Esterification

Junzo Otera

Esterification

Methods, Reactions, and Applications

Junzo Otera

Esterification

Further Reading from WILEY-VCH

D. Astruc (Ed.)

Modern Arene Chemistry

2002. 3-527-30489-4

C. Reichardt

Solvents and Solvent Effects

in Organic Chemistry, 3. Ed.

2002. 3-527-30618-8

P. Wasserscheid, T. Welton (Eds.)

Ionic Liquids in Synthesis

2002. 3-527-30515-7

K. Drauz, H. Waldmann (Eds.)

Enzyme Catalysis in Organic Synthesis

2002. 3-527-29949-1

Junzo Otera

Esterification

Methods, Reactions, and Applications

Author

Professor Dr. Junzo Otera

Department of Chemistry

Okayama University of Science

Ridai-Cho

Okayama 700-0005

Japan

[email protected]

This book was carefully produced. Never-

theless author and publisher do not warrant

the information contained therein to be free

of errors. Readers are advised to keep in

mind that statements, data, illustrations,

procedural details or other items may

inadvertently be inaccurate

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Data: A catalogue record for this book is

available from the British Library.

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Die Deutsche Bibliothek

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in the Deutsche Nationalbibliografie;

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Internet at <http://dnb.ddb.de>.

2003 WILEY-VCH Verlag GmbH & Co.

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ünstadt

ISBN 3-527-30490-8



Preface

Few would dispute that the synthesis of esters has played a most important role in

organic synthesis from its infancy. This importance stemmed from its utility in di-

verse fields both in the laboratory and in industry. Ester moieties, irrespective of

whether acyclic or cyclic, constitute major backbones, as well as functional groups of

chemical significance, in numerous natural products and synthetic compounds. The

essential feature of esterification that particularly distinguishes it from other reac-

tions lies in its broad utilization in industry. Just a brief chronological look quickly

reminds us of aspirin (acetyl salicylic acid), fatty acid esters, polyesters, macrolides,

and so on. In addition to being essential molecular components in their own right,

ester groups also play versatile temporary roles in organic synthesis for protection of

carboxylic acids and hydroxy groups. The synthesis of natural products, especially

macrolides, sugars, and peptides, depends heavily on acylation technology.

Being carboxylic acid derivatives, esters are largely produced from the reactions

between the corresponding acids and alcohols. Transformation from one ester into

another (transesterification) is also useful. On the other hand, since esters are also

derivatives of alcohols, ester synthesis is also important from the standpoint of alco-

hol chemistry, such as acylation. A variety of routes to arrive at esters are therefore

feasible, and numerous methods have been reported. Surprisingly, though, no book

focussed solely on “esters” has been available up to now, esterification or transesteri-

fication usually being included in many books as a sub-class of functional group

transformations. Obviously, this is not a fair treatment if the central position of

(trans)esterification in organic synthesis is taken into account. Why did such biased

circumstances arise? A number of reasons can be counted immediately, but only a

few representatives among them are given here. Since (trans)esterification has such

a long history and the reaction itself is simple, many people, especially in academia,

take it for granted that little room is left for further scientific improvements. In in-

dustry, on the other hand, (trans)esterification still has permanent significance and

so many new technologies remain undisclosed, as know-how. Since the utility of

(trans)esterification has spread into diverse fields, it is indeed laborious to cover the

whole. As such, even people involved in the (trans)esterification field, regardless of

whether in academia or in industry, have rather limited knowledge about what is

going on outside the very narrow disciplines close to them. Despite such undesirable

circumstances, (trans)esterification has in fact been, and is still undergoing, exten-

sive innovations. It is the aim of this book to inform a broad range of chemists and

technicians on the state of the art relating both to fundamental ideas and to practical

facets of (trans)esterification.

This book consists of two parts. The first thoroughly reviews the (trans)esterifica-

tion reaction, from conventional approaches to the most up-to-date progress in terms

of reaction patterns, catalysts, reaction media, etc., so that readers may acquire gen-

eral, basic knowledge of the reaction. In addition, those wanting to survey suitable

methods for a specific target will find great help from consulting this part. A number

of “Experimental Procedures” given may help readers judge which reactions are sui-

table for their purposes.

Synthetic applications of (trans)esterification are the subjects of Part II. These re-

actions, many of which may already have appeared in Part I, are reorganized accord-

ing to their respective synthetic purposes. Various aspects of interest to synthetic

chemists are summarized, followed by an overview of industrial utilization.

Because of its long history, it has been impracticable to survey the literature of es-

terification completely from the beginning. A full survey on the literature since

1990 has therefore been made by use of commercial databases. Reference works ap-

pearing before 1990 have been selected arbitrarily depending on their importance. I

believe that this treatment is fully acceptable to cover the literature that is basically

significant and represents recent progress to meet the requirements for “modern es-

terification“. As a result, we encountered more than 5,000 references, but for reasons

of space not all of them could be accommodated in the text of this book. Only exam-

ples selected in terms of their fundamentality and generality have been taken, to pro-

vide a comprehensive view on the overall aspects as broadly as possible. All collected

references are collected in a database library, a copy of which is provided on disc at

the end of this book. Those who wish to obtain more detailed information will be

able to consult this library through keyword access.

Last, but not least, I would like to express my sincere appreciation to Miss Masayo

Kajitani, who contributed greatly in the literature survey and the illustrations. With-

out her collaboration and patience, this book might have not been completed.

Junzo Otera

Okayama, November 2002

Preface

Database

The database on the disk in the back of this book is accommodated in a FileMaker

Developer 6 version for which both Windows and Macintosh operation systems are

available. The database contains about 5,000 references, on which this book is based

and the keyword access with schematic representation is feasible. Basically, the refer-

ences are accessed according to the numbers of (sub)headings of the text. In addi-

tion, the following keywords are employable for more selective access.

