Carboxylic Ortho Acid Derivatives: Preparation and Synthetic Applications

562 Pages·1970·9.22 MB·English

by  ROBERT H. DEWOLFE (Eds.)

ORGANIC CHEMISTRY
A SERIES OF MONOGRAPHS
Edited by
ALFRED T. BLOMQUIST
Department of Chemistry, Cornell University, Ithaca, New York
1. Wolfgang Kirmse. CARBENE CHEMISTRY, 1964
2. Brandes H. Smith. BRIDGED AROMATIC COMPOUNDS, 1964
3. Michael Hanack. CONFORMATION THEORY, 1965
4· Donald J. Cram. FUNDAMENTAL OF CARBANION CHEMISTRY, 1965
5. Kenneth B. Wiberg (Editor). OXIDATION IN ORGANIC CHEMISTRY, PART A,
1965; PART B, In preparation
6. R. F. Hudson. STRUCTURE AND MECHANISM IN ORGANO-PHOSPHORUS
CHEMISTRY, 1965
7. A. William Johnson. YLID CHEMISTRY, 1966
8. Jan Hamer (Editor). 1,4-CYCLOADDITION REACTIONS, 1967
9. Henri Ulrich. CYCLOADDITION REACTIONS OF HETEROCUMULENES, 1967
10. M. P. Cava and M. J. Mitchell. CYCLOBUTADIENE AND RELATED COM
POUNDS, 1967
11. Reinhard W. Hoffman. DEHYDROBENZENE AND CYCLOALKYNES, 1967
12. Stanley R. Sandler and Wolf Karo. ORGANIC FUNCTIONAL GROUP
PREPARATIONS, 1968
13. Robert J. Cotter and Markus Matzner. RING-FORMING POLYMERIZATIONS,
PART A, 1969; PART B, In preparation
14. R. H. DeWolfe. CARBOXYLIC ORTHO ACID DERIVATIVES, 1970
15. R. Foster. ORGANIC CHARGE-TRANSFER COMPLEXES, 1969
16. James P. Snyder (Editor). NONBENZENOID AROMATICS, I, 1969
In preparation
C. H. Rochester. ACIDITY FUNCTIONS
Carboxylic Ortho Acid Derivatives
Preparation and Synthetic Applications
ROBERT H. DeWOLFE
UNIVERSITY OF CALIFORNIA
SANTA BARBARA, CALIFORNIA
ACADEMIC PRESS New York and London
COPYRIGHT © 1970, BY ACADEMIC PRESS, INC.
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Preface
This book is a critical survey of the preparation, properties, and reactions of
the principal classes of ortho acid derivatives. It grew out of a literature survey
on the chemistry of ortho esters, undertaken in connection with a research
program. As the survey progressed, it became clear that the voluminous liter­
ature on reactions of ortho acid derivatives, poorly indexed by the abstract
journals, is not readily accessible to one unfamiliar with the field. Yet these
reactions are synthetically useful and mechanistically interesting, and merit the
attention of chemists interested in a broad spectrum of problems.
Ortho acid derivatives are substances which have three or four oxygen, nitro­
gen, sulfur, or halogen atoms bonded to the same carbon atom. The more
important classes of ortho acid derivatives are the ortho esters, the ortho thio-
esters, the amide acetals, the ester aminals, and the ortho amides. These sub­
stances are extremely versatile intermediates in synthetic organic chemistry, and
are the reagents of choice for the preparation of a large number of acyclic and
heterocyclic compounds. In spite of their importance, no recent review of the
chemistry of ortho acid derivatives is available. Post's book on ortho esters,
published twenty-five years ago, covers only about a fourth of the literature on
these compounds. The ortho amides, amide acetals, and ester aminals were
discovered relatively recently, and their chemistry has not been summarized.
ν
vi PREFACE
Where justified, mechanistic interpretations are provided for the various
reactions discussed. Since the long-term value of this type of treatise is as a key
to the literature, I have made every effort to make the bibliography as complete
as possible through mid-1968.
