Esters of pyromellitic acid. Part I. Esters of achiral alcohols: Regioselective synthesis of partial and mixed pyromellitate esters, mechanism of transesterification in the quantitative esterification of the pyromellitate system using orthoformate esters, and a facile synthesis of the ortho pyromellitate diester substitution pattern

Article abstract of DOI:10.1021/jo800543w

(Chemical Equation Presented) Mild conditions and reversible anhydride formation allow a relative differentiation to be made of the four equivalent carbonyl groups of pyromellitic dianhydride (PMDA, benzene-1,2,4,5- tetracarboxylic dianhydride) in esterification, leading to regioselective methods to generate a wide range of partially or totally esterified products or products bearing differing esterifying groups at the different positions. Pyromellitate monoester anhydrides form efficiently in dichloromethane/ triethylamine from 1 equiv of the alcohol. Under the same conditions, two different alcohols can be made to react sequentially. With 2 equiv of an alcohol, the usual mixture of meta and para diesters is obtained, separated by crystallization from HOAc. Meta and para dibenzyl pyromellitates served as regiospecific sources of other diesters, by further esterification followed by hydrogenolysis. Refluxing orthoformate triesters were found to effect quantitative esterification of the pyromellitate system under autocatalytic conditions; minor ester exchange with pre-existing esters (0-5% of total product) was ascribed to reversible anhydride formation. For general esterification with alcohols, partial ester acid chlorides were obtained using oxalyl chloride. Pyromellitate triesters afforded the ortho diester anhydrides upon distillation, thereby providing facile entry into the mostly novel ortho substitution pattern in this system. The requisite triesters were prepared by selective saponification or by the prior incorporation of one benzyl ester substituent, which could be removed by catalytic hydrogenolysis. The various benzyl esters of pyromellitates hydrogenolyzed smoothly to release the carboxylic acid groups without disturbance of pyromellitate aromaticity.

Full text of DOI:10.1021/jo800543w

Esters of Pyromellitic Acid. Part I. Esters of Achiral Alcohols:
Regioselective Synthesis of Partial and Mixed Pyromellitate Esters,
Mechanism of Transesterification in the Quantitative Esterification
of the Pyromellitate System Using Orthoformate Esters, and a
Facile Synthesis of the Ortho Pyromellitate Diester Substitution
Pattern
John B. Paine III*
Philip Morris U.S.A., Research Center, P.O. Box 26583, Richmond, Virginia 23261
John.B.Paine@pmusa.com
ReceiVed March 10, 2008
Mild conditions and reversible anhydride formation allow a relative differentiation to be made of the
four equivalent carbonyl groups of pyromellitic dianhydride (PMDA, benzene-1,2,4,5-tetracarboxylic
dianhydride) in esterification, leading to regioselective methods to generate a wide range of partially or
totally esterified products or products bearing differing esterifying groups at the different positions.
Pyromellitate monoester anhydrides form efficiently in dichloromethane/triethylamine from 1 equiv of
the alcohol. Under the same conditions, two different alcohols can be made to react sequentially. With
2 equiv of an alcohol, the usual mixture of meta and para diesters is obtained, separated by crystallization
from HOAc. Meta and para dibenzyl pyromellitates served as regiospecific sources of other diesters, by
further esterification followed by hydrogenolysis. Refluxing orthoformate triesters were found to effect
quantitatiVe esterification of the pyromellitate system under autocatalytic conditions; minor ester exchange
with pre-existing esters (0-5% of total product) was ascribed to reversible anhydride formation. For
general esterification with alcohols, partial ester acid chlorides were obtained using oxalyl chloride.
Pyromellitate triesters afforded the ortho diester anhydrides upon distillation, thereby providing facile
entry into the mostly novel ortho substitution pattern in this system. The requisite triesters were prepared
by selective saponification or by the prior incorporation of one benzyl ester substituent, which could be
removed by catalytic hydrogenolysis. The various benzyl esters of pyromellitates hydrogenolyzed smoothly
to release the carboxylic acid groups without disturbance of pyromellitate aromaticity.
Introduction
esters did not appear in the literature4 until the advent of NMR
allowed definite structural assignment of the products.
Pyromellitic dianhydride (PMDA) (1H,3H-benzo[1,2-c:4,5-
c′]difuran-1,3,5,7-tetrone or benzene-1,2,4,5-tetracarboxylic di-
anhydride) (1) is of commercial importance for the production
of specialty polymers1 (e.g., polyimides) and plasticizers.2 De-
spite the importance and ready availability of 1 (several thousand
tons per annum worldwide1 and growing), the reported chem-
istry of PMDA or of pyromellitic acid has been remarkably
sparse, particularly outside the context of polymers. The
tetramethyl (4a) and tetraethyl (4b) esters have been known
since before the first edition of Beilstein,3 but the first partial
Interest here arose in the pyromellitate system while novel
resolving agents were being sought, and it was decided to react
PMDA with (lR,2S,5R)-(-)-menthol. The chemistry of a wide
range of chiral derivatives of pyromellitic acid5 and of other
(1) (a) Bemis, A. G. ; Dindorf, J. A.; Horwood, B.; Samans, C. Phthalic
Acids and other Benzenepolycarboxylic Acids In Kirk-Othmer Encyclopedia of
Chemical Technology, 3rd ed.; John Wiley & Sons: New York, 1982; Vol. 17,
pp 732-777. (b) Park, C.-M.; Sheehan, R. J. Phthalic Acids and other
Benzenepolycarboxylic Acids In Kirk-Othmer Encyclopedia of Chemical Tech-
nology, 4th ed.; John Wiley & Sons: New York, 1996; Vol. 18, pp 991-1043,
particularly 1034-1037.
10.1021/jo800543w CCC: $40.75
Published on Web 06/04/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4929–4938 4929

Paine
SCHEME 1. Alcoholysis of PMDA (1) and Further Esterification of Pyromellitate Diesters with Orthoformates; Illustration of
the Trivial Nomenclaturea
a Compound numbering for 2-8: “a” series, R1 ) Me, R2 ) Et; “b” series, R1 ) Et, R2 ) Me. Reagents and conditions: (a) R1OH, reflux; (b) HC(OR1)3,
reflux; (c) HC(OR2)3, reflux; (d) R1OH, Et3N/CH2Cl2; (e) HCl; (f) H2O/HOAc. Note 1: if en route to 3 and 4.
aromatic polycarboxylic acids6 constitutes the subject of the
following paper and another in preparation. Here, attention will
be confined to the achiral partial and mixed esters of pyromellitic
acid that were prepared in the course of modeling the chemistry
to be applied to chiral analogs. It was found that the unique
features of symmetry and topology of the PMDA system
allowed a considerable relative differentiation to be made among
the four carbonyl groups. This allowed a wide range of
regiospecific products to be prepared efficiently in a readily
isolated and purified form. Of importance to the success of this
work was the development of a mild but efficient esterification
method for the pyromellitate system that minimized transes-
terification of pre-existing esters.
To simplify the following discussion, a trivial nomenclature
will be adopted that is appropriate to the topology of the
benzene-1,2,4,5-tetracarboxylate system. Pyromellitate deriva-
tives containing one or two pairs of identical substituents can
be conveniently referred to as “ortho” (e.g., 8 or 12), “meta”
(e.g., 4 or 7), or “para” (e.g., 3 or 6), in reference to the
respective relative relationships held by the identical substituents.
(4) diesters (Scheme 1),4,7–11 separated by chromatography or
fractional crystallization.
In general, the para diesters (3), functional derivatives of
terephthalic acid, have been found both here and elsewhere to
be less soluble and more easily isolated than their meta analogs
(4), derivatives of isophthalic acid. Evidently the two isomer
series show only a slight tendency to mutual solid solution, since
even the crude first crops of the para diesters have been found
here to be usually isomerically pure, as observed by NMR. The
wide melting range reported9 for para dimethyl pyromellitate
(3a), which was attributed to isomeric impurity, was more likely
due to a decomposition of the material upon fusion. Pyromel-
litate diesters do not melt reversibly or sharply if at temperatures
above ca. 200 °C, regardless of purity, due to the onset of
pyrolytic decomposition involving anhydride formation. For both
1H and 13C NMR, the meta and para diesters are easily dis-
tinguished. C-3 and C-6 and their appended protons are
chemically and magnetically equivalent for the “para” (and
“ortho”) isomers, but distinct for the “meta” isomers.