KeyWords

For Chiral Compounds: Chiral Carboxylic Acids, Chiral Esters, Chiral Anhydrides,

S-preference

For Selectivities: Primary/Primary, Primary/Primary and Secondary, Primary/Second-

ary, Primary/Secondary and Tertiary, Primary/Tertiary, Primary/Secondary and Phe-

nol, Primary/Phenol, Secondary/Primary, Secondary/Primary and Secondary, Second-

ary/Primary and Tertiary and Phenol, Secondary/Secondary, Secondary/Secondary

and Tertiary, Secondary/Secondary and Phenol, Secondary/Tertiary, Secondary/Phe-

nol, Tertiary/Tertiary, Phenol/Secondary, Phenol/Secondary and Phenol, Phenol/Phe-

nol, Secondary and Phenol/Secondary, Secondary and Phenol/Phenol, Primary and

Secondary/Secondary, Secondary and Tertiary/Secondary, Identical hydroxyl-groups,

Identical carboxylic-groups, Identical ester-groups, Identical acid chlorides

For Reaction Media: Ionic Liquids, Fluorous Biphasic Technology, Phase Transfer

Catalysts, Surfactant-type Catalysts, Immobilization, Cyclodextrin, Supercritical Sol-

vents

For Natural Products: The natural products which appear in 7.4 are accessed by their

names as well.

Others: Yamaguchi method, Distannoxanes, TiTADDOLates, Al, B, Bi, Cu, Fe, Hf, I,

Ni, Sc, Sn, Ti, Zn, Py, DMAP, NEt

, NEt

,NH

, PhNEt

, PhNMe

, EtNMe

DBU, NHMe

, NHCy

, Cinchona Alkaloids, Guanidine,TMEDA, Imidazoles.

VII

Contents

Preface V

Database

VII

Introduction

Part I Methodology

1 Reaction of Alcohols with Carboxylic Acids

and their Derivatives

1.1 Reaction with Carboxylic Acids

1.1.1 Without Activator 5

1.1.2 Acid Catalysts 6

1.1.3 Base Activators 19

1.1.4 Carbodiimide Activators 21

1.1.5 The Mitsunobu Reaction 24

1.1.6 Activation of Carboxylic Acids 30

1.1.7 Enzymes 41

1.1.8 -Acids 44

1.2 Reaction with Esters: Transesterification 45

1.2.1 Without Activator 45

1.2.2 Acid Catalysts 48

1.2.3 Base Activators 64

1.2.4 Other Activators 83

1.2.5 Enzymes 83

1.3 Reaction with Acid Anhydrides 91

1.3.1 Without Activator 91

1.3.2 Acid Catalysts 92

1.3.3 Base Activators 103

1.3.4 Enzymes 116

1.3.5 Mixed Anhydrides 117

1.4 Reaction with Acid Halides and Other Acyl Derivatives 124

1.4.1 Without Activator 124

1.4.2 Acid Catalysts 125

1.4.3 Base Activators 131

1.4.4 Other Activators 141

1.4.5 Enzymes 143

2 Use of Tin and Other Metal Alkoxides 145

3 Conversion of Carboxylic Acids into Esters without Use of Alcohols 157

3.1 Treatment with Diazomethane 157

3.2 Reaction with Alkyl Halides 159

3.3 Treatment with Other Electrophiles 166

4 Ester-Interchange Reactions 173

Part II Synthetic Applications

5 Kinetic Resolution 177

5.1 Enzymatic Resolution 177

5.2 Nonenzymatic Resolution 184

5.3 Dynamic Kinetic Resolution 190

5.4 Parallel Kinetic Resolution 194

6 Asymmetric Desymmetrization 197

7 Miscellaneous Topics 203

7.1 Selective Esterification 203

7.1.1 Differentiation between Primary, Secondary, and Tertiary Alcohols

and Phenols 203

7.1.2 Differentiation between Identical or Similar Functions 210

7.2 Use of Theoretical Amounts of Reactants 215

7.3 New Reaction Media 219

7.4 Application to Natural Products Synthesis 226

8 Industrial Uses 249

8.1 Polyesters 249

8.2 Oils and Fats 254

8.2.1 Food Emulsifiers 254

8.2.2 Soaps 255

8.3 Amino Acid Esters 255

8.4 Flavoring Agents and Fragrances 257

8.5 Pyrethroids 262

Epilogue 265

Reference Code Index 267

References 269

Index 297

Contents

Introduction

The biggest problem frequently encountered in (trans)esterification technology

arises from equilibration. To bias the equilibrium to the product side, one of the reac-

tants must be used in excess and/or one of the products must be removed constantly

during the reaction. Use of a non-equilibrium reaction approach, with the aid of acti-

vated reactants such as acid anhydrides and halides or alkoxides, can be effective to

bypass the problem on some occasions but is not always general. Ester synthesis re-

actions are usually conducted with the aid of acid or base catalysts, and so the em-

ployment of catalysts or promoters that are suitably active but also compatible with

other functional groups is of great importance. Progress has been made to overcome

these problems in (trans)esterification reactions.

Esterification can be regarded as the transformation of carboxylic acids or their de-

rivatives into esters, as carried out in many natural products syntheses, in the protec-

tion or kinetic resolution of carboxylic acids, and in the fatty acids industry. However,

its counterpart reaction – the transformation of alcohols into esters, as in protective

acylation of hydroxy groups, kinetic resolution of alcohols, etc. – is equally impor-

tant. The normal substrate/reagent relationship cannot therefore be straightfor-

wardly applied to esterification. Moreover, in intramolecular cases (lactonization)

and polycondensation, both functions as equal partners. In Chapter 1 the alcohol

component is regarded as the substrate, because modifications of carboxylic acids

are available in greater variety. Of course, such a classification is not strict: the car-

boxylic acid component might as well be taken as a substrate in, for instance, the di-

rect reaction between neat alcohol and carboxylic acid. In any event, the chapter is

subdivided into sections according to the means by which the carboxylic acid is mod-

ified. Each section is then further sub-classified according to the activation modes.

