Acid-amide intermolecular hydrogen bonding

Article abstract of DOI:10.1021/ja963416e

A 2,2-dimethylbutynoic acid with a pyridone terminus (1) acts as its self-complement in molecular recognition to form an intermolecularly hydrogen-bonded dimer with hydrogen bonding between the amide and carboxylic acid group. The dimer is found in crystals of 1 by X-ray diffraction, in chloroform solution by ¹H-NMR experiments and vapor pressure osmometry, and in the gas phase by FAB-MS.

Full text of DOI:10.1021/ja963416e

3802
J. Am. Chem. Soc. 1997, 119, 3802-3806
Acid-Amide Intermolecular Hydrogen Bonding
Paul L. Wash,1a Emily Maverick,1b John Chiefari,1a and David A. Lightner*,1a
Contribution from the Department of Chemistry, UniVersity of NeVada,
Reno, NeVada 89557-0020, and the Department of Chemistry and Biochemistry,
UniVersity of California, Los Angeles, California 90095-1569
ReceiVed September 30, 1996X
Abstract: A 2,2-dimethylbutynoic acid with a pyridone terminus (1) acts as its self-complement in molecular
recognition to form an intermolecularly hydrogen-bonded dimer with hydrogen bonding between the amide and
carboxylic acid group. The dimer is found in crystals of 1 by X-ray diffraction, in chloroform solution by 1H-NMR
experiments and vapor pressure osmometry, and in the gas phase by FAB-MS.
Introduction
Hydrogen bonds2-5 are among the more important of the
weak electrostatic binding interactions found in nucleic acid
structure,2-6 protein conformation,2-5,7 and supramolecular
chemistry.8-10 Although hydrogen bonds may be formed from
many different types of components,2-10 the amide and car-
boxylic acid functional groups, either of which can act as proton
donor and acceptor, are among the most studied.2-5,10 Acetic
acid, for example, has been shown to form an intermolecularly
hydrogen-bonded dimer in CCl4 solvent, with an association
constant of Kassoc) 2370 M-1 at 24 °C,11 and δ-valerolactam
forms a dimer, with Kassoc ) 206 M-1 at 30 °C.12 Many other
examples of complementary acid-acid (Figure 1A) and amide-
amide (Figure 1B) association complex formation have been
recognized,2-10 with the latter being among the most frequently
encountered in molecular recognition studies.10,13 Surprisingly,
there were few well-documented examples of carboxylic acid
to amide hydrogen bonding (Figure 1C) prior to its observation
in the bile pigment, bilirubin (Figure 1E).14
Figure 1. (A) Carboxylic acid-carboxylic acid hydrogen bonds. (B)
Amide-amide hydrogen bonds. (C) Amide-carboxylic acid hydrogen
bonds. (D) Dipyrrinone to carboxylic acid hydrogen bonds. (E)
Bilirubin-IXR held in a ridge-tile conformation by intramolecular amide-
carboxylic acid hydrogen bonds.
X Abstract published in AdVance ACS Abstracts, April 1, 1997.
(1) (a) University of Nevada. (b) University of California.
(2) Aakero¨y, C. B.; Seddon, K. R. Chem. Soc. ReV. 1993, 397-407.
(3) Joesten, M. D.; Schaad, L. J. Hydrogen Bonding; Marcel Dekker:
New York, 1974.
(4) Hamilton, W. C.; Ibers, J. A. Hydrogen Bonding in Solids; W. A.
Benjamin, Inc.: New York, 1968.
(5) Pimentel, G. C.; McClellan, A. L. The Hydrogen Bond; W. H.
Freeman & Co., Reinhold Publishing: San Francisco, CA, 1960.
(6) Saenger, W. Principles of Nucleic Acid Structure; Springer-Verlag:
New York, 1984.
(7) Schulz, G. E.; Schirmer, R. H. Principles of Protein Structure;
Springer-Verlag: New York, 1985.
(8) Lehn, J.-M. Supramolecular Chemistry; VCH Publishers: Weinheim,
1995.
(9) Diederich, F. Cyclophanes; Royal Society of Chemistry, Cambridge,
1991.
The three-dimensional structure of bilirubin in the crystal14
and in solution14-16 is dominated by a ridge-tile-shaped
conformation stabilized by intramolecular hydrogen bonding
between propionic acid groups and lactam NHCdO and pyrrole
NH components of the opposing dipyrrinones. Recently, this
unusual carboxylic acid to dipyrrinone intermolecular hydrogen
bonding (Figure 1D) has been detected in solutions of certain
dipyrrinone acids, which in nonpolar solvents adopt a π-facial
dimer structure.17 In both cases, carboxylic acid to amide
hydrogen bonding (Figure 1C) is probably further stabilized by
additional hydrogen bonding from the pyrrole NH to the acid
carbonyl oxygen.
