Access to aryl mellitic acid esters through a surprising oxidative esterification reaction

Article abstract of DOI:10.1021/jo5005185

A serendipitously discovered oxidative esterification reaction of cyclohexane hexacarboxylic acid with phosphorus pentachloride and phenols provides one-pot access to previously unknown aryl mellitic acid esters. The reaction features a solvent-free digestion and chromatography-free purifications and demonstrates the possibility of cyclohexane-to-benzene conversions under relatively mild, metal-free conditions.

Full text of DOI:10.1021/jo5005185

Note
pubs.acs.org/joc
Access to Aryl Mellitic Acid Esters through a Surprising Oxidative
Esterification Reaction
Margarita R. Geraskina, Mark J. Juetten, and Arthur H. Winter*
Department of Chemistry, Iowa State University, 2101d Hach Hall, Ames, Iowa 50011, United States
S
* Supporting Information
ABSTRACT: A serendipitously discovered oxidative esterification re-
action of cyclohexane hexacarboxylic acid with phosphorus pentachloride
and phenols provides one-pot access to previously unknown aryl mellitic
acid esters. The reaction features a solvent-free digestion and chromato-
graphy-free purifications and demonstrates the possibility of cyclohexane-
to-benzene conversions under relatively mild, metal-free conditions.
Table 1. Optimization of Reaction Conditions
umerous synthetic methods are known to make alkyl
1−5
Nesters of mellitic acid,
but aryl esters of mellitic acid
yield
temp (°C) PCl5 (equiv) time (step 1, step 2, step 3) (h) (isolated %)
a
have not been reported to date. We are interested in aryl esters
of mellitic acid because of their possible use as scaffolds for fast-
releasing domino self-immolative linkers,6 but they are also
structurally interesting paddlewheel motifs that may find use as
the cores of hexagonally branched dendrimers. Additionally,
some hindered mellitic acid esters are of interest for their
anomalous fluorescence behavior.7
130
130
130
130
130
130
100
160
6
9
1, 4, 2
1, 4, 2
1, 4, 2
1, 1, 1
24, 24, 24
1, 4, 2
1, 4, 2
1, 4, 2
49
31
63
45
52
0
12
12
12
18
12
12
Perhaps unsurprisingly given the absence of all methods to
prepare these structures in the literature, all our attempts to
prepare aryl mellitic acid esters via its acid chloride or through
direct esterification of mellitic acid with standard coupling
reagents (DCC/DMAP, PyBOP, CDI, etc.) were unsuccessful.
In contrast, alkyl esters of mellitic acid can be made easily
through these methods. The sterically hindered nature of these
aryl esters may explain why they are difficult to prepare via
direct methods. Fortunately, we serendipitously discovered a
surprising oxidative esterification reaction by digesting all-cis-
1,2,3,4,5,6-cyclohexanehexacarboxylic acid with phosphorus
pentachloride and phenols that leads to the ring-oxidized aryl
mellitic acid esters in one pot. The aryl esters can be purified
through washing procedures, avoiding chromatography.
The reaction optimization, which was performed using p-
methoxyphenol, included variation of following parameters:
equivalents of PCl5, temperature, and time for each reaction
step (Table 1). It was found that 12 equiv of PCl5 (2 equiv per
acid moiety) results in the best yield for solvent-free digestion
at 130 °C. Addition of pyridine in the final step was used in all
cases except for the synthesis of mellitic acid, where addition of
water led to product in the absence of pyridine.
58
47
a
step 1 = PCl5 digestion; step 2 = addition of phenol; step 3 = addition
of pyridine.
methoxy phenol, alkyl phenols) as well as some electron-poor
phenols (halophenols, cyanophenol) with some exceptions.