Tin alkoxides, together with some other metal alkoxides, are useful for selective

acylation of polyols and, in particular, play an important role in sugar chemistry.

This subject is grouped separately in Chapter 2.

In Chapter 3, the carboxylic acid component is treated as substrate, in reaction

with various reagents other than alcohols. Chapter 4 deals with interconversion be-

tween different esters.

The first two chapters in Part II, Chapters 5 and 6, are both associated with chiral-

ity. In response to the increasing need for optically active compounds in modern syn-

thetic chemistry, great progress has been achieved in ester technology, serving for

the production of enantiomerically enriched or enantiomerically pure alcohols and

carboxylic acids through kinetic resolution and desymmetrization.

Chapter 7 covers miscellaneous topics of great significance in terms of synthetic

utility and various selectivities. Natural products syntheses in which esterification

has played a crucial role are also described.

Finally, in Chapter 8, industrial uses of esterification technology are examined.

Since many currently operational, especially state of the art, processes are veiled in

darkness as know-how, it is not an easy task to delineate the real features. What can

be done best is to sketch profiles that are either common knowledge or available

from the literature. Despite such limitations, readers should acquire an idea of how

and where esterification is utilized in practice.

Introduction

Part I

Methodology

Reaction of Alcohols with Carboxylic Acids and their Derivatives

1.1

Reaction with Carboxylic Acids

1.1.1

Without Activator

Although the direct reaction between alcohol and carboxylic acid is conventionally

conducted under acid or base catalysis conditions, the catalyst-free reaction is more

desirable. This requirement is satisfied when the reaction is carried out at high tem-

peratures. A literature survey (refer to the database disc) shows eight papers appear-

ing in this category. For example, propanol or hexanol can be treated with various ali-

phaticcarboxylicacids(1.35equiv.)inanautoclaveat150 °Ctofurnishestersin

poor to excellent yields (Scheme 1-1) [95ZPK(68)335]. The reaction is strongly influ-

encedbythereactiontemperature;theyieldofpropylacetateisonly18%at85 °C.

Scheme 1-1

Interestingly, condensation between sugars and a -hydroxycarboxylic acids can be

performedinwater(Scheme1-2)[99SC951].Thereactiontakesplaceat60 °C,regio-

selectively on the primary hydroxy groups of mannose, galactose, and glucose. The

avoidance of any catalysts or additives allows the instant application of the products

in food technology and cosmetic formulation.

Experimental Procedure Scheme 1-2 [99SC951]

General procedure: A mixture of hydroxycarboxylic acid, carbohydrate, and water is

heatedto60 °Cinairfor24h.Toisolatetheproductasapurecompoundforcharac-

terization the reaction mixture is extracted twice with diisopropyl ether, the solvent

is removed in vacuo, and the residue is chromatographed on silica gel (CH

MeOH 85 :15).

R OH

R OR'

150°C

2.5h

R'OH

17~94%

O OH

R OH

Chiral

C,24h

Scheme 1-2

The equilibrium in the reaction between ethanol and acetic acid can be shifted in

favor of the ester by application of CO

pressure (Scheme 1-3) [2001GC17]. The ester

yield is therefore increased from 63% in neat solution to 72% in CO

at 333 K/

58.6 bar. This outcome is far from satisfactory, though the possibility does suggest it-

self that the equilibrium may be improved by changing the reaction conditions.

high pressur e CO

(as a solvent )

Scheme 1-3

On the whole, the catalyst-free reaction is ideal but difficult to achieve. Some spe-

cial conditions are necessary, and employable reactants are rather limited. Nonethe-

less, it is obvious that this line of technology should be advanced more extensively in

the context of green chemistry.

1.1.2

Acid Catalysts

1.1.2.1 Br

ønsted Acids

Since acid catalysis is one of the most popular methods for esterification, numerous

papers are available (refer to the database disc). When the substrates are acid-resis-

tant, the reaction is usually carried out in the presence of Br

ønsted acid such as HCl,

HBr, H

, NaHSO

, ClSO

H, NH

H, H

, HBF

, AcOH, camphorsulfonic

acid, etc. (Scheme 1-4). In cases in which the acidity is not high enough to trigger

the desired reaction, the acid is combined with an activator. For example, the lactoni-

zation shown in Scheme 1-5 proceeds sluggishly with HCl only, but the reaction is

effectedsmoothlyinthepresenceofHCland3Åmolecularsieves[97CL765].Thees-

terification of phenols with both aliphatic and aromatic carboxylic acids – difficult to

achieve under normal conditions – can be catalyzed by a combination of H

and

(Scheme 1-6) [71TL3453].

R OH

R OR'

R'OH

Scheme 1-4

1 Reaction of Alcohols with Carboxylic Acids and their Derivatives

OH OH OH

HCl

mol . sieves 3A

toluene

Chira l

Chiral

85%

C,24h

Scheme 1-5

R'COOH

R'= al iphatic and aromatic

58~94%

solvent

Scheme 1-6

Other ways to activate the acid catalysts are provided by the use of ultrasound and

microwaves. H

-catalyzed esterification, which usually requires a long reaction

time under refluxing conditions, is complete at room temperature in several hours

on exposure to ultrasonic waves [90SC2267]. Microwave irradiation accelerates p-to-

luenesulfonic acid-catalyzed esterification, the reaction finishing within 10 minutes

[93CJC90].