More recently, amide to carboxylic acid hydrogen bonds have
become important in molecular recognition chemistry, where
amide hosts have been designed and constructed for binding
(10) Hamilton, A. D. in AdVances in Supramolecular Chemistry; Gokel,
G., Ed.; JAI Press, Inc.: London, 1990; Vol. 1.
(11) Wenograd, J.; Spurr, R. A. J. Am. Chem. Soc. 1957, 79, 5844-
5848.
(12) Tsuboi, M. Bull. Chem. Soc. Jpn. 1951, 24, 75.
(13) (a) For leading references, see: Branda, N.; Grotzfeld, R. M.; Valde´s,
C.; Rebek, J., Jr. J. Am. Chem. Soc. 1995, 117, 85-88. (b) Kato, Y.; Toledo,
L. M.; Rebek, J., Jr. J. Am. Chem. Soc. 1996, 118, 8575-8579. (c) Zafar,
A.; Yang, J.; Geib, S. J.; Hamilton, A. D. Tetrahedron Lett. 1996, 37, 2327-
2330. (d) Boucher, E.; Simard, M.; Wuest, J. D. J. Org. Chem. 1995, 60,
1408-1412. (e) Mathias, J. P.; Seto, C. T.; Simanek, E. E.; Whitesides, G.
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H.; Wilcox, C. S. Chem. Soc. ReV. 1993, 383-395. (h) Zimmerman, S. C.;
Duerr, B. F. J. Org. Chem. 1992, 57, 2215-2217. (i) Chang, S.-K.; Van
Engen, D.; Fan, E.; Hamilton, A. D. J. Am. Chem. Soc. 1991, 133, 7640-
7645.
(14) (a) Bonnett, R.; Davies, J. E.; Hursthouse, M. B.; Sheldrick, G. M.
Proc. R. Soc. London, Ser. B 1978, 202, 249-268. (b) LeBas, G.; Allegret,
A.; Mauguen, Y.; DeRango, C.; Bailly, M. Acta Crystallogr., Sect. B 1980,
B36, 3007-3011. (c) Becker, W.; Sheldrick, W. S. Acta Crystallogr., Sect.
B 1978, B34, 1298-1304. (d) Mugnoli, A.; Manitto, P.; Monti, D. Acta
Crystallogr., Sect. C 1983, 39, 1287-1291.
(15) Nogales, D.; Lightner, D. A. J. Biol. Chem. 1995, 270, 73-77.
(16) Boiadjiev, S. E.; Person, R. V.; Puzicha, G.; Knobler, C.; Maverick,
E.; Trueblood, K. N.; Lightner, D. A. J. Am. Chem. Soc. 1992, 114, 10123-
10133.
(17) (a) Boiadjiev, S. E.; Anstine, D. T.; Lightner, D. A. J. Am. Chem.
Soc. 1995, 117, 8727-8736. (b) Boiadjiev, S. E.; Anstine, D. T.; Maverick,
E.; Lightner, D. A. Tetrahedron: Asymm. 1995, 6, 2253-2270.
S0002-7863(96)03416-6 CCC: $14.00 © 1997 American Chemical Society

Acid-Amide Intermolecular Hydrogen Bonding
J. Am. Chem. Soc., Vol. 119, No. 16, 1997 3803
Scheme 1a-g
Figure 2. (A) Pyridone acid 1 dimer formed by intermolecular
carboxylic acid to amide hydrogen bonds. (B) Bispyridone 2 dimer
formed by intermolecular amide-amide hydrogen bonds.
carboxylic acid18 and carboxylate ion19 guests. However, in
only two examples18b,c is the amide carbonyl designed to be a
part of the hydrogen bonding motif (as in Figure 1C). In one
of the two relevant examples18c the acid carbonyl is hydrogen
bonded to two amide N-H groupssan arrangement similar to
that observed in dipyrrinones (Figure 1, parts D and E). There
are extremely few examples of carboxylic acid to amide
hydrogen bonding of the type shown in Figure 1C; among them
are several cyclic amide-carboxylic acid complexes.13b,18f-h,20c
One such arrangement is the linkage between two molecules
of 6-methyluracil-5-acetic acid.18h Another is the involuntary
intramolecular carboxylic acid to amide (Figure 1C) hydrogen
bonding studied by Rebek and coworkers13b in a cleverly-
designed system involving a monoamide derivative of m-
xylidenediamine bis(Kemp’s triacid) imide.