Of the various classes of ortho acid derivatives, two are discussed only as
intermediates in the preparation of other ortho acid derivatives. These are the
halides derived from ortho acids (dihaloethers and haloacetals), and carbonium
salts having two oxygen, nitrogen, or sulfur functions bonded to the carbonium
carbon. Trinitromethane and its derivatives, which differ fundamentally in
their chemical properties from other ortho acid derivatives, are not considered.
I am indebted to Professor Stanley J. Cristol and his colleagues in the
Department of Chemistry at the University of Colorado for their hospitality
during the fall and winter of 1965, when this project was begun, and to my wife
Barbara, whose helpful suggestions contributed much to its completion.
Santa Barbara, California ROBERT H. DEWOLFE
May, 1969
CHAPTER I
Synthesis and Properties of
Carboxylic Ortho Esters and Related Compounds
I. INTRODUCTION
Carboxylic ortho acids, RC(OH) , are hydrates of ordinary carboxylic
3
acids. They are thermodynamically so unstable relative to the carboxylic acid
and water that the equilibrium concentration of ortho acid in aqueous solu
tions of carboxylic acids is ordinarily too small to be detectable (63b).
Although ortho acids themselves have not been isolated, a number of their
derivatives are reasonably stable substances. This chapter discusses the
preparation and properties of carboxylic ortho acid derivatives in which
three oxygen atoms are bonded to an acyl carbon by single bonds—that is,
compounds having the grouping
O—
o—
in their structures.
Substances possessing this structural feature include the carboxylic ortho
esters, RC(OR') , and heterocyclic compounds related to them. Closely
3
related to the ortho esters are peroxy ortho esters, which have an -OOR or
-OOH group bonded to the acyl carbon; hydrogen ortho esters, which have
2 1. CARBOXYLIC ORTHO ESTERS AND RELATED COMPOUNDS
an -OH group bonded to the acyl carbon; and acyloxy ortho esters, which
have an -OCOR group bonded to the acyl carbon.
Several of the reactions used for preparing ortho esters and related com
pounds are widely applicable; their scope, limitations, and mechanisms are
discussed in detail. Other reactions, which were used to synthesize one or a
few ortho esters, or which yield an ortho ester as a by-product, are described
briefly.
The last section of the chapter is a compilation of physical properties of
ortho esters and related compounds, together with methods which have been
used to synthesize each compound and references to the original literature.
This should provide a convenient source of information on known ortho
esters and suggest methods of synthesizing related esters which have not yet
been described in the literature.
II. SYNTHESIS OF ORTHO ESTERS FROM NITRILES AND
IMIDIC ESTERS
A. Introduction
The most generally applicable synthesis of ortho esters involves alcoholysis
of imidic ester hydrochlorides, which are usually prepared by the addition of
an alcohol to a nitrile in the presence of anhydrous hydrogen chloride.
RCN + R'OH + HC1 RC(=NH)OR'+ CI" (1)
2
RC(=NH)OR, + Cl- + 2 R'OH -> RC(OR') + NH + C1" (2)
2 3 4
This reaction, sometimes called the Pinner synthesis, was first used in 1883
for the preparation of a series of trialkyl orthoformates from hydrogen
cyanide (275, 276). Pinner, whose main interest was the preparation and
properties of imidic esters and their salts (278), alcoholyzed only alkyl
formimidate salts.
A quarter of a century elapsed before Pinner's reaction was used to
synthesize ortho esters from nitriles. In 1907 Reitter and Hess described the
preparation of triethyl orthoacetate and triethyl orthopropionate [Eq. (2),
R = CH , C H ; R' = C H ] by this method (286). Fifteen years later
3 2 5 2 5
Staudinger and Rathsam prepared triethyl phenylorthoacetate from phenyl-
acetonitrile (333), and shortly after this Sah reported the synthesis of a series
of orthoacetates and phenylorthoacetates from the corresponding nitriles
(309, 311, 313). In 1935 Brooker and White described improved procedures
for the conversion of nitriles to ortho esters, and reported the synthesis of
trimethyl esters of orthopropionic, orthobutyric, orthovaleric, orthocaproic,
SYNTHESIS FROM NITRILES AND IMIDIC ESTERS 3
and orthoisocaproic acids, as well as triethyl phenoxyorthoacetate and triethyl
orthobenzoate (50).