Aqueous HCl is not employable for water-sensitive compounds. In such cases, dry

HCl gas must be used, but generation of this is not operationally simple. Alterna-

tively, generation of HCl under anhydrous conditions is conveniently feasible by ad-

dition of acetyl chloride to methanol or ethanol. Treatment of alcohol and carboxylic

acid in the HCl solution obtained provides the desired ester (Scheme 1-7) [98SC471].

By this method, the concentration of HCl can readily be adjusted by changing the

amount of acetyl chloride.

Experimental Procedure Scheme 1-7 [98SC471]

A typical experimental procedure involves the addition of a known amount of acetyl

chloride, usually from a weighed syringe, to an ice-cold solution of an equivalent or

excess amount of methanol (or ethanol) in an inert organic solvent, such as ethyl

acetate, containing an equivalent amount of the compound to be treated. The acidic

solution may also be prepared in the pure alcohol. Ice-cold solutions are used in or-

der to increase the solubility of the HCl and to prevent its escape, the initial genera-

tion of the HCl being exothermic. In cases in which simple esterifications are to be

carried out, excess acetyl chloride may be used without detrimental effects, since the

1.1 Reaction with Carboxylic Acids

OEt

AcCl

57%

EtOH

Scheme 1-7

workup involves simple evaporation of the solvent(s) and excess HCl. The solutions

are allowed to warm to room temperature and the reactions are complete within

0.5–24 h.

A similar protocol is available with TMSCl (trimethylsilyl chloride) (Scheme 1-8)

[81BCJ1267]. In this case, TMSCl is added to a mixture of alcohol and carboxylic

acid. It has been suggested that the reactant alcohol works as a proton donor as well,

while on the other hand the initial formation of the silyl ester is another proposed

mechanism for a similar reaction (Scheme 1-9) [83S201].

TMSCl

+R'OH

TMSOR'

HCl

TMSOR'

TMSO H

HCl

TMSOH

R'OH TMSOR' + H

2TMSOH

TMS

O+

RCOOR'

RCOOH

Scheme 1-8

R OH

+TMSCl

R OTMS

+ HCl

R'OH/H

R OR'

TMSO H

TMSCl

TMS

O+

HCl

Scheme 1-9

Despite the rather harsh conditions, the Brùnsted acid-catalyzed reaction some-

times enjoys selectivities. Continuous extraction technology enables selective monoa-

cetylation in reasonable yields upon treatment of a 1,n-diol with acetic acid in the

presence of H

(Scheme 1-10) [79TL1971]. Stereoselectivity is also attained in

TFA-catalyzed esterification (TFA = trifluoroacetic acid), as shown in Scheme 1-11

[95JOC1148]. In this reaction, the inversion of the stereochemistry at C-4 proceeds

effectively via the carbocation, the nucleophilic attack of an acetate anion on the car-

bocation taking place preferentially from the opposite side of the bulky 3,4-(methyle-

nedioxy)benzoyl group in the Felkin-like model to afford the anti acetate.

1 Reaction of Alcohols with Carboxylic Acids and their Derivatives

HO (CH

)

OH HO (CH

)

OAc

AcOH

n= 8 (75%)

n= 10 (66%)

n= 6 (94%)

continuous extraction

technology

Scheme 1-10

TFA

62%

AcOH

OMe

MeO

AcO

OMe

MeO

Scheme 1-11

A unique formation of tert-butyl esters is notable. When a mixture of carboxylic

acid and tert-butanol is exposed to H

absorbed on MgSO

, esterification takes

place smoothly (Scheme 1-12) [97TL7345]. The reaction is successful for various aro-

matic, aliphatic, olefinic, heteroaromatic, and protected amino acids. No reaction oc-

curs with the use of anhydrous MgSO

or H

alone. The reaction is initiated by

dehydration of tert-butanol followed by addition of carboxylic acid to the resulting

isobutylene.

Experimental Procedure Scheme 1-12 [97TL7345]

In a typical small-scale experiment, concentrated sulfuric acid (0.55 mL, 10 mmol) is

added to a vigorously stirred suspension of anhydrous magnesium sulfate (4.81 g,

40 mmol) in 40 mL of solvent. The mixture is stirred for 15 minutes, after which the

carboxylic acid (10 mmol) is added. Tertiary butanol (4.78 mL, 50 mmol) is added

last.Themixtureisstopperedtightlyandstirredfor18hat25 °C,oruntilthereac-

tion is complete by TLC analysis. The reaction mixture is then quenched with 75 mL

of saturated sodium bicarbonate solution and stirred until all magnesium sulfate

has dissolved. The solvent phase is separated, washed with brine, dried (MgSO

and concentrated to afford the crude tert-butyl ester, which is purified by chromato-

graphy, distillation, or recrystallization as appropriate.

R OH

R O

MgSO

co nc. H

(cat.)

BuOH

-H

RCO O

Mech ani sm;

RCOOH

Scheme 1-12

1.1 Reaction with Carboxylic Acids

Hydrophobic polystyrene-supported sulfonic acids catalyze reactions between car-

boxylic acids and alcohols in water [2002ASC(343)270]. The catalysts are recovered

and reused for further reactions.