When bilirubin and its analogs constituted the only well-
documented examples of carboxylic acid to amide hydrogen
bonding, we designed a very different model compound (1), a
carboxylic acid possessing an amide terminus, that we expected
would exhibit strong intermolecular hydrogen bonding in a
dimer formed when the termini are oriented head-to-tail (Figure
2A). Inspiration for 1 came from the work of Wuest et al.,20a
who showed that bis-pyridone 2 forms an extraordinarily stable
dimer in CHCl3 (-∆G° > 6.5 kcal/mol) with intermolecular
amide-amide hydrogen bonds (Figure 2B). In the following,
we report on the synthesis and characterization of 1 and show
by X-ray crystallography, vapor pressure osmometry, mass
spectrometry, and 1H-NMR that it forms a very stable associa-
tion dimer.
a Potassium tert-butoxide, CH3I. b PCl5, then NaOH. c NaNH2.
d CH2N2. e Pd(PPh3)4, CuI, Et3N. f NaOH. g CF3CO2H.
we identified the two key synthetic intermediates to be used in
the preparation of 1: methyl 2,2-dimethyl-3-butynoate (5) and
2-(benzyloxy)-6-bromopyridine (6). The parent acid (7) of the
former was prepared by the method of Engel and Schexnayder21
from ethyl acetoacetate, as outlined in Scheme 1. Pyridine 6
was prepared from 2,6-dibromopyridine by the method of
Duggan et al.22 by reaction with benzyl alcohol with KOH and
18-crown-6 in dry toluene. Previously, we reported on the
Pd(PPh3)4 catalyzed coupling of 6 and 7, which led to a furanone
through intramolecular cyclization of the carboxyl and acetylene
groups.23 Coupling of 5 and 6, however, led smoothly to 4,
which was first saponified and then deprotected using TFA to
give 1. Crystallization of 1 from dichloromethane-toluene gave
small, thin needles. Needles suitable for X-ray crystallography
were grown in chloroform with ethyl acetate added by vapor
diffusion at room temperature.
Molecular Structure. The structure assigned to 1 is
consistent with its spectroscopic properties, in particular, with
its 13C-NMR spectrum, in which all carbon resonances were
1
assigned by long-range H{13C}-COSY experiments. X-ray
crystallography confirmed the constitutional structure of 1 and
clearly indicated that it is a hydrogen-bonded dimer (Figures
2A and 3). In the crystal, H atoms are well located, and two
sets of two nearly linear hydrogen bonds, directed approxi-
mately toward receptor CdO lone pairs, complete the 8-mem-
bered ring arrangement (Figures 1C, 2A, and 3). The H-bond
geometry is shown in Table 1, where the same parameters for
other cyclic amide-carboxyl pairs18f-h,20c are given for com-
parison. The O‚‚‚O and N‚‚‚O distances in 1 (2.55 and 2.79
Å) may also be compared to the intramolecular mean values of
2.61 and 2.64 Å (O‚‚‚O) and 2.84 and 2.87 Å (N‚‚‚O) in
bilirubin14b and mesobilirubin,14c respectively. Similar (amide)
H‚‚‚O (carboxyl) distances, 1.88-2.14 Å, are found in the
complexes of bis(amidopyridines) with dicarboxylic acids of
varying chain length;18e in these complexes, the second H-bond
in the 8-membered ring is (carboxyl) H‚‚‚N (pyridine), 1.60-
2.33 Å. The lactam-carboxyl cyclic grouping found in 1
implies stronger intermolecular hydrogen bonds than those in
lactam dimers, in which typical N‚‚‚O distances are about 2.82
Å.23
Results and Discussion
Synthesis. Adopting the methodology employed by Wuest
et al.20 for coupling 2-(benzyloxy)bromopyridines to acetylenes,
(18) (a) Goodman, M. S.; Hamilton, A. D.; Weiss, J. J. Am. Chem. Soc.
1995, 117, 8447-8455. (b) Mussons, M. L.; Raposo, C.; Grego, M.; Anaya,
J.; Caballero, M. C.; Mora´n, J. R. Tetrahedron Lett. 1994, 35, 7061-7064.
(c) Crego, M.; Raposo, C.; Caballero, M. C.; Garc´ıa, E.; Saez, J. G.; Mora´n,
J. R. Tetrahedron Lett. 1992, 33, 7437-7440. (d) Montero, V. A.;
Tomlinson, L.; Houk, K. N.; Diederich, F. Tetrahedron Lett. 1991, 32,
5309-5312. (e) Garcia-Tellado, F.; Geib, S. J.; Goswami, S.; Hamilton,
A. D. J. Am. Chem. Soc. 1991, 113, 9265-9269. (f) Varughese, K. I.;
Kartha, G. Acta Crystallogr., Sect. B 1982, B38, 301-302. (g) Ishikawa,
T.-I.; Takenaka, A.; Sasada, Y.; Ohki, M. Acta Crystallogr., Sect. C 1986,
C42, 860-861. (h) Destro, R.; Marsh, R. E. Acta Crystallogr., Sect. B 1972,
B28, 2971-2977.