To achieve the efficient formation of pyromellitate monoesters
(e.g., 9), the supply of reacting alcohol has to be restricted to 1
equiv. PMDA (1) is nearly insoluble in dichloromethane, or in
CH2Cl2 containing either stoichiometric alcohol (primary or
secondary) or triethylamine. However, it was found to dissolve
violently when both are present in stoichiometric amounts,
bringing the solvent to a boil at the concentrations typically
used. (In practice, it became usual to add the amine gradually
to a mixture of the other ingredients.) With 2 equiv of reagents,
Results and Discussion
Alcoholysis of PMDA (1) to Monoesters and Diesters. The
autocatalyzed alcoholysis of PMDA (1) in excess alcohol has
been shown to give the expected mixture of para (3) and meta
(2) (a) Stozhkova; G. A.; Bondarenko, A. V.; Farberov; M. I.; Priborets, V. M.
Uch. Zap. Yarosl. Tekhnol, Inst. 1969, 11, 185–192. (CA 75: 64779s). (b) Sung,
C-K.; Lee, D. C.; Shin, D. K. Haksurwon Nonmunjip, Cha’yon Kwahak P’yon
1974, 13, 9–15. (CA 84: 136493e). (c) Nanu, I.; Tolan, M.; Coseriu, C. Mater.
Plast. (Bucharest, Rom.) 1975, 12, 138–142. (CA 84: 181040r).
(3) Beilstein, Vol. 9, 997-998 (System Number 1025).
(7) Bell, V. L.; Jewell, R. A. J. Polym. Sci. Part A-1 1967, 5, 3043–3060.
(8) Bell, V. L. Polym. Lett. 1967, 5, 941-946; J. Polym. Sci., Part B 1967,
5, 941-946.
(9) Alvino, W. M.; Edelman, L. E. J. Appl. Polym. Sci. 1978, 22, 1983–
1990.
(4) Jones, J. I.; Ochynski, F. W.; Rackley, F. A. Chem. Ind. (London) 1962,
1686–1688.
(10) Nishizaki, S.; Moriwaki, T. Kogyo Kagaku Zaashi 1968, 71, 1559.
(11) Ueda, M.; Takahashi, M.; Hishiki, S.; Imai, Y. J. Polym. Sci. Polym.
Chem. Ed. 1979, 17, 2459–2468.
(5) Paine, J. B. J. Org. Chem. 2008, 73, 4939–4948.
(6) Paine, J. B., III; Pierotti, J. A. Manuscript in preparation.
4930 J. Org. Chem. Vol. 73, No. 13, 2008

Esters of Pyromellitic Acid. Part I
SCHEME 2. Products and Ester-Exchanged Byproducts
Noted from the Reaction of Pyromellitate Partial Esters with
Trialkyl Orthoformatesa
SCHEME 3. Synthesis of Ortho Diethyl Pyromellitate
Anhydride (14) by Pyrolysis of Triethyl Pyromellitate (10b)
and Further Transformations of 14a
a Reagents: (a) HC(OMe)3; (b) HC(OEt)3.
a Reagents and conditions: (a) NaOH, H2O, EtOH, rt; (b) HCl; (c)
pyrolysis/distillation, >180 °C, loss of EtOH; (d) EtOH, reflux; (e) H2O,
HOAc, reflux; (f) MeOH, HC(OMe)3, reflux; (g) HC(OMe)3, reflux.
this boiling was observed to continue for some time after the
solution became homogeneous (a fact more obvious with larger
scale reactions), suggesting that the second anhydride ring to
react was significantly less reactive than the first. Thus, sub-
sequently, when only 1 equiV of an alcohol was used, a
homogeneous reaction mixture was also found to result, and
pyromellitate monoesters (e.g., 9, Scheme 1 or 17, Scheme 4)
could be obtained in good yield upon workup.
since under concentrated preparative conditions, where the
acidity is higher than obtained at high dilution, more favorable
proportions of the para isomer appear to result; here, an isolated
yield of 55% of the para dimethyl ester (3a) was obtained.
Pyromellitate Tetraesters. To esterify the pyromellitate
system beyond the diester stage has generally required condi-
tions that were harsh (prolonged reflux of alcoholic solutions
with mineral acids18 or acylization in concentrated H2SO4
followed by alcoholic quenching19), undesirable (reagents such
as diazomethane or dimethyl sulfate), or impractical3 (silver
salts, alkyl iodides). Such conditions as the Fischer-Speier
synthesis do not lend themselves to selectivity or differentiability
within the pyromellitate system and give only moderately high
yields. A reported20 esterification of pyromellitic acid involving
the use of tertiary amines and p-toluenesulfonyl chloride as
condensing reagents for alcohols appears to be of limited
preparative value. Pyromellitate partial esters had been report-
edly21 esterified further by reaction with olefins under catalysis
by boron trifluoride etherate.
Esterification with Orthoformate Esters. It has been found
here that refluxing orthoformate esters22a,b (triethyl or trimethyl),
taken in permanent excess, effect quantitatiVe esterification of
the pyromellitate system within a few hours (Scheme 1).
Depending on the choice of orthoformate ester, the various
pyromellitate partial esters (such as 3 or 4) are converted to
tetraesters (5) or regiospecific para or meta bis-diesters (6 or 7,
respectively). PMDA (1) reacts directly with mixtures of
orthoformate esters and the corresponding alcohol to give the
A significantly greater reactivity of the first-reacting anhydride
ring of 1 relative to that remaining on the intermediary triethyl-
ammonium salt of the pyromellitate monoester anhydride (e.g.,
the Et3NH+ salt of 2) is consistent with a report12 on the kinetics
of the hydrolysis of PMDA (1): the first anhydride ring to react
reportedly did so at a rate of about 20 times faster than the
second one. Previous syntheses of monoesters had tended to
use great excesses of PMDA in pyridine13,14 or particular
solvents such as dioxane.15 A study had also been made of ester
formation from PMDA in the presence of aqueous alcohols.16
With 2 equiv of an alcohol, however, the two diesters (3 and
4) were formed. These could be isolated by acidification of the
triethylammonium salts with HCl and separated by fractional
crystallization. For products derived from sufficiently bulky
esterifying alcohols, such as benzyl (Scheme 5), a particularly
good solvent system for effecting fractional crystallization
proved to be acetic acid-H2O. The para diester (3 or 21) could
be obtained first from glacial acetic acid; the meta diester (4 or
22) usually crystallized upon aqueous dilution of the filtrates.
The meta to para ratios under the various conditions appear to
fall somewhere in the range of 40:60 to 60:40 as estimated by
NMR and display no obvious correlation to the reaction
conditions. A detailed study was not made of this point. A recent
study used HPLC to determine a slight preference for the
formation of the meta diester (4a)17 from PMDA (1) and
methanol. This result may have been concentration-dependent,
(17) (a) Huang, W.; Gao, L.; Zhang, X.; Xu, J; Ding, M. Macromol. Chem.
Phys. 1996, 197 (4), 1473–1484. (b) Huang, W.; Gao, L.; Yang, Z.; Zhang, X.;
Xu, J; Ding, M. Polymer 1997, 38 (9), 2033–2039.
(18) Sheridan, J. P.; Capeless, M. A.; Martire, D. E. J. Am. Chem. Soc. 1972,
94, 3298–3302.
(12) Kreuz, J. A.; Angelo, R. J.; Barth, W. E. J. Polym. Sci., Part A-1 1967,
5, 2961–2963.
(19) (a) Tolan, M.; Dinca, I. ReV. Chim. (Bucharest, Rom.) 1975, 26, 97–
101. (CA 83: 78051a. (b) Fedorova, V. A.; Donchak, V. A.; Martynyuk-
Lototskaya, A. N. Visn. L’ViV. Politekh. Inst. 1980, 139, 31–33. (CA 95: 24460n)
(20) Urbanska, H.; Urbanski, J. Pol. J. Chem. 1978, 52 (3), 523–528.
(21) Raether, L. O. ; Gamrath, H. R. U.S. Patent 2,975,210, 1961. (CA 56:
3420i).
(13) Apell, H.-J.; Bamberg, E.; Alpes, H.; Lauger, P. J. Membr. Biol. 1977,
31, 171–188.
(14) Fuhrhop, J.-H.; Liman, U. J. Am. Chem. Soc. 1984, 106, 4643–4644.
(15) Naletova, G. P.; Tsypysheva, L. G.; Kruglov, E. A.; Prokof’eva, V. V.