1.1.2.2 Lewis Acids

Lewis acids are another important class of acid catalyst. In general, they are milder

thanBrønstedacidsand,moreimportantly,templateeffectsaretobeexpectedas

they are sterically bulkier than a proton. As such, the utilization of Lewis acids is ra-

pidly increasing. They are classified as follows, according to elements:

BBF

· OEt

[36JACS271,69JPS1422,70TL4011,71S316,72S628,90ACH705,

91CE277, 95CC1391, 96JHC1171, 96TL1393]; BCl

[2001TL3959]; 3,4,5-

B(OH)

[96JOC4196]

Al AlCl

(immobilized) [73TL1823]

Zn ZnO [96IVY117]; ZnCl

/microwave [2002TL45]

Sn Bu

SnO [80JACS7578, 83JACS7130]; (XR

SnOSnR

[86TL4501; 91JOC5307;

96CL225]; (XRf

SnOSnRf

2002AGC(E)4117]; Ph

SnCl

[87TL3713]

Fe Fe(ClO

)

[94IJC(B)698,92SC1087];Fe

(SO

)

· H

O[98SC1159];FeCl

[99SL1200]

Ni NiCl

· 6H

O[97T7335]

Cu CuCl

[89SC2897];Cu(NO)

· 3H

O[98SC1923];Cu(OTf)

[99TL2611]

Hf HfCl

· 2THF[2000SCI(290)1140;2001SL1117]

[2002TL879]

· OEt

istheoldestLewisacidtohavebeenemployedasanesterificationcata-

lyst since the BF

/CH

OH complex had been known to be used for conversion of

simple carboxylic acids to their methyl esters prior to GLC analysis. Although excess

· OEt

(2–3equiv.)andalcohol(>10equiv.)for1equiv.ofcarboxylicacidshould

be used, esterification is feasible for 4-aminobenzoic acid, unsaturated organic acids,

biphenyl-4,4 ´ -dicarboxylicacid,1,4-dihydrobenzoicacid,andheterocycliccarboxylic

acids.

Experimental Procedure [71S316]

The reaction mixture comprising the acid (0.1 mol), boron trifluoride etherate (0.1 or

0.2 mol, depending on the number of carboxyl groups in the acid), and the appropri-

ate alcohol (ten times in excess of the boron trifluoride etherate) is heated at reflux

for a period of time not exceeding 24 h. The esters are precipitated by dilution with a

5% solution of sodium carbonate, followed by filtration or extraction with ether, and

purified by crystallization from appropriate solvents or by distillation under reduced

pressure.

BCl

is also useful for esterification with primary alcohols, but yields are not so

high with secondary and tertiary alcohols. The disadvantage of this method is the

cleavage of coexisting methyl ether functions.

3,4,5-Trifluorobenzeneboronic acid is claimed to be the most effective catalyst

among the boronic acids (Scheme 1-13). Esterification takes place smoothly if heavy

1 Reaction of Alcohols with Carboxylic Acids and their Derivatives

alcohols such as 1-butanol are employed. The reaction is presumed to proceed via a

carboxylate intermediate.

AlCl

is one of the most popular Lewis acids, but it is not employed in esterifica-

tion because of its too strong acidity. However, polymer-supported AlCl

works as a

milder catalyst for esterification although the yields are not always as high as those

obtained by other methods. The advantage lies in the ease of separation of the cata-

lyst by filtration.

Treatment of pentaerythritol with oleic acid in the presence of ZnO as catalyst pro-

vides a triester. Production of commercially important p-hydroxybenzoic acid ester

(paraben) from p-hydroxybenzaldehyde and alcohol is catalyzed by ZnCl

under mi-

crowave irradiation conditions.

Another popular Lewis acid, SnCl

, is also not usually employed in esterification.

Organotin compounds work quite well, however, because the acidity is moderated by

the replacement of chlorine with electron-donating alkyl groups. Bu

SnO catalyzes

lactonization of seco acids on continuous dehydration with a Dean–Stark apparatus

(Scheme 1-14). This method is effective for large sized lactones but not for medium

sized ones.

Experimental Procedure Scheme 1-14 [83JACS7130]

Preparation of hexadecanolide. A mixture of 16-hydroxyhexadecanoic acid

(817.3 mg, 3.0 mmol) and dibutyltin oxide (74.7 mg, 0.3 mmol) is stirred in refluxing

1.1 Reaction with Carboxylic Acids

Scheme 1-13

HO (CH

)

(CH

)

(CH

)

OBu

(CH

)

SnO

-H

SnO -Bu

SnO

n= 7 (0%)

n= 14 (63%)

n= 15 (60%)

lactone

(CH

)

Scheme 1-14

mesitylene (100 mL) for 19 h with use of a Dean–Stark apparatus for the continuous

removalofwater.Removalofthesolventinvacuo(40 °C/0.2mmHg)yieldsayellow

oilyresidue,whichisKugelrohrdistilled(60 °C/0.2mmHg)togive457.9mg(60%)

of hexadecanolide.

Good yields of esters are obtained when carboxylic acids are treated with 1,3-disub-

stituted tetraalkyldistannoxanes, (XR

SnOSnR

, in alcohol solvent (Scheme 1-15).

The catalysts are very mild, and the reaction is sensitive to the steric bulk of the reac-

tants. The catalysts are also effective for lactonization (Scheme 1-16). The reaction

proceeds simply on heating of a decane solution of seco acids. The convenience of op-

eration is apparent from the lack of any need for dehydration apparatus and/or dehy-

dration agents. Irreversible esterification apparently takes place because of the hy-

drophobicity of the surface alkyl groups surrounding the stannoxane core. Interest-

ingly, alkyl side chains attached on the hydroxyl-bearing carbon of the -hydroxy

acids exert a profound effect on lactonization. Lactone rings with fewer than 14 mem-

bers are obtained in poor yields, while incorporation of R groups with more than

four carbon atoms dramatically increases the yield.