(19) (a) Kelly, T. R.; Kim, M. H. J. Am. Chem. Soc., 1994, 116, 7072-
7080. (b) Albert, J. S.; Hamilton, A. D. Tetrahedron Lett. 1993, 34, 7363-
7366. (c) Hamann, B. C.; Branda, N. R.; Rebek, J. Jr. Tetrahedron Lett.
1993, 34, 6837-6840. (d) Fan, E.; van Arman, S. A.; Kincaid, S.; Hamilton,
A. D. J. Am. Chem. Soc. 1993, 115, 369-70. (e) Vicent, C.; Hirst, S. C.;
Garcia-Tellado, F.; Hamilton, A. D. J. Am. Chem. Soc. 1991, 113, 5466-
5467.
(20) Ducharme, Y.; Wuest, J. D. J. Org. Chem. 1988, 53, 5787-5789.
(b) Gallant, M.; Viet, M. T. P.; Wuest, J. D. J. Am. Chem. Soc. 1991, 113,
721-723. (c) Simard, M.; Su, D.; Wuest, J. D. J. Am. Chem. Soc. 1991,
113, 4696-4698. (d) Gallant, M.; Viet, M. T. P.; Wuest, J. D. J. Org. Chem.
1991, 56, 2284-2286. (e) Persico, F.; Wuest, J. D. J. Org. Chem. 1993,
58, 95-99. (f) Boucher, E.; Simard, M.; Wuest, J. D. J. Org. Chem., 1995,
60, 1408-1412.
(21) Engel, P. S.; Schexnayder, M. A. J. Am. Chem. Soc. 1975, 97, 4825-
4836.
(22) Duggan, J. S.; Grabowski, E. J. J.; Russ, W. K. Synthesis 1980,
573-575.
(23) Maverick, E.; Chiefari, J.; Lightner, D. A. Acta Crystallogr. 1993,
C49, 338-340.

3804 J. Am. Chem. Soc., Vol. 119, No. 16, 1997
Wash et al.
and carboxylic acid hydrogens. Finally, in the FAB-mass
spectrum of 1 (glycerol matrix), a prominent m/z 411 peak is
found for the parent ion dimer in addition to the m/z 206 base
peak of the parent ion monomer.
Monomer-Dimer Equilibrium. We attempted to determine
the extent of dimerization of 1 using 1H-NMR spectroscopy to
follow changes in position of the chemical shifts (δobs) of
sensitive reporting groups such as NH and CO2H. At high
dilution, the monomer concentration can be expected to increase,
while the dimer concentration decreases. One should therefore
expect to observe a shift in δobs to higher field with increasing
dilution.27 However, this was not observed for any of the CH
signals over the concentration range 0.024 to 0.00047 M in
CDCl3. Only very minor changes were seen for δobs(NH) [12.96
ppm at 2.44 × 10-2 M and 12.80 ppm at 4.68 × 10-4 M] and
δ
obs(CO2H) [15.52 ppm at 2.44 × 10-2 M and 15.50 ppm at
4.68 × 10-4 M]. The data suggest a very large self-association
Figure 3. Drawing of the dimer of 1 in the crystal. Ellipsoids are
drawn at the 50% probability level; H atoms are represented by spheres
of arbitrary radius. The numbered molecule is related to its partner by
the symmetry operation 1 - x, -y, 2 - z.
constant, Kassoc) [dimer]/[monomer]2 M-1, for 1 in CDCl3,
exceeding 104 M-1 27
Consequently, Kassoc was determined by
.
1H-NMR spectroscopy27,28 in a solvent mixture in which
dimerization is less extensive: CDCl3 with 3% by volume
(CD3)2SO. The added (CD3)2SO, which is an excellent
hydrogen bond (acceptor) solvent,27 interferes to some extent
with dimerization of 1 by forming hydrogen bonds competitively
with it.27,28 We used the method of Horman and Dreux,28
developed for caffeine dimerization studies, to determine
Kassoc(∼510 M-1) of 1 from the 1H-NMR chemical shifts of its
amide hydrogens in 3% by volume (CD3)2SO in CDCl3 at 25
°C. For calibration, we used the same method to determine
Kassoc values for 2-pyridone in pure CDCl3 (540 M-1) and in
3% by volume (CD3)2SO in CDCl3 (50 M-1) at 25 °C. There
is wide variability in Kassoc values reported for 2-pyridone:
∼13 000 M-1 in benzene-d6 at 8 °C (1H-NMR),29 7100 M-1 in
CCl4 at 25 °C (IR),30 and 100 M-1 in CDCl3 at 25 °C (ultrasonic
measurements).31 The method of Horman and Dreux28 has been
used recently by Moore et al.32 for determining Kassoc of
phenylacetylene macrocycles. In a related experiment, Zim-
merman and Duerr33 were able to determine Kassoc ) 20 000
M-2 for amide self-trimerization in 10% (CD3)2SO-90%
CDCl3.