Khim. Fiz.-Khim. Vysokomol. Soedin. 1975, 111–116. (CA 88:37385)
(16) Artem’eva, V. N.; Cupans, P.; Smirnova, E. A.; Denisov, V. M.;
Kukarkin, E. N.; Kudryavtsev, V. V. Zh. Prikl. Khim. (Leningrad) 1990, 63 (3),
655–660.
(22) (a) Cohen, H.; Meier, J. D. Chem. Ind. (London) 1965, 349–350. (b)
Paine, J. B. J. Heterocyclic Chem. 1987, 24, 351–355. (c) Hosangadi, B. D.;
Dave, R. H. Tetrahedron Lett. 1996, 37:35, 6375–6378.
J. Org. Chem. Vol. 73, No. 13, 2008 4931

Paine
SCHEME 4. Benzyl-ester Assisted Synthesis of Pyromellitate Triesters (10)a
a Numbering for compounds 10 and 20: “a” series, R ) Me; “b” series, R ) Et. Reagents and conditions: (a) PhCH2OH, Et3N, CH2Cl2, rt to reflux;
HCl/CH2Cl2 workup; (b) H2O, HOAc, brief reflux; (c) (-COCl)2, CH2Cl2, catalytic HCONMe2, reflux; (d) HC(OR)3, reflux; (e) ROH, Et3N, CH2Cl2, rt; (f)
H2, Pd-C, THF, 1 atm, rt.
tetraesters (5) essentially quantitatively under “single pot”
conditions. The reaction is complete when low-boilers (the
alcohol and corresponding formate ester) cease forming, and
the boiling point of the excess orthoformate ester is permanently
observed in the refluxing vapors. Since no extraneous catalyst
is required (or even desirable),22a workup is a simple matter of
distillation, first to recover the unused reagent and then to
recover the product (5). Due to the vast disparity in vapor
pressure between orthoformate reagent and pyromellitate tet-
raester, even a Kugelrohr can effect total separation of the pair.
The traces of nonvolatile residue left after distillation could be
ascribed to impurities in the PMDA (1), since pure partial esters
afforded no residue when esterified further with orthoformate
and then distilled. The consumption of orthoformate ester in
the reaction was close to the theoretical of 2 molar equiv per
mole of PMDA (1). Traces of water in the alcohol used, minor
losses of reagent vapor to the removed low-boilers, or prior
hydration of some of the PMDA (1) would account for the minor
excess consumption of reagent. The pyromellitate tetraesters are
impervious to orthoformate esters, which are therefore taken in
excess to ensure that the esterification process is driven to
completion.
A most significant feature of the reaction, both from a
mechanistic standpoint and from the angle of practical synthesis,
is that little if any exchange (e.g., <5% of the total product)
appears to occur between the orthoformate ester and esters
already present on the pyromellitate system, under the recom-
mended uncatalyzed conditions. Thus, a pure sample of para
dimethyl pyromellitate7,9 (3a) was converted to para dimethyl
diethyl pyromellitate (6a) in boiling triethyl orthoformate. The
homogeneity of the recrystallized product was readily confirmed
by both NMR and GC/MS. By similar means, reasonably pure
(95+%) samples of the meta (7a ) 7b) and ortho (12) diethyl
dimethyl pyromellitates and the triethyl methyl (11) and ethyl
trimethyl (13) esters were also obtained. [These were of some
interest to see to what extent NMR (1H or 13C) could distinguish
such subtleties as the differential effects of carbomethoxy versus
carboethoxy substitution. Such differences can be seen by
inspecting the tables included in the Supporting Information.
More importantly, the availability of all three dimethyl diethyl
pyromellitate isomers was helpful in elucidating the mechanism
of the minor observed transesterification, discussed below.] Only
a limited number of pyromellitate mixed esters have been
reported to date, usually without explicit isomer attribution.
These include dibutyl di-2-octyl pyromellitate21 and dimethyl
diethyl pyromellitate.23
Mechanism of the Minor Ester Exchange Observed with
Orthoformate Esters and Pyromellitates. Minor ester ex-
change upon pre-existent ester functionality was detected by
GC/MS in several of the systems (Scheme 2). The maximum
extent of ester exchange observed was in the preparation of meta
diethyl dimethyl pyromellitate (7a ) 7b). Both possible
combinations of reagents, viz., meta dimethyl pyromellitate (4a)
with triethyl orthoformate or meta diethyl pyromellitate (4b)
with trimethyl orthoformate, gave product (7a, 7b respectively)
of 95-96% purity. The sole byproduct observed in each case
(11 or 13, respectively) bore three alkyl groups derived from
the orthoformate, and one from the original diester. No homo-
geneous tetraesters (5) corresponding to the orthoformate were
observed in any of the illustrated systems.
It was further noted that no byproduct was observed in the
esterification of ortho diethyl pyromellitate anhydride (14, see
below, Scheme 3) with trimethyl orthoformate and methanol.
Furthermore, the triethyl methyl (11) and ethyl trimethyl (13)
esters, prepared from the appropriate triester (10b or 10a,
respectively), each contained a single byproduct (1% or 4%,
respectively). This was identified as a diethyl dimethyl ester,
the GC/MS fragmentation pattern of which was characteristic
specifically of the ortho isomer 12. As can be seen from the
following discussion, the fragmentation pattern of 12 is easily
distinguishable from the fragmentation patterns of the para (6a)
or meta (7a ) 7b) isomers.
Pyromellitate tetraesters containing only methyl and/or ethyl
substituents have weak molecular ions, usually 2% or less of
the base peak in relative intensity. The most important diagnostic
fragmentation modes involve losing 31 Da if methoxy is present,
45 Da if ethoxy is present, 59 Da (31 + 28) if both methoxy
and ethoxy are present (and strong if methoxy and ethoxy are
adjacent; much weaker if they are not), and 73 Da (45 + 28) if
at least two ethoxy groups are present, and providing maximum
(23) Toker, S. U.S. Pat. 3,326,851 (CA 67: 64908t).
4932 J. Org. Chem. Vol. 73, No. 13, 2008

Esters of Pyromellitic Acid. Part I
SCHEME 5. Benzyl-ester Assisted Synthesis of Para and
Meta Pyromellitate Diestersa
reversibly from the substrate, rather than as a general property
of orthoformate esterification.
The choice of orthoformate esters as a reagent for esterifying
compatible carboxylic acids was reported in 1965,22a but the
method appears to have received surprisingly little use since.
The yields originally reported only ranged from 54% to 94%.
Such yields deceptively appear to be mediocre. However, the
original work tended to include neither an excess of orthoformate
nor an adequate reaction time. By ensuring an excess of
orthoformate reagent and adequate time, esterification can be
driven to completion. This has already been demonstrated with
substrates such as nicotinic acids.22b Orthoformate esterification
compares favorably to a recently reported22c procedure involving
the addition of thionyl chloride to an alcoholic solution of a
phthalic acid or anhydride which proceeded in yields of 61%
to 90%.
Pyromellitate Triesters: Precursors to Ortho Diesters.
While para (3) and meta (4) diesters of pyromellitic acid are
readily available by the direct reaction of PMDA (1) with
alcohols, the ortho diester (e.g., 15) requires esterification of a
pair of adjacent carboxyl groups and therefore has to be prepared
indirectly, when PMDA is the ultimate precursor. One way of
ensuring adjacent esterification is to start with the now readily
obtained tetraesters (e.g., 5b) and attempt a partial saponification
to obtain the desired result. Although reaction with 2 equiv of
alkali led to hopeless mixtures, with 1 equiv of NaOH, useful
quantities of triethyl pyromellitate (10b) could be readily
obtained, albeit in an impure form (Scheme 3).
a Numbering for compounds 25 and 26: “a”-Series: R ) Me; “b”-Series:
R ) Et. Reagents and conditions: (a) PhCH2OH, Et 3N, CH2Cl2, rt to reflux;
(b) (-COCl)2, CH2Cl2, catalytic HCONMe2, reflux; (c) HC(OR)3, reflux;
(d) ROH, Et3N, CH2Cl2, rt; (e) H2, Pd-C, THF, 1 atm, rt.
intensity if two ethoxy groups are adjacent. M-73 Da is thus
the base peak for ortho diethyl dimethyl pyromellitate (12) (at
265 Da), for triethyl methyl pyromellitate (11) (at 279 Da), and
for tetraethyl pyromellitate (5b) (at 293 Da). M-45 Da becomes
the base peak if all ethoxy groups present are nonadjacent and
thus provides the base peak for the meta (7a,7b) or para (6a)
diethyl dimethyl pyromellitates (at 293 Da) and for ethyl
trimethyl pyromellitate (13) (at 279 Da). M-59 Da (at 279 Da)
is strong (about 50% relative intensity) for 7a,b or 6a but weak
(9% relative intensity) for 12. Further differences are laid out
in tabular form in Supporting Information (Table 9).