Using our standard conditions, 4-nitrophenol, 2,2′-bisphenol, 4-
phenylphenol, 4-acetamidophenol, 4-tert-butylphenol, and 1-
and 2-naphthol failed to yield the corresponding mellitic acid
ester in significant quantities. Additionally, it was possible to
use alkyl alcohols instead of phenols, but we observed some
conversion of the alcohols to the alkyl chlorides during the PCl5
digestion step and the alkyl esters of mellitic acid are difficult to
separate from the P(OR)3 byproduct. Given that there are
numerous methods to make alkyl esters of mellitic acid via
standard procedures, we did not pursue these oxidative alkyl
esterification reactions further. Further, we note that reaction
with water instead of a phenol led to mellitic acid as an
inseparable mixture with phosphoric acid. Thus, the mellitic
acid was converted to its methyl ester to determine the reaction
yield in this one case (see the Experimental Section for details).
Mechanistic Considerations. A few additional experi-
ments shed some light on the mechanism of this remarkable
oxidative esterification reaction. First, the reaction appears to be
The reactions to prepare the aryl mellitic acid esters are one-
pot, solvent-free reactions that can be performed under air and
give products that can be purified by washing procedures to
free the aryl mellitic acid esters from byproducts (typically
P(OAr)3) and pyridine). As can be seen in Scheme 1, the
reaction can tolerate both electron-rich phenols (e.g., p-
Received: March 4, 2014
Published: May 9, 2014
© 2014 American Chemical Society
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The Journal of Organic Chemistry
Note
ring to benzene. Second, given that addition of phenols to the
acid chloride of mellitic acid leads to no esterification, it is likely
that esterification occurs prior to ring oxidation. In contrast,
esterification of the acid chloride of 1,2,3,4,5,6-cyclohexanehex-
acarboxylic acid with phenols proceeds to give the cyclohexane
hexaester in normal fashion, possibly due to a more flexible
cyclohexane ring leading to less steric hindrance between the
aryl esters. Finally, subjecting the hexaaryl ester of 1,2,3,4,5,6-
cyclohexanehexacarboxylic acid to the reaction conditions leads
to oxidation of the cyclohexane to the benzene ring, lending
support to the possibility of esterification followed by oxidation.
Additionally, the mechanism is indifferent to the stereo-
chemistry of the starting material. Reacting the all-trans-
1,2,3,4,5,6-cyclohexanehexacarboxylic acid leads to essentially
identical yields as the all-cis stereoisomer (although the all-cis
stereoisomer is available commercially, leading to our
preference to using that stereoisomer as the starting material).
As to the oxidation mechanism itself, one possibility is that it
follows an α chlorination/elimination mechanism. PCl5 is
known to be in an equilibrium with PCl3 and Cl2 at elevated
temperatures,8 so Cl2 may play a role in the oxidation process.
It may be the case that the contiguous adjacent acid groups in
the starting material allow for milder α chlorination. We tested
the importance of Cl2 in the oxidation by performing the same
reaction with PCl3 (which lacks the ability to form Cl2) and
obtained esterified product that was not ring oxidized. This
experiment implicates Cl2 as the likely oxidant in this reaction.
Isolated yields are not affected by running the reaction under
air or argon, suggesting molecular oxygen is not playing a role
in the oxidation mechanism. We also considered that pyridine
might play a role in the oxidation mechanism (e.g., by forming
N-chloropyridinium), but given that mellitic acid can be formed
by addition of water instead of a phenol without adding
pyridine, this possibility seems to be less likely. Additionally,
without pyridine we obtain the product esters, albeit in
somewhat diminished yields. The combination of these
experiments led us to suggest the mechanism shown in Scheme
2.
Scheme 1. Scope of Oxidative Esterification
Although we were unable to obtain X-ray quality crystals of
the esters, density functional theory computations (B3LYP/6-
31G(d)) on 2 suggest the phenyl rings adopt an interesting
paddlewheel-like structure to minimize strain. See Figure 1.