Table 1. Hydrogen-Bond Distances (Å) and Angles (deg) in the
Dimera of 1 in the Crystal and in Four Other Cyclic
Amide-Carboxylic Acid Structures
compound
ref
ref
ref
ref
distance (Å) or angle (deg)
1
18f 18g 18h 20c
(lactam) O7′‚‚‚ O8 (carboxyl) 2.554(2) 2.60 2.62 2.67 2.66
O7′‚‚‚ H8
1.75(2)
165(2)
1.66 1.62 1.71 1.70
176 166 174 170
O7′‚‚‚H8-O8
(lactam) N1′‚‚‚ O7 (carboxyl) 2.791(2) 2.84 2.83 2.80 2.77
H1′‚‚‚O7
N1′-H1′‚‚‚O7
1.95
167
1.94 1.84 1.93 1.86
166 161 171 173
a The hydrogen bonds in 1 are all intermolecular, the second molecule
being related to the first by the symmetry operation 1 - x, -y, 2 - z.
See Figure 3.
1
Table 2. Dilution and Temperature Effects on the H-NMRa
Chemical Shifts of 1b in CDCl3
1H-NMR Chemical Shift for H at
temp (°C) concn (M) CO2H NH CH3
3′
4′
5′
In an attempt to perturb the monomer a dimer equilibrium
by heating, we examined the 1H-NMR δobs over the range -72
to +50 °C for all of the hydrogens of 1 (Table 2). While no
large shifts occurred that might be attributed to displacing a
monomer a dimer equilibrium, we noticed that the NH and
CO2H signals broadened upon going from -72 to +50 °C, and
that δobs(CO2H) at 40 °C was ∼0.7 ppm more shielded than at
-72 °C and δobs(NH) was ∼0.2 ppm more shielded (Figure 4).
Equilibrium with a small amount of monomer with significantly
different chemical shifts might produce the observed broadening.
The C-H signals, however, did not broaden particularly, and
they were slightly more deshielded (by ∼0.1 ppm) at -72 °C
than at 50 °C. Since small deshieldings of C-H resonances
attend the shift from pyridone (δC-3) 6.59 ppm, δC-4 ) 7.48
ppm, δC-5 ) 6.29 ppm, and δC-6 ) 7.39 ppm in CDCl3) to
20
20
2.44 × 10-2 15.52 12.96 1.668 6.599 7.476 6.533
4.68 × 10-2 15.50 12.80 1.669 6.600 7.477 6.534
50
40
0
8.04 × 10-2
1.667 6.512 7.456 6.587
8.04 × 10-2 15.32 12.89 1.666 6.519 7.464 6.591
8.04 × 10-2 15.70 12.99 1.661 6.552 7.495 6.605
8.04 × 10-2 16.03 13.10 1.653 6.624 7.566 6.650
-72
a Reported in δ (ppm) downfield from (CH3)4Si. b See synthetic
scheme or Figure 2A for numbering system used.
Evidence for a predominantly dimeric structure of 1 in
solution comes from vapor pressure osmometry studies in CHCl3
at 37 °C, which gave an average molecular weight of 40924
salmost exactly twice the molecular weight (205) of the
monomer. Further evidence for the dimeric structure in
1
chloroform solution comes from H-NMR spectroscopy. The
hydroxypyridine (2-ethoxypyridine, δC-3 ) 6.71 ppm, δC-4
)
very strong deshieldings (Table 2) seen for the carboxylic acid
(∼15.5 ppm) and amide (∼13 ppm) hydrogens are characteristic
of strong hydrogen bonding,17,25,26 as might be found in the
dimeric structure shown in Figure 2C. Consistent with such a
dimer structure for 1, a strong nOe is found between the lactam
(27) Nogales, D. F.; Ma, J.-S.; Lightner, D. A. Tetrahedron 1993, 49,
2361-2372.
(28) Horman, I.; Dreux, B. HelV. Chim. Acta 1984, 67, 754-764.
(29) Inuzuka, K. Bull. Chem. Soc. Jpn. 1982, 55, 2537-2540.
(30) Kulevsky, N.; Neineke, W. J. Phys. Chem. 1968, 72, 3339-3340.
(31) Hammes, G. G.; Park, A. C. J. Am. Chem. Soc. 1969, 91, 956-
961.