The hemiphthalate side of a pyromellitate triester (10)
shares with all phthalic acid half-esters a significant interac-
tion between the adjacent carboxyl groups: the ability to form
a cyclic anhydride upon pyrolysis. The reaction between
phthalic anhydrides and alcohols to give phthalate monoesters
(hemiphthalates) is well-known to be thermally reversible. This
reversibility was invoked above as a possible explanation of
the observed transesterification byproducts and can be exploited.
The diester side of a pyromellitate triester (10) may have no
ready path for decomposition open to it, if the esterifying alkyl
groups themselves are thermally stable. [The remarkable thermal
stability of certain pyromellitate tetraesters was considered
noteworthy enough to be mentioned in Beilstein.3] Upon heating
(to above 180 °C), triethyl pyromellitate (10b) proceeded to
expel ethanol and gave ortho diethyl pyromellitate anhydride
(14). In the impure system at hand, any ortho diethyl pyrom-
ellitate (15) present also would be expected to decompose to
give 14. Meanwhile, all of the other pyromellitic acids possibly
present [meta (4b) or para (3b) diesters, the monoester (9b), or
the free parent tetracarboxylic acid] should decompose to
regenerate PMDA (1) itself. Thus in principle, the potentially
complex saponification mixture converged as it decomposed
upon distillation to give only two product anhydrides, 1 and
14. The resulting PMDA (1) was readily removed since it was
poorly soluble in CH2Cl2. Ortho diethyl pyromellitate anhydride
(14) was then readily purified by crystallization.
The above observations are consistent with the following
conclusions: (1) Adjacent (vicinal) diester moieties do not
exchange with alcohol or orthoformate under our conditions.
(Evidence: the ortho diester system leading to 12 produced no
detectable exchanged byproducts). (2) Therefore, ester exchange
is associated with the hemiphthalate moieties of a pyromellitate
and behaves as if it were to occur via reversible thermal for-
mation of the anhydride from such moieties, as will be further
discussed for Scheme 3, below. (Evidence: observation of spe-
cifically the ortho diethyl dimethyl ester 12 as byproduct from
the esterification of triesters 10a or 10b). However, the actual
mechanism could involve an intermediate condensation product
between the carboxylic acid group and the orthoformate ester,
rather than an anhydride group as such. (3) Pyromellitate diesters
do not appear to undergo ester-exchange reactions enroute to
the triester intermediates in the per-esterification (Evidence:
homogeneous tetraesters 5 were not observed among the
products of Scheme 2). (4) Therefore, the ester exchange process
operates primarily at the pyromellitate triester stage. (5) The
exchange process introduces one extra esterifying substituent
derived from the orthoformate reagent. The lack of ester
exchange among pre-existing vicinal diesters implies that these
cannot be converted to orthoesters of pyromellitates by ortho-
formate esters under our conditions. Also, the observed trans-
esterification should be seen as being idiosyncratic to situations
where cyclic anhydrides (or similar intermediates) can form
In practice, the reaction was complicated by the formation
of one additional product, the corresponding tetraester (5b), by
disproportionation. The tetraester was observed to form, even
when high-purity triester samples were pyrolyzed, and so was
not an artifact. Evidently, the evolved alcohols can be intercepted
in part, before distilling from the mixture, by high molecular
J. Org. Chem. Vol. 73, No. 13, 2008 4933

Paine
weight acyclic mixed anhydrides24 of pyromellitate triesters.
That such mixed anhydrides do not persist in the reaction mix-
ture is evidenced by the negligible residue remaining after
Kugelrohr distillation. Tetraester 5b remained in the mother
liquors of the crystallization of 14.
The purified anhydride (14) readily reacted with ethanol to
regenerate pure triethyl pyromellitate (10b). Anhydride-forma-
tion was thus an effective strategy for the purification of the
triester (10b). Alternatively, aqueous hydrolysis (in acetic acid)
of 14 led to the desired ortho diethyl pyromellitate (15) free
acid, isolated as the monohydrate. Methanol and trimethyl
orthoformate converted 14 to ortho diethyl dimethyl pyromel-
litate (12) (Scheme 3), which was found to be free of tran-
sesterified byproducts, as noted above.
followed by esterifying the remaining carboxylate groups with
the desired alcohol, using either orthoformate or acid chloride
chemistry.
A benzyl trialkyl pyromellitate (20) could be generated in a
(nearly) one-pot sequence from PMDA (1) using triethylamine/
dichloromethane, by adding 1 equiv of benzyl alcohol initially,
to be followed after an appropriate delay by the second alcohol.
After an acid workup to remove triethylamine, esterification was
completed on the crude product using the corresponding
orthoformate ester. Kugelrohr distillation of 20 served to remove
some of the ester byproducts. Inasmuch as the initial reaction
of PMDA with benzyl alcohol was not entirely selective,
dibenzyl dialkyl (e.g., 25 and 26, Scheme 5) and tetraalkyl
pyromellitates (5) were present as well. Although impure triester
product (10) resulted after hydrogenolysis, it could be handled
similarly to the crude triester resulting from the saponification
method. Left unexplored was the possible approach of trans-
esterifying tetraethyl pyromellitate (5b) with 1 equiv of benzyl
alcohol to generate 20 and then separating the resulting mixture
by Kugelrohr distillation.
Much purer benzyl trialkyl pyromellitate (20) resulted from
the use of purified monobenzyl pyromellitate (17) in the
synthesis (Scheme 4). The product (in Et3N-CH2Cl2) from the
reaction of PMDA with 1 equiv of benzyl alcohol was shaken
with excess dilute HCl, and the organic phase was isolated
promptly. Under these conditions, monobenzyl pyromellitate
anhydride (16) persisted and could be induced to crystallize. It
proved to crystallize especially well as a 1:1 adduct with acetic
acid, a feature of pyromellitate chemistry shared at least with
the mono-l-menthyl ester analog as well.5 The optimum workup
would then include the addition of acetic anhydride and acetic
acid to the CH2Cl2 phase after the HCl treatment. The resulting
crystalline monobenzyl pyromellitate anhydride (16) hydrolyzed
smoothly in aqueous acetic acid to monobenzyl pyromellitate
(17). When 17 was refluxed with trimethyl or triethyl ortho-
formate, the desired benzyl trialkyl pyromellitates (20a or 20b)
were obtained in near-quantitative yield, and the products
obtained contained only minor (<2%) quantities of the corre-
sponding tetraalkyl esters 5a or 5b. Hydrogenolysis of either
20a or 20b led to the appropriate trialkyl pyromellitate (10a or
10b), from which in turn were also prepared the mixed ethyl
trimethyl (13) and triethyl methyl (11) derivatives, in addition
to the anhydrides (14 and 14a, “Et” ) Me).
Characterization of the anhydrides we report was done by
NMR and not IR spectroscopy. The presence of the anhydride
ring makes itself obvious in 13C NMR spectra of pyromellitate
derivatives, as can be observed by comparing the spectra of 14
and 15. Ortho diethyl pyromellitate 15 has its carboxylic acid
carbonyl groups at δ 171 and its ester groups at δ 165.4, typical
of pyromellitate esters. Anhydride 14 has ester carbonyls at the
normal δ 165.0, but the anhydride carbonyls occur at δ 161.1.
The benzene ring also reflects major differences. Whereas
the unstrained diacid 15 has carbonyl-substituted carbons at
δ 133 and 135 and the protonated carbons at the normal
position at δ 129.7, for the anhydride 14, these carbon
resonances are significantly shifted, occurring at δ 132.9 and
significantly downfield at δ 139.5 for the carbonyl-substituted
carbons and significantly shifted upfield at δ 126.2 for the
protonated carbons. Similar features are also observed in the
other anhydrides we report.
This strategic approach to ortho disubstituted pyromellitates
would appear to be quite general, subject only to limitation by
the possible thermal instability of the chosen esterifying group.