Scheme 2. Plausible Mechanism of Oxidative Esterification
Reaction
specific to the 1,2,3,4,5,6-cyclohexanehexacarboxylic acid
scaffold. Subjecting 1,3,5-cyclohexanetricarboxylic acid (all-cis)
and 1,2-cyclohexanedicarboxylic acid (both cis and trans) leads
to typical esterification with no oxidation of the cyclohexane
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mixture, which as heated at the same temperature for 4 h followed by
addition of pyridine (3 mL). The reaction mixture was refluxed for 2 h.
Pyridine was distilled off, and the reaction mixture was filtered and
solid product was washed with cold methanol to afford 0.429 g (67%)
1
of the product as a white amorphous solid. Mp: 248.0−249.0 °C. H
NMR (600 MHz): δ (ppm) 7.14 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 9.0
Hz, 2H), 2.35 (s, 3H). 13C NMR (150 MHz): δ (ppm) 163.5, 148.2,
136.6, 134.5, 130.3, 121.1, 21.1. HRMS (ESI) m/z: [M + Na]+ calcd
for C54H42NaO12 905.2574, found 905.2526.
Mellitic Acid (Hexa-4-ethylphenyl) Ester (4). PCl5 (1.794 g, 8.6
mmol) was added to 1,2,3,4,5,6-cyclohexanehexacarboxylic acid (0.250
g, 0.7 mmol) and digested for 1 h at 130 °C. Then 4-ethylphenol
(3.508 g, 28.7 mmol) was added to reaction mixture, which was heated
at the same temperature for 4 h followed by addition of pyridine (3
mL). The reaction mixture was refluxed for 2 h. Pyridine was distilled
off, the reaction mixture was filtered, and solid product was washed
with cold methanol to afford 0.435 g (63%) of the product as a beige
amorphous solid. Mp: 189.0−190.0 °C. 1H NMR (600 MHz): δ
(ppm) 7.16 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.5 Hz, 2H), 2.65 (q, J =
8.0 Hz, 2H), 1.24 (t, J = 8.0 Hz, 3H). 13C NMR (150 MHz): δ (ppm)
163.4, 148.4, 142.9, 134.5, 129.1, 121.1, 28.5, 15.7. HRMS (ESI) m/z:
[M + Na]+ calcd for C60H54NaO12 989.3513, found 989.3520.
Mellitic Acid (Hexa-4-isopropylphenyl) Ester (5). PCl5 (1.794
g, 8.6 mmol) was added to 1,2,3,4,5,6-cyclohexanehexacarboxylic acid
(0.250 g, 0.7 mmol) and digested for 1 h at 130 °C. Then 4-
isopropylphenol (3.911 g, 28.7 mmol) was added to reaction mixture,
which was heated at the same temperature for 4 h followed by addition
of pyridine (3 mL). The reaction mixture was refluxed for 2 h. Pyridine
was distilled off, and the reaction mixture was filtered, the solid
product was washed with cold methanol to afford 0.169 g (22%) of the
Figure 1. Density functional theory (B3LYP/6-31G(d)) computed
structure of 2 showing paddlewheel-like arrangement of the aryl rings:
left, side view; right, top view.
In conclusion, we have developed a simple procedure to
access previously unknown aryl mellitic acid esters via a novel
oxidative esterification reaction. This approach has obvious
synthetic advantages as the reaction is carried out via a solvent-
free, one-pot digestion and has a washing workup that avoids
chromography. This reaction is novel because oxidations of
cyclohexane rings to benzene typically require high temper-
atures in excess of 200 °C and a metal catalyst, whereas this
reaction is performed in the absence of metal and at
comparatively low temperatures. Aryl mellitic acid esters may
prove to be useful in domino self-immolative linkers or as the
cores of structurally interesting dendrimers.