Most of our knowledge of the mechanism of the Pinner synthesis and the
side reactions which interfere with it is due to McElvain and co-workers, who
used the reaction to prepare ortho esters as intermediates in the synthesis of
ketene acetals (35, 202, 203, 206, 208, 213, 214, 217, 221-223, 225-230).
B. Synthesis of Imidic Ester Hydrochlorides
The synthesis of ortho esters from nitriles is usually carried out as a
two-step process, the first step of which is preparation of an imidic ester
hydrochloride [Eq. (1)].
Preparation of lower aliphatic imidic ester hydrochlorides usually involves
addition of a slight excess of anhydrous hydrogen chloride to a chilled solu­
tion of 1 equivalent of the nitrile in about 1.1 equivalents of the alcohol. The
resulting solution is allowed to stand in the cold until the imidate hydro­
chloride begins to precipitate. Anhydrous diethyl ether is then added to the
reaction mixture, the suspension is allowed to stand in the cold, and the
imidic ester hydrochloride is collected by suction filtration and freed from
solvent and hydrogen chloride. In a variant of this procedure the ether is
added before the hydrogen chloride. Yields of imidic ester hydrochlorides
usually exceed 70% of theoretical and may be nearly quantitative. The dry
salts are reasonably stable if protected from moisture. Detailed procedures
are described in the literature (127, 132, 222, 236, 309).
The purpose of the ether is to prevent the imidate salt from crystallizing
in a hard cake containing occluded solvent and reactants. It does not improve
yields. Other inert solvents, including benzene, chloroform, nitrobenzene, and
1,4-dioxane have also been used. Dioxane is particularly useful as a solvent
and diluent if the nitrile is only slightly soluble in ether (46, 167, 223).
1. FACTORS INFLUENCING RATES AND YIELDS IN IMIDATE SYNTHESES
Although satisfactory yields of imidic ester hydrochlorides are obtainable
from most nitriles, both the yield of the imidate salt and its rate of formation
are influenced by the structure of the nitrile.
Yields seem to be determined mainly by steric factors. For example, ethyl
isovalerimidate hydrochloride was obtained in only 35-40% yields under
conditions which gave yields of imidic ester hydrochlorides of 70% or higher
from most aliphatic nitriles (222). Some ^-substituted benzonitriles and some
α-naphthonitriles cannot be converted to imidic ester hydrochlorides by
Pinner's method (191, 277), and 2,2-diphenyl-4-chlorobutyronitrile did not
4 1. CARBOXYLIC ORTHO ESTERS AND RELATED COMPOUNDS
react with alcoholic hydrogen chloride in 44 days (166). Yields reported in the
literature for syntheses of a number of imidic ester hydrochlorides from the
corresponding nitriles are given in Table I.