This substitution pattern may well have application in the syn-
thesis of ester-substituted phthalocyanines.25,26
Trimethyl pyromellitate has been reported27 as the result of
a selective saponification of tetramethyl pyromellitate (6a) with
1,1-dimethylhydrazine. This reagent effects SN2 attack on the
ester methyl group to give a 1,1,1-trimethylhydrazinium salt
and may well be ineffective for more hindered esters. A bis
tributylstannyl derivative of ortho substitution pattern has been
reported28 for pyromellitic acid.
Since the orthoformate esters are impractical for most desired
substituents, a more general alternative approach to benzyl
trialkyl pyromellitates was devised involving the use of acid-
chloride chemistry (Scheme 4). Monobenzyl pyromellitate (17)
reacted with excess oxalyl chloride in CH2Cl2 containing
Benzyl Esters of Pyromellitic Acid and Application to
the Regioselective Synthesis of Other Esters. Benzyl Ester
Routes to Triesters. Because of the awkward solubility pro-
perties associated with higher molecular weight materials, other
pyromellitate tetraesters would not be expected to saponify as
smoothly as the ethyl ester (5b). Thus an alternative approach
to pyromellitate triesters was devised employing benzyl esters,
which can be selectively cleaved by catalytic hydrogenolysis
over palladium (Scheme 4). This relied on the prior differentia-
tion of one of the carboxylate groups as a benzyl ester, to be
catalytic N,N-dimethylformamide to give (as evidenced by 13
C
NMR) two principal products. Surprisingly, the originally
expected monobenzyl pyromellitate anhydride acid chloride (18)
was only a minor (<20%) component.29 The principal product
(ca. 80%) proved to be monobenzyl pyromellitate triacid
chloride (19). This actually simplified matters for the case at
hand: the crude triacid chloride (19) as obtained above was
reacted with an excess of an alcohol and Et3N in CH2Cl2 to
(24) Sanchez, L. A.; Wedgewood, A. R. Appl. Spectrosc. 1987, 41 (3), 479–
482.
(29) (a) The current relative inaccessibility of pyromellitate anhydride acid
chlorides such as 15 stymied a facile synthesis of triesters, which would have
entailed their reaction with 2 equiv of an alcohol. Pyromellitic anhydride diacid
chloride has been reported29b and could presumably be used similarly with 3
equiv of an alcohol. (b) Baker, W. R.; Rosenberg, S. H.; Fung, K. L. A.;
Rockway, T. W.; Fakhoury, S. A.; Garvey, D. S.; Donner, B. G.; O’Connor,
S. J.; Prasad, R. N.; Shen, W.; Stout, D. M.; Sullivan, G.M. WO 9634851 A1
961107 (CA 126:59751)
(25) Solov’eva, L. I.; Luk’yanets, E. A. Zh. Obshch. Khim. 1980, 50, 1122–
1131. (CA 93: 87581g). Consultants Bureau translation: pp 907-915.
(26) Cobb, R. L.; Vives, V. C.; Mahan, J. E. J. Org. Chem. 1978, 43, 931–
936.
(27) Kasina, S.; Nematollahi, J. Tetrahedron Lett. 1978, 1403–1406.
(28) Murayama, Y.; Niino, H.; Taki, K. Japanese Patent 68 26,858, 1968
(CA 70:87953e).
4934 J. Org. Chem. Vol. 73, No. 13, 2008

Esters of Pyromellitic Acid. Part I
SCHEME 6. Synthesis of Ortho Dibenzyl Pyromellitate
Anhydride (26)a
give the benzyl trialkyl pyromellitate (20). This could be readily
isolated in pure form by chromatography. Since this chemistry
was all performed with chiral derivatives (l-menthol), the
experimental details are presented in the following paper.5
Benzyl Ester Routes to Diesters. Benzyl esters could be
similarly employed to prepare specific dialkyl pyromellitates
(Scheme 5). The reaction of PMDA (1) with 2 equiv of benzyl
alcohol in Et3N-CH2Cl2, followed by the usual workup, led to
the meta- para mixture of dibenzyl esters30 (21,22). This mixture
could be separated by sequential crystallization from acetic acid
- water. The benzyl ester system was therefore much more easily
separable (by crystallization) than the mixtures derived from
the direct reaction of PMDA with the lower alcohols (methanol,
ethanol, etc.). Thus, pure samples of the para or meta dimethyl
or diethyl pyromellitates (3a,b; 4a,b) were obtained by reaction
of the appropriate pure dibenzyl ester isomer with the desired
orthoformate ester, followed by hydrogenolytic cleavage of the
benzyl groups (Scheme 5). Since the dibenzyl dialkyl pyrom-
ellitates (25, 26) that were prepared were crystalline substances,
any traces of transesterification products were lost in the mother
liquors of the crystallization procedure.
Alternatively, reaction of either dibenzyl ester isomer (21,
22) with oxalyl chloride in CH2Cl2 with DMF catalysis afforded
the crystalline para (23) or meta (24) dibenzyl pyromellitate
diacid chlorides. To avoid solubility losses, for maximal yield
in use, the acid chlorides would be used without purification
and reacted directly with alcohols and Et3N in CH2Cl2. Again,
the examples of this entailed the use of chiral alcohols and so
the experimental procedures for the alcoholysis are deferred until
the following paper.5 The use of a specific dibenzyl ester would
allow the minimal diversion of Valuable alcoholic substrates
into the formation of the “wrong” isomer, an unavoidable feature
of the direct reaction of an alcohol with PMDA. Oxalyl chloride
was used for the acid chloride synthesis rather than thionyl
chloride so as to avoid any chance of sulfur-containing
impurities interfering with subsequent hydrogenolyses.
a Reagents and conditions: (a) PhCH2OH, catalytic NaH, xylene, reflux;
(b) 2 PhCH2OH, Et3N, CH2Cl2, rt to reflux; (c) H2O, HOAc, brief reflux;
(d) pyrolysis in vacuo; distillation.
Triester 29 decomposed in the usual manner upon Kugelrohr
distillation to give benzyl alcohol and the anticipated ortho
dibenzyl pyromellitate anhydride (30), which could be distilled
away from any contaminating 27. The experimental details are
less polished than for the remaining work and are therefore
confined to the Supporting Information. Enough was ac-
complished to demonstrate that the approach was viable; in
particular, it was established that it was possible for the ortho-
paired benzyl esters to survive the pyrolysis conditions, given
a suitably high vacuum.
General Synthesis of Pyromellitate Esters from PMDA.
In principle, the chemistry described herein could allow up to
four different esterifying groups to be appended to the pyrom-
ellitate system. The overall strategy involves sequential esteri-
fication of monobenzyl pyromellitate anhydride (16) by two
different alcohols to generate a tetraester meta/para mixture.
Removal of the benzyl group by hydrogenolysis, and pyrolytic
anhydride formation should lead convergingly from the mixture
to an ortho diester anhydride with two different esterifying
groups. Further alcoholysis will then provide a binary mixture
in need of separation and characterization, before further
esterification.
Since the availability of ortho dibenzyl pyromellitate anhy-
dride (30) would similarly ease the path to a wide range of ortho
pyromellitate diesters, an approach to that substance was
investigated (Scheme 6).
Tetrabenzyl pyromellitate31 (27) was prepared by a method
also used for terpene-derived pyromellitate tetraesters,5 viz., the
base-catalyzed (NaH) transesterification of tetraethyl pyromel-
litate (5b) in boiling xylene with a moderate excess of benzyl
alcohol (Scheme 6). The resulting tetrabenzyl pyromellitate (27)
proved to be far too insoluble in any of the desired solvents to
be of practical use. Therefore, instead of attempting the approach
to 30 by degradation of a tetraester, the alternative of synthesis
by assembly was examined. The above-noted reluctance of
monobenzyl pyromellitate anhydride acid chloride (18) to form
from monobenzyl pyromellitate (17) under our chosen condi-
tions ruled out a smooth synthesis of the tribenzyl ester (29)
involving the reaction of 17 with 2 equiv of benzyl alcohol.
Instead, monobenzyl pyromellitate anhydride (16) was converted
to crude monobenzyl pyromellitate triacid chloride (19), and
the latter was reacted with about 2 equiv of benzyl alcohol.
Crude tribenzyl pyromellitate (29) arose thereby, contaminated
by the poorly soluble tetraester (27) (Scheme 6).