EXPERIMENTAL SECTION
■
1
product as a yellow amorphous solid. Mp: 201.0−203.5 °C. H NMR
General Procedure. Aryl mellitic acid esters were prepared by
using PCl5 (1.794 g, 8.6 mmol) and 1,2,3,4,5,6-cyclohexanehexacar-
boxylic acid (0.250 g, 0.7 mmol). This mixture was digested for 1 h at
130 °C. Various phenols were then added in excess to the reaction
mixture, which was heated at the same temperature for 4 h followed by
addition of pyridine (3 mL). The reaction mixture was allowed to
continue refluxing for 2 h. Pyridine was distilled off, and the product
was filtered and washed with cold methanol or acetone. The target
(600 MHz): δ (ppm) 7.18 (d, J = 8.5 Hz, 2H), 7.06 (d, J = 8.5 Hz,
2H), 2.91 (m, 1H), 1.25 (s, 6H). 13C NMR (150 MHz): δ (ppm)
163.4, 148.4, 147.5, 134.5, 127.6, 121.1, 33.8, 24.1. HRMS (ESI) m/z:
[M + Na]+ calcd for C66H66NaO12 1073.4452, found 1073.4460.
Mellitic Acid (Hexa-4-methoxyphenyl) Ester (6). PCl5 (1.794
g, 8.6 mmol) was added to 1,2,3,4,5,6-cyclohexanehexacarboxylic acid
(0.250 g, 0.7 mmol) and digested for 1 h at 130 °C. Then 4-
methoxyphenol (3.565 g, 28.7 mmol) was added to reaction mixture,
which was heated at the same temperature for 4 h followed by addition
of pyridine (3 mL). The reaction mixture was refluxed for 2 h. Pyridine
was distilled off, the reaction mixture was filtered, and the solid
product was washed with cold methanol to afford 0.442 g (63%) of the
1
product was characterized by H NMR, 13C NMR, and HRMS.
Mellitic Acid (1). PCl5 (1.794 g, 8.6 mmol) was added to
1,2,3,4,5,6-cyclohexanehexacarboxylic acid (0.250 g, 0.7 mmol) and
digested for 1 h at 130 °C. Then water (10 mL) was added to the
reaction mixture, which was heated at the same temperature for 4 h.
Water was removed using a rotary evaporator, leaving a white solid in
the flask that contained mellitic acid and phosphoric acid byproduct,
which made purification and yield determination difficult. To find the
percent yield, the mellitic acid/byproduct mixture was derivatized by
esterification to methyl ester of mellitic acid using a known procedure9
which has a yield of 81% (verified independently by us). The yield
from starting material to the mellitic acid methyl ester was 0.291g
(54%). From this, we could determine that the reaction to form
mellitic acid 1 affords 0.162 g (66%). 13C NMR (150 MHz): δ (ppm)
169.3, 133.7.
1
product as a white amorphous solid. Mp: 223.0−223.5 °C. H NMR
(600 MHz): δ (ppm) 7.05 (d, J = 9.0 Hz, 2H), 6.85 (d, J = 9.0 Hz,
2H), 3.80 (s, 3H). 13C NMR (150 MHz): δ (ppm) 163.6, 158.1,
143.9, 134.5, 122.2, 114.8, 55.8. HRMS (ESI) m/z: [M + Na]+ calcd
for C54H42O18Na 1001.2263, found 1001.2291.
Mellitic Acid (Hexa-4-chlorophenyl) Ester (7). PCl5 (1.794 g,
8.6 mmol) was added to 1,2,3,4,5,6-cyclohexanehexacarboxylic acid
(0.250 g, 0.7 mmol) and digested for 1 h at 130 °C. Then 4-
chlorophenol (3.692 g, 28.7 mmol) was added to reaction mixture,
which was heated at the same temperature for 4 h followed by addition
of pyridine (3 mL). The reaction mixture was refluxed for 2 h. Pyridine
was distilled off, the reaction mixture was filtered, and the solid
product was washed with cold acetone to afford 0.423 g (58%) of the
Mellitic Acid Hexaphenyl Ester (2). PCl5 (1.794 g, 8.6 mmol)
was added to 1,2,3,4,5,6-cyclohexanehexacarboxylic acid (0.250 g, 0.7
mmol) and digested for 1 h at 130 °C. Then, phenol (2.703 g, 28.7
mmol) was added to reaction mixture, which was heated at the same
temperature for 4 h followed by addition of pyridine (3 mL). The
reaction mixture was allowed to continue refluxing for 2 h. Pyridine
was distilled off, the reaction mixture was filtered, and the solid
product was washed with cold methanol to afford 0.341 g (60%) of the
1
product as a white amorphous solid. Mp: > 260 °C. H NMR (600
MHz): δ(ppm) 7.34 (d, J = 9.0 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H). 13C
NMR (150 MHz): δ (ppm) 162.7, 148.6, 134.4, 132.9, 130.1, 122.5.