(32) Shetty, A. S.; Zhang, J.; Moore, J. S. J. Am. Chem. Soc. 1996, 118,
1019-1027.
(33) Zimmerman, S. C.; Duerr, B. F. J. Org. Chem. 1992, 57, 2215-
2217.
(24) Vapor-pressure osmometry studies were carried out at the University
of Go¨ttingen, Germany, through the courtesy of Prof. D. Armin de Meijere.
(25) Trull, F. R.; Ma, J. S.; Landen, G. L.; Lightner, D. A. Isr. J. Chem.
1983, 23 (2), 211-218.
(26) For leading references, see: Falk, H. The Chemistry of Linear
Oligopyrroles and Bile Pigments; Springer Verlag: New York, 1989.

Acid-Amide Intermolecular Hydrogen Bonding
J. Am. Chem. Soc., Vol. 119, No. 16, 1997 3805
NMR spectral data were obtained in spectral grade solvents from
Cambridge Isotope Laboratories. Deuterated chloroform and dimethyl
sulfoxide ((CD3)2SO) were distilled from calcium hydride. Ethyl
acetoacetate, methyl iodide, trifluoroacetic acid, cuprous iodide and
triethylamine were obtained from Aldrich or Fisher and used as received
unless otherwise specified. Palladium tetrakis(triphenylphosphine) was
synthesized from PdCl2.34
Crystal Structure. Compound 1, formula C11H11NO3, formula
weight 205.21, was crystallized from chloroform by vapor diffusion
with ethyl acetate. The crystal used for diffraction measurements was
a colorless, cut needle: 0.2 × 0.2 × 0.5 mm, space group P21/c (no.
14), a ) 9.3619(6) Å, b ) 5.9057(4) Å, c ) 18.5810(10) Å, â )
95.566(2)˚, V ) 1022.47(11) Å, Z ) 4. Intensities were measured at
156 K on a modified Picker FACS-1 diffractometer with Mo KR
radiation; 3633 reflections were collected with 0 < Θ e 30°. Data
collection and reduction, as well as other necessary calculations, were
performed with the UCLA Crystallographic Package.35 The structure
was solved with SHELXS8636a and refined on F2 by full-matrix least
squares with SHELXL.36b All non-H atoms were refined anisotropi-
cally. The four hydrogen atoms attached to C and N in the lactam
moiety were riding on their attached atoms with fixed distances (default
values, N-H ) 0.86 Å, C-H ) 0.93 Å)36b and a common isotropic
displacement parameter. Methyl hydrogens were treated as rigid groups
with C-H ) 0.96 Å and a common isotropic displacement parameter.
Positional and isotropic displacement parameters for the carboxyl H
were refined independently. The final R(F) for 142 parameters is 0.094
for all 3008 unique reflections and 0.043 for the 1833 reflections with
I g 2σ(I), Rw(F2) is 0.128, and the “goodness-of-fit” S is 1.04. In the
crystal, 1 forms dimers, joined in R22(8) patterns (8-membered rings
with 2 donors and 2 acceptors)37 by N-H‚‚‚O and O-H‚‚‚O hydrogen
bonds, across a center of symmetry (see Figure 338 ). Coordinates for
the compounds in refs 18g and 20c for use in Table 1 were obtained
from the Cambridge Structural Database.39
Figure 4. Temperature dependence of NH and OH 1H-NMR chemical
shifts of 0.08 M 1 in CDCl3 from +50 (top) to -72 °C (bottom).
Temperatures are indicated on each spectrum.
Ethyl 2,2-Dimethyl-3-oxobutanoate (7). The ester was prepared
in 75% yield by the method of Schexnayder and Engel:21 bp 71-73
1
°C (10 mmHg) [lit.40 bp 180-184 °C (atm)]; H-NMR δ 1.24 (t, 3H,
J ) 7.2 Hz), 1.34 (s, 6H), 2.14 (s, 3H), 4.17 (q, 2H, J ) 7.2 Hz) ppm;
13C-NMR δ 13.98 (q), 21.80 (q), 55.68 (t), 61.27 (s), 173.6 (s), 205.9
(s) ppm; IR (film) ν 1740, 1716 cm-1; mass spectrum (m/z, rel intensity)
158 (0.3) [M•+], 116 (86), 88 (100), 73 (68), 57 (19) amu.
2,2-Dimethyl-3-chloro-3-butenoic Acid (6). The chloro acid was
prepared in 50% yield from 7 in two steps as described previously:
Figure 5. Lactam (left)-lactim (right) tautomerism in the hydrogen-
bonded dimer of 1. The tautomerism shown in both hydrogen bonded
pairs might also occur in just one pair.