Experimental Section
General Procedures. Reagents were used as received, unless
otherwise noted. Methanol was distilled from magnesium meth-
oxide, benzyl alcohol was distilled (1 atm) from K2CO3, and
triethylamine was distilled twice, the first time being from phthalic
anhydride (this serves to remove lower amines that result from
autoxidation during storage). Mass spectra were obtained under GC/
MS conditions, unless otherwise noted. The Kugelrohr used was
an older version heated by variable transformer, without thermo-
static temperature control; external temperatures varied over a wide
range during distillations. Where xylene is specified as solvent, any
isomer or mixture will do. Melting points were determined (in air)
preliminarily in capillary tubes and then refined using a hot stage
with polarizing microscope and slow heating rates, to better observe
phase transitions.
(30) Takuma, H.; Irisato, Y.; Yoshitome, H. Jpn. Kokai Tokkyo Koho, JP
07140719 A2 950602 (CA 123:213130).
(31) Aoki, N.; Ebisawa, M.; Morya, K. Jpn. Kokai Tokkyo Koho, JP
01121393 A2 890515.
Tetraethyl Benzene-1,2,4,5-tetracarboxylate (Tetraethyl Py-
(32) Campbell, W. P.; Soffer, M. D. J. Am. Chem. Soc. 1942, 64, 417–425.
romellitate) (5b). PMDA (1) (219.3 g, 1.005 mol), triethyl or-
J. Org. Chem. Vol. 73, No. 13, 2008 4935

Paine
thoformate (505 mL, 3.036 mol), and EtOH (120 mL, 100%, 2.056
mol) were refluxed (Vigreux column with “solvent” still head) for
4.5 h. Low-boilers were removed from the trap periodically and
discarded if boiling below 80 °C or recycled if boiling above.
Heating was terminated when the vapor temperature atop the
Vigreux column exceeded and remained above 146 °C with total
reflux. (Reaction completion was confirmed by TLC.) The excess
triethyl orthoformate was removed [rotary evaporator/boiling water
bath, followed by Kugelrohr distillation: bp e142 °C (external)/1
Torr]. The product was recovered by Kugelrohr distillation into a
fresh set of receiver bulbs, bp 185-227 °C (external)/0.5 Torr. The
distillate solidified in the receiver. It was remelted (heat gun) to
facilitate bottling. Yield: 365.5 g (0.998 mol, 99.2%). Mp (of the
solidified distillate) 53.3-55.0 °C (lit.3 53 °C); 1H NMR (CDCl3)
δ 1.38 (12H, t, J ) 7.2 Hz), 4.39 (8H, q, J ) 7.2 Hz), 8.04 (2H,
s); 13C NMR (CDCl3 at 77.1) δ 166.0 (4C), 134.4 (4C), 129.5 (2C),
62.2 (4C), 14.1 (4C); MS, m/z (relative intensity) 366 [M+] (2),
322 (2), 321 (43), 294 (11), 293 (100), 276 (2), 265 (12), 248 (3),
247 (5), 237 (4), 221 (14), 219 (15), 193 (18), 176 (5), 165 (5),
149 (2), 148 (22), 147 (20), 120 (5), 119 (6), 109 (4), 103 (3), 102
(2), 92 (3), 91 (9), 81 (5), 75 (4), 73 (4), 64 (3), 63 (3), 53 (3), 45
(6), 44 (6), 43 (3).
precipitation. After 30 min at 100 °C, the solvent was removed in
vacuo and chased with H2O. The residue crystallized on standing.
It was triturated with minimal H2O. The solids were filtered off,
washed with minimal H2O, and dried. Yield: 6.18 g (0.0188 mol,
94%). Mp 110.0-115.5 °C, with dehydration and partial recrys-
1
tallization; remelted 155.5-161.1 °C; H NMR (CDCl3) δ 1.40
(6H, t, J ) 7 Hz), 4.43 (4H, q, J ) 7 Hz), 7.55 (4H, br s), 8.19
(2H, s); 13C NMR (CDCl3 at 76.9) δ 171.3, 165.4, 135.0, 133.0,
129.7, 62.4, 14.0 (2C each peak). Anal. Calcd for C14H14O8: C,
54.20; H, 4.55. Calcd. for C14H14O8.H2O: C, 51.22; H, 4.91. Found:
C, 50.85; H, 4.78
2,4,5-Tris(ethoxycarbonyl)benzoic Acid (Triethyl Pyromel-
litate) (10b). Method A. A solution of ortho diethyl pyromellitate
anhydride (14, from Method A) (5.85 g, 0.02 mol) in absolute EtOH
(50 mL) was refluxed for 10 min. The solvent was removed in
vacuo, and the residual viscous oil gradually crystallized. Yield:
6.78 g (0.02 mol, quantitative). A sample (5.59 g) was recrystallized
from aqueous acetic acid, with repeated warming and cooling to
overcome a tendency to oil. Recovery: 4.12 g. Mp 73.4-76.3 °C;
1H NMR (CDCl3) δ 1.39 (3H, t, J ) 7 Hz), 1.40 (6H, t, J ) 7 Hz),
4.420 and 4.422 (6H, overlapping q, J ) 7 Hz), 8.03 (H, s), 8.25
(H, s), 10.97 (H, br s); 13C NMR (CDCl3 at 76.9) δ 170.4, 165.96,
165.69, 165.41, 135.33, 135.25, 133.8, 131.9, 130.1, 129.1, 62.42,
62.26 (2C), 14.03 (2C), 13.87 (each peak 1C unless otherwise
noted). Anal. Calcd for C16H18O8: C, 56.80; H, 5.36. Found: C,
56.62; H, 5.67. Method B. A solution of benzyl triethyl pyrom-
ellitate (20b) (21.52 g, 50.23 mmol) in THF (153 mL, freshly
redistilled through a rotary evaporator to remove preservatives or
other nonvolatiles) with 10% Pd/C (0.74 g), was stirred under H2
(1 atm, ambient temperature) until gas uptake ceased. The catalyst
was removed by filtration, and the filtrates were evaporated to
dryness on the rotary evaporator. The resulting residual oil cry-
stallized over several days after seeding. Traces of remaining toluene
were permitted to evaporate as the solidification proceeded. Yield:
quantitative (50.2 mmol, 17 g). Mp 72.0-76.0 °C. The material
was identical (1H and 13C NMR) with material prepared previously
by Method A.
Diethyl 1,3-Dioxo-1,3-dihydroisobenzofuran-5,6-dicarboxy-
late (Ortho Diethyl Pyromellitate Anhydride) (14). Method A.
A magnetically stirred solution of tetraethyl pyromellitate (5b) (73.3
g, 0.20 mol) and thymolphthalein (ca. 200 mg) in EtOH (400.9 g,
100%) was treated, at room temperature, slowly dropwise with a
solution of NaOH (7.25 g, 0.18 mol) in H2O (100 mL). The NaOH
solution was rinsed in with EtOH (24.2 g, 100%). The mixture
was stirred until the indicator faded and then let stand overnight.
The solvent was removed (rotary evaporator), and the residue was
partitioned between H2O (500 mL) and Et2O (250 mL, then 200
mL) [From this, 20.74 g (28.3%) of tetraethyl pyromellitate (5b)
was recovered.] The aqueous phase was acidified with concentrated
HCl (21.4 mL) and extracted with Et2O (2 × 200 mL). The solvent
was removed (rotary evaporator), and the resulting residue (crude
10b, 48.1 g) was distilled (Kugelrohr). Triethyl pyromellitate (10b)
decomposed above ca. 180 °C. The resulting anhydride (14) distilled
over at ca. 265-270 °C (external)/5 Torr (est), solidifying promptly
in the receiver. The yield of crude distillate was 42.4 g. The product
(40.4 g) was stirred with CH2Cl2 (100 mL) until the lumps
disintegrated. Byproduct PMDA (1) (1.6 g) was filtered off and
rinsed with CH2Cl2 (40 mL). n-Hexane (100 mL) was added to the
filtrates, which were then concentrated carefully on a rotary
evaporator at 50 °C until colorless needles separated in quantity.
Further n-hexane (100 mL) was added, and the evaporation
continued until a thick slurry resulted. The solids were filtered off,
rinsed with n-hexane, and then dried in a desiccator over KOH.