Anal. Calcd for C48H24Cl6O12: C, 57.29; H, 2.39. Found: C, 57.05; H,
2.18%.
1
Mellitic Acid (Hexa-4-bromophenyl) Ester (8). PCl5 (1.794 g,
8.6 mmol) was added to 1,2,3,4,5,6-cyclohexanehexacarboxylic acid
(0.250 g, 0.7 mmol) and digested for 1 h at 130 °C. Then 4-
bromophenol (4.968 g, 28.7 mmol) was added to reaction mixture,
which was heated at the same temperature for 4 h followed by addition
of pyridine (3 mL). The reaction mixture was refluxed for 2 h. Pyridine
was distilled off, the reaction mixture was filtered, and the solid
product was washed with cold acetone to afford 0.453 g (50%) of the
product as a yellow amorphous solid. Mp: 230.5−231.5 °C. H NMR
(600 MHz): δ (ppm) 7.35 (t, J = 7.0 Hz, 2H), 7.28 (t, J = 7.0 Hz, 1H),
7.14 (d, J = 8.0 Hz, 2H). 13C NMR (150 MHz): δ (ppm) 163.2, 150.4,
134.5, 129.8, 127.0, 121.4. HRMS (ESI) m/z: [M + H2O]+ calcd for
C48H32O13 816.1843, found 816.2109.
Mellitic Acid Hexa(4-methylphenyl) Ester (3). PCl5 (1.794 g,
8.6 mmol) was added to 1,2,3,4,5,6-cyclohexanehexacarboxylic acid
(0.250 g, 0.7 mmol) and digested for 1 h at 130 °C. Then 4-
methylphenol (p-cresol, 3.105 g, 28.7 mmol) was added to reaction
1
product as a beige amorphous solid. Mp: > 260 °C. H NMR (600
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Note
MHz): δ (ppm) 7.49 (d, J = 9.0 Hz, 2H), 6.97 (d, J = 9.0 Hz, 2H). 13
C
(3) Kotha, S.; Khedkar, P. Eur. J. Org. Chem. 2009, 730.
NMR (150 MHz): δ (ppm) 162.6, 149.1, 134.4, 133.1, 122.9, 120.6.
HRMS (ESI) m/z: [M + Na]+ calcd for C48H24Br6NaO12 1294.6204,
found 1294.6212.
(4) Saino, N.; Amemiya, F.; Tanabe, E.; Kase, K.; Okamoto, S. Org.
Lett. 2006, 8, 1439.
(5) Takeuchi, R.; Nakaya, Y. Org. Lett. 2003, 5, 3659.
(6) Mahoney, K. M.; Goswami, P. P.; Winter, A. H. J. Org. Chem.
2013, 78, 702.
(7) Yamasaki, N.; Inoue, Y.; Yokoyama, T.; Tai, A.; Ishida, A.;
Takamuku, S. J. Am. Chem. Soc. 1991, 113, 1933.
(8) Berger, U.; Dannhardt, G.; Wiegrebe, W. Arch. Pharm.
(Weinheim) 1984, 317, 488.
(9) Ranganathan, S.; Muraleedharan, K. M.; Chandrashekhar Rao, C.
H.; Vairamani, M.; Karle, I. L.; Gilardi, R. D. Chem. Commun.