1
mp 62-64 °C (lit.21 mp 60.5-63 °C); H-NMR δ 1.48 (s, 6H), 5.37
(d, 1H, J ) 2.1 Hz), 5.39 (d, 1H, J ) 2.1 Hz), 11.73 (br s, 1H) ppm;
13C-NMR δ 24.44 (q), 50.29 (s), 112.64 (t), 144.8 (s), 180.4 (s) ppm;
IR (film) ν 2902, 1704, 1686 cm-1; mass spectrum (m/z, rel intensity)
148 (9) [M•+], 133 (52), 103 (41), 67 (100), 53 (32) amu.
7.55 ppm, δC-5 ) 6.84 ppm, and δC-6 ) 8.14 ppm in CDCl3)
tautomers, the data might also be interpreted in terms of a
lactam-lactim tautomerization in the dimer where one or both
pyridones (Figure 5) adopt the hydroxypyridine tautomeric
structure at low temperatures.
2,2-Dimethyl-3-butynoic Acid (5). The alkyne acid was prepared
in 80% yield as described previously: bp 80-82 °C (8 mmHg) [lit.21
bp 77-78 °C (5 mmHg)]; 1H-NMR δ 1.53 (s, 6H), 2.31 (s, 1H), 10.66
(br s, 1H) ppm; 13C-NMR δ 26.93 (q), 38.15 (s), 70.45 (d), 85.47 (s),
179.9 (s) ppm; IR (film) ν 3298, 3099, 2119, 1713 cm-1; mass spectrum
(m/z, rel intensity) 112 (4) [M•+], 97 (7), 67 (100), 51 (32) amu.
Methyl 2,2-Dimethyl-3-butynoate (4). Acid 5 was methylated in
ether with diazomethane generated in ether from N-methyl-N-nitroso-
urea. The ether solution was evaporated to leave 4 as a clear liquid
(4.34 g, 0.034 mol, 96%): 1H-NMR δ 1.48 (s, 6H), 2.26 (s, 1H), 3.74
(s, 3H) ppm; 13C-NMR δ 27.13 (q), 37.99 (s), 52.79 (q), 69.88 (d),
86.2 (s), 173.9 (s) ppm; IR (film) ν 3290, 2119, 1743 cm-1; mass
Concluding Comments
Pyridone acid 1 forms an intermolecularly hydrogen-bonded
dimer in the crystal and in solutions in nonpolar organic solvents
such as chloroform, where the dimerization constant exceeds
104 M-1. The dimer of 1 thus constitutes one of the rare
examples of strong carboxylic acid to amide hydrogen bonding.
(34) Coulson, D. R. Inorg. Synth. 1972, 13, 121-123.
(35) UCLA Crystallographic Package; J. D. McCullough Laboratory of
X-ray Crystallography, University of California: Los Angeles, 1984.
(36) (a) Sheldrick, G. M. Acta Crystallogr., Sect. A 1990, A46, 467-
473. (b) Sheldrick, G. M. SHELXL93. Program for the Refinement of Crystal
Structures; University of Go¨ttingen: Go¨ttingen, Germany, 1993.
(37) Etter, M. C.; MacDonald, J. C.; Bernstein, J. Acta Crystallogr., Sect.
B 1990, B46, 256-262.
Experimental Section
General Procedures. All nuclear magnetic resonance (NMR)
spectra were measured in CDCl3 and reported in δ (ppm) downfield
from (CH3)4Si on a GE QE-300, unless otherwise indicated. Infrared
spectra were recorded on a Perkin-Elmer model 1610 FT instrument.
Low-resolution mass spectra (MS) were measured on a Hewlett Packard
5970 or a Finnigan MAT SSQ 710 spectrometer. Melting points were
determined on a Thomas-Hoover capillary apparatus and are uncor-
rected. Combustion analyses were carried out at Desert Analytics,
Tucson, AZ. Chromatography was carried out on silica gel (60-200
mesh, column chromatography grade, Schoofs, Inc.).
(38) Johnson, C. K. ORTEPII; Report ORNL-5138; Oak Ridge National
Laboratory: Oak Ridge, TN, 1976.
(39) Allen, F. H.; Davies, J. E.; Galloy, J. J.; Johnson, O.; Kennard, O.;
Macrae, C. F.; Mitchell, E. M.; Mitchell, G. F.; Smith, J. M.; Watson, D.
G. J. Chem. Inf. Comput. Sci. 1991, 31, 187-204.
(40) Cannon, W. N.; Marshall, F. J. J. Org. Chem. 1956, 21, 245-247.

3806 J. Am. Chem. Soc., Vol. 119, No. 16, 1997
Wash et al.
spectrum (m/z, rel intensity) 126 (4) [M•+], 125 (23), 111 (35), 83 (13),
67 (100), 51 (31) amu.
