useful in the cases where there are no substantial electronic or steric differences between the carboxylic groups.
30
30
REFRENCES
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