(Cambridge) 2001, 2544.
Mellitic Acid (Hexa-4-fluorophenyl) Ester (9). PCl5 (1.794 g,
8.6 mmol) was added to 1,2,3,4,5,6-cyclohexanehexacarboxylic acid
(0.250 g, 0.7 mmol) and digested for 1 h at 130 °C. Then 4-
fluorophenol (3.219 g, 28.7 mmol) was added to the reaction mixture,
which was heated at the same temperature for 4 h followed by addition
of pyridine (3 mL). The reaction mixture was refluxed for 2 h. Pyridine
was distilled off, the reaction mixture was filtered, and the solid
product was washed with cold acetone to afford 0.404 g (62%) of the
1
product as a white amorphous solid. Mp: 210.0−210.5 °C. H NMR
(600 MHz): δ (ppm) 7.17 (m, 2H), 7.12 (m, 2H). 13C NMR (150
MHz): δ (ppm) 163.1, 161.8, 160.2, 146.0, 134.5, 122.7, 116.8. HRMS
(ESI) m/z: [M + Na]+ calcd for C48H24F6NaO12 929.1070, found
929.1066.
Mellitic Acid (Hexa-3-methyl-4-bromophenyl) Ester (10).
PCl5 (1.794 g, 8.6 mmol) was added to 1,2,3,4,5,6-cyclohexanehex-
acarboxylic acid (0.250 g, 0.7 mmol) and digested for 1 h at 130 °C.
Then 3-methyl-4-bromophenol (5.371 g, 28.7 mmol) was added to
reaction mixture, which was heated at the same temperature for 4 h
followed by addition of pyridine (3 mL). The reaction mixture was
refluxed for 2 h. Pyridine was distilled off and the reaction mixture was
filtered and solid product was washed with cold acetone to afford
0.416 g (43%) of the product as a beige amorphous solid. Mp: 201.5−
202.5 °C. 1H NMR (600 MHz): δ (ppm) 7.53 (d, J = 8.5 Hz, H), 6.97
(d, J = 8.5 Hz, H), 6.85 (dd, H), 2.31 (s, 3H). 13C NMR (150 MHz):
δ (ppm) 162.7, 149.1, 140.1, 134.4, 133.6, 123.4, 122.9, 120.1, 23.2.
Anal. Calcd for C54H36Br6O12Na: C, 46.98; H, 2.61. Found: C, 46.96;
H, 2.44.
Mellitic Acid (Hexa-4-cyanophenyl) ester (11). PCl5 (1.794 g,
8.6 mmol) was added to 1,2,3,4,5,6-cyclohexanehexacarboxylic acid
(0.250 g, 0.7 mmol) and digested for 1 h at 130 °C. Then 4-
cyanophenol (3.421 g, 28.7 mmol) was added to reaction mixture,
which was heated at the same temperature for 4 h followed by addition
of pyridine (3 mL). The reaction mixture was refluxed for 2 h. Pyridine
was distilled off, the reaction mixture was filtered, and the solid
product was washed with cold acetone to afford 0.494 g (71%) of the
1
product as a light brown amorphous solid. Mp: > 260 °C. H NMR
(600 MHz): δ (ppm) 7.70 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.5 Hz,
2H). 13C NMR (150 MHz): δ (ppm) 161.9, 152.8, 134.4, 134.4, 122.1,
117.5, 112.0. HRMS (ESI) m/z: [M + Na]+ calcd for C54H24N6NaO12
971.1350, found 971.1347.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H NMR, 13C NMR, and HRMS spectra. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: winter@iastate.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge support from the Cottrell Scholar Award from
the Research Corporation for Scientific Advancement and
support from the Petroleum Research Fund.
REFERENCES
■
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2006, 128, 15094.
(2) Geny, A.; Agenet, N.; Iannazzo, L.; Malacria, M.; Aubert, C.;
Gandon, V. Angew. Chem., Int. Ed. 2009, 48, 1810.
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