Yield: 31.8 g (0.109 mol, 57.1% or 79.6% based on unrecovered
1,2-Diethyl 4,5-Dimethyl Benzene-1,2,4,5-tetracarboxylate
(Ortho Diethyl Dimethyl Pyromellitate) (12). From ortho diethyl
pyromellitate anhydride (14) (5.85 g, 0.02 mol), MeOH (10 mL),
and trimethyl orthoformate (30.7 mL) after reflux (3 h) and
distillation (Kugelrohr) at 218-224 °C (external)/0.34 Torr. The
product was isolated as an oil, in quantitative yield (6.77 g, 0.02
1
mol). H NMR (CDCl3) δ 1.38 (6H, t, J ) 7.1 Hz), 3.94 (6H, s),
4.41 (4H, q, J ) 7.1 Hz), 8.09 (2H, s); 13C NMR (CDCl3 at 77.3)
δ 166.4, 165.9, 134.6, 134.1, 129.6, 62.3, 53.1, 14.1 (2C all peaks);
GC/MS m/z (relative. intensity) 338 [M+] (2), 307 (25), 293 (30),
279 (9), 266 (13), 265 (100), 251 (6), 237 (5), 234 (5), 233 (20),
221 (4), 220 (5), 207 (37), 179 (5), 177 (21), 163 (24), 161 (30),
148 (25), 136 (6), 133 (7), 119 (27), 104 (7), 103 (10), 102 (12),
91 (19), 77 (7), 76 (14), 75 (45), 65 (16), 59 (18). Anal. Calcd for
C16H18O8: C, 56.80; H, 5.36. Found: C, 56.91; H, 5.26.
1
5b). Mp 99-104 °C, with recrystallization at 103.5 °C; H NMR
(CDCl3) δ 1.42 (6H, t, J ) 7.2 Hz), 4.46 (4H, q, J ) 7.2 Hz), 8.33
(2H, s); 13C NMR (CDCl3 at 77.1) δ 165.0, 161.1, 139.5, 132.9,
126.2, 63.0, 14.0 (2 C all peaks); MS (direct probe) m/z (relative
intensity) 293 (1), 292 [M+](2), 265 (2), 248 (5), 247 (32), 237
(1), 221 (2), 220 (9), 219 (100), 192 (3), 191 (4), 176 (3), 175 (5),
174 (18), 148 (10), 147 (54), 120 (4), 119 (11), 103 (8), 102 (36),
91 (30), 76 (2), 75 (14), 74 (37), 73 (14), 65 (3), 63 (9), 62 (6), 61
(2), 53 (4), 51 (4), 50 (3), 47 (6), 45 (14), 44 (6), 43 (5), 39 (1).
Anal. Calcd for C14H12O7: C, 57.54; H, 4.14. Found: C, 57.46; H,
4.01. Method B. A Kugelrohr distillation of triethyl pyromellitate
(10b) (3.39 g, 10.02 mmol), derived from the hydrogenolysis of
benzyl triethyl pyromellitate (20b) (see below), gave 2.81 g (96.0%)
of crude 14 [bp 177-202 °C (external)/0.75-1 Torr].
5-(Benzyloxycarbonyl)-1,2,4-benzenetricarboxylic Acid (Ben-
zyl Pyromellitate) (17). A stirred suspension of PMDA (1)(234.2
g, 1.074 mol) in a solution of benzyl alcohol (110.2 g, 1.019 mol)
in CH2Cl2 (775 mL) was treated, over a 2 min period, with a steady
stream of Et3N (111.5 g, 154 mL, 1.102 mol). The PMDA dissolved
during this addition, and the mixture boiled spontaneously. After
1 h, the solution was filtered, and the apparatus and filter were
rinsed with CH2Cl2 (225 mL). The CH2Cl2 phase was shaken with
concentrated HCl (100 mL) in H2O (530 mL) and quickly isolated
from the aqueous phase, before product could crystallize. The
organic phase soon became thick with solids. These were filtered
off and rinsed with CH2Cl2. A second crop was obtained after
concentrating the filtrates to 25% of the original volume. (See the
preparation of l-menthyl pyromellitate in the following paper5 for
a modification, i.e., workup with acetic acid/acetic anhydride, that
should improve the yield here as well.)
4,5-Bis(ethoxycarbonyl)phthalic Acid Monohydrate (Ortho
Diethyl Pyromellitate Monohydrate) (15). Ortho diethyl pyrom-
ellitate anhydride (14, from Method A) (5.85 g, 0.02 mol) was
dissolved in glacial HOAc (10.0 mL). H2O (10.0 mL) was added
slowly until permanent opalescence. On heating (water bath) it
became possible to add the remaining H2O without causing
4936 J. Org. Chem. Vol. 73, No. 13, 2008

Esters of Pyromellitic Acid. Part I
The light tan monobenzyl pyromellitate anhydride (16) (moist
filter cake) was slurried in glacial HOAc (250 mL) and then rotary
evaporated at 100 °C to remove CH2Cl2. Further HOAc (250 mL)
was added, followed by H2O (100 mL). The slurry was heated
(water bath, 100 °C), and the solids dissolved completely. After a
few minutes, product began to crystallize out. About 400 mL of
the solvent was removed in vacuo (rotary evaporator). Water (100
mL) was added to the remainder, and the product was isolated by
filtration. The solids were washed with 50% (v/v) aqueous acetic
acid and H2O, and then allowed to dry in air. Yield: 159.6 g,
(45.5%). A similar hydrolysis of the second crop anhydride (16)
afforded an additional 37.9 g (10.8%). Total: 197.5 g, (0.574 mol,
added to the magnetically stirred solution (2L Erlenmeyer) over 1
min. The mixture boiled vigorously and cleared as the amine was
added. After standing overnight, the organic phase was shaken with
concentrated HCl (101 mL)-H2O (400 mL), and washed once with
H2O. The organic phase was stirred with Na2SO4 until clear and
then decanted. Glacial acetic acid (300 mL) was added to the
solution, which upon concentration in vacuo (rotary evaporator)
deposited solids. The slurry was filtered, and the product was rinsed
with HOAc. The filtrates, ca. 320 mL, were set aside, and the solids
were rinsed further with 1:1 Et2O-HOAc, and finally Et2O. Yield:
73.6 g (0.169 mol, 33.8%), pure para isomer by NMR. A sample
was recrystallized for analysis from EtOAc-THF. Mp 201.0-206.5
°C (dec); 1H NMR (CD3OD) δ 5.08 (H2O), 5.33 (4 H, s),
7.274-7.438 (10 H, complex m), 8.06 (2 H, s); 13C NMR (CD3OD
at 48.8) δ 168.53, 167.95, 136.67, 136.05, 135.90, 130.5, 129.56
(4 C), 129.47 (4 C), 129.41, 69.1 (all peaks 2C unless otherwise
noted). Anal. Calcd for C24H18O8: C, 66.36; H, 4.18. Found: C,
66.11; H 4.37.
(B) 4,6-Bis(benzyloxycarbonyl)isophthalic Acid (Meta Diben-
zyl Pyromellitate) (22). The HOAc filtrates from the preceding
experiment (320 mL) were diluted with H2O (103 mL), without
causing permanent opalescence. Overnight, the solution deposited
masses of silky fibers. These were filtered off, washed thoroughly
with 50% (v/v) aqueous acetic acid and then H2O, and dried.
Yield: 62.34 g (0.144 mol, 28.6%). This was found to be the
pure meta isomer. The filtrates proved intractable and were
discarded. Total yield of the pure isomers: 62.3%. A sample
was recrystallized for analysis from ethyl acetate. Mp 183.5-187.5
°C; 1H HNR (CD3OD) δ 5.02 (H2O, br s), 5.32 (4 H, s),
7.295-7.426 (10 H, complex m), 7.92 (H, s), 8.19 (H, s); 13C
NMR (CD3OD at 49.0) δ 168.6, 168.0, 136.68, 136.40, 135.6,
131.1 (1C), 129.87 (1C), 129.58 (4C), 129.50 (4C), 129.44, 69.1
(all peaks 2C unless otherwise noted). Anal. Calcd for C24H18O8:
C, 66.36; H, 4.18. Found: C, 66.22; H, 4.05.
1
56.3%). Mp 210.0-222.0 °C (dec); H NMR (CD3OD) δ 4.95
(CO2H, H2O), 5.35 (2H, s), 7.32-7.45 (5H, m), 7.98 (H, s), 8.12
(H, s); 13C NMR (CD3OD at 49.0) δ 169.37, 169.33, 168.7, 168.1,
136.63, 136.55, 136.14, 135.98, 135.42, 130.7, 130.0, 129.55 (2C),
129.43 (2C), 129.40, 69.1 (1C each peak unless otherwise noted).