TABLE I
YIELDS OBTAINED IN THE SYNTHESIS OF IMIDIC ESTER HYDROCHLORIDES AND ORTHO
ESTERS
Yield of Yield of
RC(=NH)OR' + Cl- RC(OR') from Refer­
2 3
R R' from RCN RC(=NH)OR/ + Cl- ences
2
Η CH 90 74 236
3
Η C2H5 90 70 236
CH C2H5 90 77 222
3
C2H5 CH 88 69 50
3
C2H5 CH 90 77 222
2 5
C3H7 CH 77 79 208, 214
3
C3H7 CHs 67 62 222
2
CH(CH) CH 99 70 202
3 2 3
CH(CH) CH 80 28 222
3 2 2 5
C4H9 CH 79 79 214
3
C4H9 C2H5 75 60 222
CHCH(CH) C2H5 37 22 222
2 3 2
C5H11 CH 75 40 50
3
(CH)CH(CH) CH 71 9 50
2 2 3 2 3
Cyclopentyl CH 97 84 225
3
Cyclohexyl CH 100 58 225
3
C7H15 CH — 68 214
3
CeHi7 CH 79 78 214
3
CH C2H5 90 30 50,168
6 5
CHCH(CH) CH 91 21 227
6 5 3 3
C6H5CH2 CH 95 67 226
3
C6H5CH2 C2H5 75 66 226
CeHsCL^CH^ CH 38 30 217
2 5
C1CH CH5 85 72 222
2 2
NCCH CH 87 65 223
2 3
NCCH CH 99 62 223
2 2 5
CHSCH CH — 25 169
3 2 2 5
CHOCH CH 88 47 230
2 5 2 2 5
(CHO)CH C2H5 71 12 206
2 s 2
C H OCH C2H5 82 30 50
6 5 2
C H50 CCH2 C2H5 93 82 223
2 2
NCCHCH CH 80 77 223
2 2 3
C1CH2CH CH 92 84 223
3 2 3
CH 0 CCH CH2 CH 93 63 223
3 2 2 3
SYNTHESIS FROM NITRILES AND IMIDIC ESTERS 5
The rate of reaction of nitriles with alcoholic hydrogen chloride is in
fluenced by both steric and electronic factors. Rates of formation of ethyl
imidate hydrochlorides decrease as the size of R in RCN increases. In the
case of hydrogen cyanide, the exothermic addition reaction is so rapid that
special care must be taken to provide for adequate cooling (59, 236). With
acetonitrile, the reaction is complete in 2 hours, and with propionitrile about
6 hours are required (222). One to 2 days is an adequate reaction period for
most of the higher aliphatic nitriles.
No systematic study of electronic substituent effects on rate of imidic ester
formation has been reported. The limited data available indicate that, as
expected for a nucleophilic addition, electron-withdrawing substituents in
the nitrile facilitate formation of the imidate hydrochloride. For example,
bromo- and chloroacetonitrile react with phenol and hydrogen chloride much
more rapidly than does acetonitrile (213).
2. ALCOHOLS USED IN THE PINNER IMIDIC ESTER SYNTHESIS
The alcohols most often used in the preparation of imidic ester hydro
chlorides are methanol and ethanol. Other primary alcohols such as 1-pro-
panol (122), 1-butanol (271), 1-decanol (271), 2-methyl-l-propanol (279), and
benzyl alcohol (148) have also been used, as have the secondary alcohols
2-propanol (67) and 2-butanol (336). Phenols have also been used (147, 213).
Most of these imidic ester hydrochlorides were not converted to ortho esters.
A more detailed survey of the literature on imidic ester syntheses is given by
Roger and Nielson (302).
3. SIDE REACTIONS IN THE SYNTHESIS OF IMIDIC ESTER HYDROCHLORIDES
The most serious competing reaction in the conversion of nitriles to imidic
ester hydrochlorides is decomposition of the imidate salt to an amide and an
alkyl chloride [Eq. (3)]. This reaction is minimized by carrying out the
addition reaction at low temperatures.
RC(=NH+)OR/Cl- -> RCONH + R'Cl (3)
2 2
C. Alcoholysis of Imidic Ester Hydrochlorides
Imidic ester hydrochlorides are converted to ortho esters by reaction with
alcohols [Eq. (2)]. In the simplest alcoholysis procedure a solution of the
imidic ester hydrochloride in an excess of the alcohol is allowed to stand at
room temperature until precipitation of ammonium chloride is complete (50,
309, 311, 313). This process is time-consuming (up to 6 weeks is required for
complete reaction in some cases), and frequently gives poor yields of the
ortho ester.