R OH

R'OH

OR'

R= C

R'=

Bu (0%)

R= C

R'= CH(CH

)CH

(20%)

R= C

R'= CH

CH(CH

)

(100%)

Bu, R'= C

(33%)

R= C

R'= C

(100 %)

R= Ph, R'= C

(38%)

Pr, R'= C

(97%)

Sn O

Sn Y

Y Sn O Sn

R''

R''= Bu, Me

X = NCS, Cl

Y = NCS, Cl, OH

,neat

Scheme 1-15

HO (CH

)

(CH

)

R= H, n= 14 (81%)

R= H, n= 13 (78%)

R= H, n= 10 (0%)

R= C

, n= 10 (90%)

(ClSnBu

OSnBu

OH)

decane

Scheme 1-16

Use of a fluoroalkyldistannoxane catalyst (XRf

SnOSnRf

achieves a highly

atom-efficient process in the context of fluorous biphasic technology (see Sections

7.2 and 7.3). Virtually 100 % yields are available by the use of carboxylic acid and alco-

hol in a strict 1:1 ratio. The catalyst is recovered quantitatively and the catalyst solu-

tion in perfluoro-organic solvent is recycled repeatedly.

1 Reaction of Alcohols with Carboxylic Acids and their Derivatives

Experimental Procedure [2002AGC(E)4117]

A test tube (50 mL) is charged with 3-phenylpropanoic acid (300 mg, 2.0 mmol), ben-

zyl alcohol (216 mg, 2.0 mmol), (ClRf

SnOSnRf

Cl)

(Rf = C

) (172 mg,

0.10 mmol, 5 mol %), and FC-72 (5.0 mL). The test tube is placed in a stainless steel

pressurebottleandheatedat150 °Cfor10h.Thepressurebottleiscooled,andto-

luene (5.0 mL) is added to the reaction mixture. The toluene and FC-72 layers are sepa-

rated, and the latter layer is extracted with toluene (2.0 mL × 2). The combined organic

layer is analyzed with GC to provide a quantitative yield of benzyl 3-phenylpropanoate.

Simple dimethyl- and diphenyltin dichlorides catalyze esterification of carboxylic

acids in refluxing C

alcohol.

Fe(III) salts are also effective. Fe(ClO

)

Opromotesesterificationofcarboxylic

acids in alcohol. The reaction proceeds at room temperature, but a stoichiometric

amount of the salt is needed. A catalytic version is available with Fe

(SO

)

· xH

(2 wt % cat. per acid) and FeCl

(5 mol % per acid). The reaction requires an excess

amount of one reaction component in refluxing benzene or toluene. A similar outcome

is obtained with NiCl

· 6H

Ocatalyst.

Experimental Procedure [98SC1159]

The Esterification of Adipic Acid with Ethanol in the presence of Ferric Sulfate: A

mixture of adipic acid (14.5 g, 0.1 mol), absolute ethyl alcohol (18.5 g, 0.4 mol), dry

benzene (35 mL), and commercial ferric sulfate (0.3 g) is placed in a flask equipped

with an automatic water separator fitted with an efficient reflux condenser at its

upper end. The mixture is heated at reflux on a steam bath for 3 h or until water no

longer collects in appreciable amount in the water separator. The catalyst is filtered

off and washed with two 20 mL portions of ether. The combined filtrate is washed

with saturated sodium carbonate solution and then with cool water, and is dried with

anhydrous magnesium sulfate. Most of the ether and benzene is removed by distilla-

tion under normal pressure, and the residue is then evaporated under reduced pres-

sure to give the diethyl adipate at 116 ~ 117/9 mm. The yield is 19.4 g (96%).

Cupric salts are another class of species that work as catalyst. CuCl

· xH

Ocatalyzes

conversionofcarboxylicacidsinmethanolsolventat130 °C,whileCu(NO

)

· 3H

effects acetylation of alcohols in refluxing acetic acid. Cu(OTf)

is used for acetylation

of alcohols, but to a somewhat limited extent.

HfCl

· 2THFinthepresenceof4Åmolecularsievesenablestheuseofequimo-

lar amounts of alcohol and carboxylic acid to afford good to excellent yields of the de-

sired esters (see Part II). This commercially available catalyst is highly active (usually

0.1 ~ 0.2 mol% loading) and hydrolytically stable. Polycondensations of -hydroxy

acids or between dicarboxylic acids and diols to furnish polyesters are also feasible.

The selective esterification of primary alcohols in the presence of secondary alcohols

or phenol can be achieved with this catalyst (Scheme 1-17).

1.1 Reaction with Carboxylic Acids

Experimental Procedure Scheme 1-17 [2000SCI1140]

The typical polycondensation procedure is as follows. A flame-dried, 5-mL, single-

necked, round-bottomed flask fitted with a Teflon-coated magnetic stirring bar and a

5mLpressure-equalizedadditionfunnel[containingacottonplugand4Åmolecular

sieves (~1.5 g)] surmounted by a reflux condenser is charged with -hydroxycar-

boxylic acid (10 mmol) or , -dicarboxylic acid (10.0 mmol) and , -diol (10.0 mmol)

as substrates and HfCl

2THF(0.200mmol)asacatalystino-xylene(2mL).The

mixture is brought to reflux with the removal of water. After 1 day, the resulting mix-

ture is cooled to ambient temperature, dissolved in chloroform, and precipitated with

acetone or methanol to furnish pure polyester as a white solid in quantitative yield.

CO OH

O OC

O O

cHex

HfCl

· (THF)

(cat.),toluene

>99

Scheme 1-17

When a carboxylic acid is heated in alcohol with a catalytic amount of iodine, ester-

ification takes place [2002TL879]. Primary, secondary, and even tertiary alcohols are

employable, although the yields are rather low (56%) in the last case. The reaction is

tolerant of high amounts of water. It is claimed that the iodine works as a Lewis acid.