Anal. Calcd for C17H12O8: C, 59.31; H, 3.51. Found: C, 59.09; H,
3.45.
6-(Benzyloxycarbonyl)-1,3-dioxo-1,3-dihydroisobenzofuran-
5-carboxylic Acid, 1:1 Solvate with Acetic Acid. (Monobenzyl
Pyromellitate Anhydride, 1:1 Acetic Acid Adduct) (16). A
suspension of monobenzyl pyromellitate (17) (34.6 g, 0.101 mol)
in glacial HOAc (100 mL) was heated to boiling. Acetic anhydride
(20 mL) was added. Within minutes, the solids dissolved. After 1
min of further reflux, the hot solution was decanted from the boiling
chips. The cooling solution deposited coarse transparent chunky
needles. These were filtered off, rinsed with EtOAc, EtOAc/hexane,
and finally hexane, and dried over KOH. Yield: 33.71 g (0.0873
mol, 86.8%). Mp 180.5-184.5 °C (dec), after slow heating to drive
1
off acetic acid; H NMR (acetone-d6) δ 1.97 (3 H, s, CH3CO2H),
5.39 (2 H, s, PhCH2O), 7.34-7.42 (3 H, m, Ph), 7.46-7.50 (2 H,
m, Ph), 8.32 (H, d, J ) 0.79 Hz), 8.40 (H, d, J ) 0.78 Hz).
(Spectrum not observed beyond δ 8.9.); 13C NMR (acetone-d6 at
29.8 and 207.0) δ 172.8, 166.36, 166.23, 162.4, (4 peaks for 5
CdO, it was unclear from the spectrum appearance as to which
peak was degenerate, although logically the degenerate peak should
be that for the anhydride carbonyls at 162; significant shifts were
noted here as compared to the l-menthyl analog in CDCl3 (see
following paper); the compound was hydrolyzed in DMSO-d6)
140.4, 139.6, 136.1, 134.53, 134.24, 129.31 (2 C), 129.20 (3 C),
126.7, 126.2, 68.8, 20.5 (1C each peak unless otherwise noted).
Anal. Calcd for C17H10O7: C, 62.58; H, 3.09. Calcd for C17H10-
O7.C2H4O2: C, 59.07; H, 3.65. Found: C, 58.90; H, 3.55.
Dibenzyl 2,5-Bis(chlorocarbonyl)terephthalate (Para Diben-
zyl Pyromellitate Diacid Chloride) (23). Para dibenzyl pyromel-
litate (21) (4.36 g, 0.01 mol), oxalyl chloride (3 mL, 4.37 g, 0.034
mol), N,N-dimethyl formamide (DMF) (3 drops), and dichlo-
romethane (100 mL) were kept overnight at room temperature under
moisture-exclusion conditions. The solution was filtered and then
concentrated in vacuo (50 °C bath) until crystals appeared. n-Hexane
(15 mL) was added to the crystallizing solution in portions. The
dense colorless crystals were filtered, rinsed with 10% (v/v) CH2Cl2
in n-hexane (10 mL) and then n-hexane, and dried over KOH. Yield:
3.52 g (0.008 mol, 80.1%) Mp 129.5-133.5 °C (mostly 131.5-133.5
1-Benzyl 2,4,5-Triethyl Benzene-1,2,4,5-tetracarboxylate (Ben-
zyl Triethyl Pyromellitate) (20b). A mixture of monobenzyl
pyromellitate (14) (36.2 g, 0.105 mol), triethyl orthoformate (150
mL), and EtOH (50 mL, 100%) was refluxed, with periodic removal
of low-boilers, until the vapor temperature reached 146 °C (5
h). Solids persisted for the first 2 h. When TLC (CH2Cl2-SiO2)
showed complete reaction, the excess reagent was removed
(rotary evaporator, then Kugelrohr). The product was distilled
[Kugelrohr, bp 222-237 °C (external)/0.72 to 0.95 Torr]. Yield:
1
°C); H NMR (CDCl3) δ 5.39 (4H, s), 7.36-7.44 (10H, m), 8.14
(2H, s); 13C NMR (CDCl3 at 77.0) δ 166.6, 163.4, 139.7, 134.1,
132.0, 129.2, 128.97, 128.88 (4C), 128.76 (4C), 69.0 (2C each peak
unless otherwise noted). Anal. Calcd for C24H16Cl2O6: C, 61.16;
H, 3.42; Cl, 15.04. Found: C, 61.02; H, 3.44; Cl, 15.22.
Dibenzyl 4,6-Bis(chlorocarbonyl)isophthalate (Meta Diben-
zyl Pyromellitate Diacid Chloride) (24). This was prepared from
meta dibenzyl pyromellitate (22) (8.70 g, 20.03 mmol), oxalyl
chloride (6 mL), and DMF (5 drops) in CH2Cl2 (100 mL). It
crystallized in large chunks from dichloromethane-hexane. Minor
tarry byproduct (Vilsmeier-reagent ?) which contaminated the early
crops was eliminated by fractional crystallization. Yield: 3.93 g
(0.00898 mol, 44.8%) in two crops. Mp 84-87 °C (mostly 85-86
1
43.6 g (0.102 mol, 96.4%) as a viscous oil. H NMR (CDCl3) δ
1.282 (3H, t, J ) 7 Hz, Et), 1.367 (3H, t, J ) 7 Hz, Et), 1.372
(3H, t, J ) 7 Hz, Et), 4.254 (2H, q, J ) 7 Hz, Et), 4.384 (2H,
q, J ) 7 Hz, Et), 4.389 (2H, q, J ) 7 Hz, Et), 5.360 (2H, s,
PhCH2O), 7.314-7.437 (5H, m, Ph), 8.053 (H, s), 8.075 (H, s);
13C NMR (CDCl3 at 77.1) δ 165.95 (3C), 165.85, 134.99, 134.53
(2C), 134.43, 133.96, 129.62, 129.54, 128.65, 128.59 (2C),
128.55 (2C), 68.0, 62.2 (3C), 14.05 (2C), 13.98 (each peak 1C
unless otherwise noted), Anal. Calcd for C23H24O8: C, 64.48;
H, 5.65. Found: C, 64.48; H, 5.76.
1
°C); H NMR (CDCl3) δ 5.39 (4H, s), 7.35-7.43 (10H, m), 7.94
(H, d, J ) 0.5 Hz), 8.37 (H, d, J ) 0.5 Hz); 13C NMR (CDCl3 at
77.0) δ 166.5, 163.6, 139.8, 134.1, 132.0, 131.6 (1C), 128.91,
128.81 (4C), 128.74 (4C), 127.2 (1C), 68.9 (2C each peak unless
otherwise noted). Anal. Calcd for C24H16Cl2O6: C, 61.16; H, 3.42;
Cl, 15.40. Found: C, 61.11; H, 3.49; Cl, 14.79.
Dibenzyl Esters of Pyromellitic Acid (Para and Meta Diben-
zyl Pyromellitate).30 (A) 2,5-Bis(benzyloxycarbonyl)terephthalic
Acid (Para Dibenzyl Pyromellitate) (21). PMDA (1) (109.5 g,
0.502 mol) and benzyl alcohol (111.0 g., 1.027 mol) (freshly
distilled at 1 atm from K2CO3) were suspended in CH2Cl2 (560
mL). Redistilled triethylamine (105.5 g, 145 mL, 1.042 mol) was
Acknowledgment. The encouragement and support of the
management and staff of Philip Morris USA throughout all this
work are gratefully recorded. This work was presented in part
at the 220th National Meeting of the American Chemical Society
J. Org. Chem. Vol. 73, No. 13, 2008 4937

Paine
1
in Washington, DC, August 20-24, 2000, abstracts ORGN 346
and 27; 13C NMR chemical shift comparison tables, and H
and ORGN 518.
NMR chemical shift comparison tables, and mass-spectral
comparison of the methyl/ethyl pyromellitate mixed tetraester
system. This material is available free of charge via the Internet
at http://pubs.acs.org.
Supporting Information Available: Experimental proce-
dures and full characterization for compounds 2a, 2b, 3a, 3b,
4a, 5a, 6a, 6b, 7a, 11, 12, 17a, 22a, 22b, 23a, 23b, and 24;
experimental procedures and partial characterization for 8a, 26,
JO800543W
4938 J. Org. Chem. Vol. 73, No. 13, 2008