Experimental Procedure [2002TL879]

Stearic acid (5 g, 17.6 mmol), methanol (10 mL), and iodine (50 mg,) are heated at re-

flux for the specified time, the progress of the reaction being monitored by TLC. After

the reaction, excess alcohol is removed under reduced pressure and the residue is ex-

tracted with diethyl ether. The ether extract is washed with a solution of sodium thio-

sulfate and subsequently with distilled water, dried over anhydrous sodium sulfate,

and concentrated in vacuo to yield the crude product, which is purified by column

chromatography (hexane/ether, 9 : 1) to give the desired carboxylic ester (5.1 g, 98%).

1.1.2.3 Solid Acids

Various solid acids are utilized for esterification, although the substrates that can be

employed suffer from considerable limitations due to the strong acidity. Neverthe-

less, solid acids have a great advantage in that they can be removed from the reaction

mixture by filtration and thus applied to large-scale production.

Nafion-H

Nafion-H is the oldest solid acid to have been utilized as an esterification catalyst

[78S929]. When a mixture of carboxylic acid and alcohol is allowed to flow over this

catalystat95–125 °C,highyieldsofthecorrespondingestersareobtainedwithacon-

tact time of ~5 sec. A batch reaction is also employable [91BKC9; 92BKC586].

1 Reaction of Alcohols with Carboxylic Acids and their Derivatives

a o

Experimental Procedure [78S929]

Typical Esterification Procedure: The reactor is charged with activated Nafion-H cata-

lyst (2.0 g). Carrier nitrogen gas is passed through the catalyst at a rate of 30 mL

min

–1

. A mixture of hexanoic (caproic) acid (2.6 g, 0.025 mol) and ethanol (2.9 g,

0.062mol)ispassedthroughthecatalystat125 °atarateof0.082mLmin

–1

,corre-

sponding to contact time of 5–7 sec. The two-phase product mixture is diluted with

ether (30 mL) and washed with 5% sodium hydrogen carbonate solution (2 × 20 mL),

and then with water (2 × 20 mL). The organic layer is dried with magnesium sulfate

and the solvent is evaporated. The residue is reasonably pure ethyl hexanoate, which

maybedistilledforfurtherpurification;yield:3.5g(98%);b.p.167°.

Amberlyst 15

-Hydroxy esters [94SC2743] and -amino acids [98SC1963] are successfully

converted into the corresponding esters with this catalyst, while catechol under-

goes esterification with acrylic acid to afford 7-hydroxycoumarin (Scheme 1-18)

[95CC225].

HO OH

HO O O

Amberlyst 15 ( cat.)

toluene

73%

Scheme 1-18

Experimental Procedure [94SC2743]

A solution of -butyrolactone (11.6 mmol) in anhydrous methanol (25 mL) is stored

on Amberlyst-15 (25 g) with occasional shaking for 20 h. Methanol is decanted and

the Amberlyst is washed with methanol (2 × 20 mL). The combined methanol frac-

tions are evaporated and the residue is distilled to give methyl 4-hydroxybutanoate,

b.p. 110–114/8–10 mm.

Amberlite IR120

Various substrates with hydroxy and related functions, such as sugars [93LA975;

95SC1099] and shikimic and quinic acids [91JCR(S)56], are esterified with this resin.

Experimental Procedure [93LA975]

5-O-( -D-Glucopyranosyl)-D-arabinono-1,4-lactone: A solution of potassium 5-O-( -

D-glucopyranosyl)-D-arabinonate (7.7 g, 20 mmol) in water (20 mL) is passed

through an ion-exchange column (Amberlite IR-120 H

, 200 mL) and eluted with

water (500 ml). Concentration of the eluent, followed by drying in vacuo (10

–2

Torr),

gives 5-O-( -D-glucopyranosyl)-D-arabinono-1,4-lactone (3.2 g, 99%) as an amor-

phoussolid,softeningaround88–90 °C.

Wolfatit KSP200

Esterification of chiral -hydroxy carboxylic acids without racemization is feasible by

heating in EtOH or MeOH/CHCl

in the presence of the ion-exchange resin Wolfatit

1.1 Reaction with Carboxylic Acids

KSP200 (Scheme 1-19) [91CB1651]. The products are useful intermediates for synth-

esis of the corresponding -hydroxy aldehydes.

R'OH

Wolfati t KSP200

CHCl

reflux

Scheme 1-19

Zeolite

The rare earth-exchanged RE H-Y zeolite is the best of the various zeolite catalysts

[96IJC(B)1174]. Heating of alcohol solutions of carboxylic acids in the presence of

thefreshlyactivatedzeoliteat150 °Cprovidesgoodtoexcellentyieldsofesters.The

same type of zeolite is also useful for lactonization of seco acids [98TL293].

Experimental Procedure [96IJC(B)1174]

A mixture of phenylacetic acid (5 g, 0.036 mole) and ethanol (50 mL) is placed in a

Parr reactor, and freshly activated zeolite (RE H-Y, 5 g) is slowly added. It is then

heatedat150 °Cunderautogeneouspressurefor8h.Thereactorisallowedtocoolto

room temperature and the catalyst is filtered off and washed with ethanol (2 × 25 mL).

The ethanol is removed from the filtrate by distillation. The residue is diluted with

dichloromethane (50 mL) and washed with 5% aq. sodium carbonate solution

(2 × 25mL) to remove the unreacted acid, then with water (2 × 25 mL), and finally with

brine (20 mL), and dried over anhydrous sodium sulfate. Removal of the solvent pro-

vides pure ethyl phenylacetate (5.51 g, 91%).

· n H

This catalyst is claimed to be more active than cation-exchange resin, SiO

AlO

and solid super acids [84CL1085].

FeCl

supported on salicylic resin

Azeotropic dehydration by heating of a mixture of carboxylic acid and alcohol (1:3 mo-

lar ratio) in benzene in the presence of the catalyst resin affords quantitative yields of

esters [98SC1233]. The use of smaller amounts of alcohol gives rise to lower yields.

Fe(ClO

)

(ROH)

/SiO

Grinding this “supported regent” with an equimolar amount of carboxylic acid pro-

vides esters [98SC2821]. This protocol is operationally simple, but requires a stoi-

chiometric amount of the promoter.

NaHSO

/SiO

Aliphatic carboxylic acids are esterified preferentially over aromatic ones at room

temperature with the aid of NaHSO

supported on silica gel (Scheme 1-20)

[2000SL59].

1 Reaction of Alcohols with Carboxylic Acids and their Derivatives

Scheme 1-20

Phosphorus oxides

Phosphorus pentoxide can be used for dehydration between carboxylic acid and alco-

hol. Heating of a mixture of alcohol, carboxylic acid, and P

is the simplest treat-

ment [83JOC3106]. In addition to intermolecular esterification, lactonization is also

achievable [91T10129, 91H(32)669]. This procedure can be modified by initial treat-

ment of P

with alcohol to furnish an equimolar mixture of mono- and dialkyl-

phosphates (Scheme 1-21) [83T1475]. In practice, isolation of these compounds is

not necessary, a carboxylic acid being added to the mixture to produce the ester.

Experimental Procedure Scheme 1-21 [83T1475]

Esterification of a Liquid Carboxylic Acid: Glacial acetic acid (0.6 mole, 36.0 g) is

added to the alkyl phosphate reagent (0.1 mole equivalent), and the reaction mixture

is heated at reflux on a water bath for 3 h, with ice-cold water being circulated

through the condenser. The reaction mixture is allowed to come to room tempera-

ture and extracted with ether (2 × 100 mL), and the organic layer is washed

(aq. NaHCO

,2× 100mL) and dried (Na

). After removal of the solvent, the resi-

dual liquid is distilled through a fractionating column to yield methyl acetate (39 g,

90%),b.p.54–56 °.

Esterification of Solid Acid: Phenylacetic acid (82.2 g, 0.6 mol) is added to the alkyl

phosphate reagent. In this case, any required alkanol is added to ensure homoge-

neous solution. The reaction mixture is heated at reflux for 3 h. It is then diluted

with water (100 mL) and extracted with ether (2 × 100 mL), and the organic layer is

washed (aq. NaHCO

,2× 100 mL) and dried (Na

). After removal of solvent, the

residualliquidisdistilledofftoyieldethylphenylacetate(85g,86%),b.p.224–226 °.

Scheme 1-21

A flow system that uses a vertical column is available, although a mixture of

/CuSO

/Na

is better than simple P

for this purpose [83JOC3106].

CuSO

serves both as a water scavenger and, through its color change, as an indica-

tor of the progress of the reaction and the duration of the reactivity of the column,

1.1 Reaction with Carboxylic Acids

while Na

retains the desired porosity and is useful for sustained reactivity of the

column with its water-absorbing property. This packing reagent is also used for a

batch reaction [83JOC3106; 87JIC34].

Experimental Procedure [83JOC3106]

Mixtures of various organic acids (0.05 mol), freshly prepared packing reagent (2.5 g),

and ethanol (50 mL) are taken in Erlenmeyer flasks and left at room temperature for

20 h with occasional shaking. Removal of the solvent (ca. 30 mL) on a steam bath (15–

20 min) leaves a residue, which furnishes the ethyl esters on conventional workup.

SbO/P

The characteristic feature of this catalyst system is that the reaction temperature

(25–85 °C)islowerthanthoseusedinotherprocedures[91AOMC513].

· xH

Various bromoacetates are obtained by treatment of bromoacetic acids (1.0 mol) with

alcohol (1.1 mol) in the presence of 12-tungstophosphoric acid [91AOMC183].

Experimental Procedure [91AOMC183]

Bromoacetic acid (1.0 mol), alcohol (1.1 mol), benzene (70 mL), and H

condenser and the mixture is heated at reflux for 3–4 h until 15–18 mL of water have

been collected. The crude solution is separated, washed with water, twice with a satu-

rated sodium bicarbonate solution, and finally again with water, and is then dried

over magnesium sulfate and sodium sulfate (1: 1), filtered, and distilled under nor-

mal pressure or under vacuum.

SiW

Heteropoly acids often leak out of catalyst supports, because these acids are extraor-

dinary soluble in water and several organic solvents. Activated carbon can tightly im-

mobilize or entrap a certain amount of the acids. With H

SiW

entrapped in car-

bon, vapor-phase esterification of acetic acid with ethanol can be conducted effi-

ciently [81CL663].

ZrO

· nH

O and Mo-ZrO

Hydrous ZrO

, which catalyzes reactions between carboxylic acids and alcohols, exhi-

bits the following advantages: (1) the catalyst is easily prepared and stable in air, and

(2) the reaction does not require water-free conditions [89BCJ2353]. The catalytic ac-

tivity is further improved by use of Mo-ZrO

mixed oxide, because electron-deficient

sites are formed by introduction of Mo cations into the lattice of the solid ZrO

[98SC3183].

Experimental Procedure [89BCJ2353]

General Procedures for Vapor-Phase Reactions: The catalytic esterification is carried

out in a glass-flow reactor (6.5 mm in diameter) with a fixed-bed catalyst: flow rate of

1 Reaction of Alcohols with Carboxylic Acids and their Derivatives

O (0.4 g) are placed in a 250 mL round-bottomed flask fitted with a Dean-Stark