2,2-Dimethyl-4-(2-oxo-1H-6-pyridyl)-3-butynoic acid (1). Benzyl
ether (2) (64 mg, 0.22 mmol) was stirred in neat trifluoroacetic acid
(TFA) for 2 days, after which excess TFA was removed by azeotroping
with toluene. The white crystalline residue was taken up in a minimal
amount of methylene chloride. Toluene was then added and recrys-
tallization occurred overnight. Compound 1 crystallized as small thin
needles (37 mg, 0.18 mmol, 83%) with mp 190-193 °C: 1H-NMR δ
1.67 (s, 6H, CH3), 6.54 (dd, 1H, J ) 0.6, 6.9 Hz, C6-H), 6.62 (dd,
1H, J ) 0.6, 9.0 Hz, C4-H), 7.48 (dd, 1H, J ) 6.9, 9.2 Hz, C5-H),
12.95 (br s, 1H, NH), 15.50 (br s, 1H, COOH) ppm; 13C-NMR δ, 26.91
(CH3), 40.55 (C2), 75.27 (C4), 98.33 (C3), 112.7 (C3′), 119.6 (C5′), 129.4
(C6′), 142.6 (C4′), 165.1 (C2′, CONH), 179.1 (C1, COOH) ppm; IR (film)
ν 2932, 2233, 1686, 1658 cm-1; mass spectrum (m/z, rel intensity):
205 (70) [M•+], 160 (100), 130 (10), 117 (19), 89 (7), 65 (6) amu.
13C-NMR assignments are from long-range H-C COSY experiments;
1H-NMR are from H-C COSY.
Methyl 2,2-Dimethyl-4-(2-(benzyloxy)-6-pyridyl)-3-butynoate (3).
Diethylamine (30 mL) was added to a glass pressure tube followed by
the alkyne-ester 4 (0.5 g, 4.0 mmol) and 2-(benzyloxy)-6-bromopyri-
dine22 (1.15 g, 4.4 mmol). Cuprous iodide (50 mg, 0.26 mmol) was
then added followed by palladium tetrakis(triphenylphosphine) (302
mg, 0.26 mmol) after which the tube was sealed under argon and heated
to 75 °C overnight. The contents were then poured into 100 mL of
water and extracted with ether (2 × 100 mL). The combined organic
fractions were then dried over anhydrous magnesium sulfate and
evaporated to leave a yellow oil. The oil was passed through a small
column of silica gel (ether eluent) to remove trace catalyst and yielded
compound 3 as a light-yellow oil (1.16 g, 3.76 mmol, 95%): 1H-NMR
δ 1.62 (s, 6H), 3.79 (s, 3H), 5.39 (s, 2H), 6.74 (d, 1H, J ) 8.4 Hz),
7.06 (d, 1H, J ) 7.2 Hz), 7.32-7.48 (m, 5H), 7.52 (dd, 1H, J ) 7.9,
8.1 Hz) ppm; 13C-NMR δ 27.12 (q), 38.67 (s), 52.85 (q), 67.94 (t),
81.50 (s), 91.19 (s), 111.1 (d), 121.0 (d), 127.7 (d), 128.2 (d), 128.4
(d), 137.1 (s), 138.6 (d), 140.1 (s), 163.2 (s), 173.9 (s) ppm; IR (film)
ν 2231, 1741 cm-1; mass spectrum (m/z, rel intensity) 309 (40) [M•+],
250 (15), 232 (11), 203 (9), 143 (10), 91 (100), 65 (31) amu.
Anal. Calcd for C19H19NO3 (309.4): C, 73.77; H, 6.19; N, 4.53.
Found: C, 73.63; H, 6.04; N, 4.42.
2,2-Dimethyl-4-(2-(benzyloxy)-6-pyridyl)-3-butynoic Acid (2).
Sodium hydroxide (2 N, 20 mL) was added to methyl ester 3 (200 mg,
0.65 mmol) followed by sufficient 95% ethanol to form a solution.
The resulting creme-colored solution was heated at reflux for 2 h, after
which it was acidified (concentrated HCl) and extracted with methylene
chloride (2 × 40 mL). The combined organic fractions were dried
over anhydrous magnesium sulfate and evaporated to leave a tan oil
which was purified by passage through a small column of silica gel
(methylene chloride eluent) to leave a clear viscous oil, which solidified
upon standing (180 mg, 0.61 mmol, 94%): mp 73-75 °C; 1H-NMR δ
1.66 (s, 6H), 5.39 (s, 2H), 6.75 (d, 1H, J ) 8.4 Hz), 7.07 (d, 1H, J )
7.2 Hz), 7.32-7.40 (m, 5H), 7.52 (dd, 1H, J ) 7.5, 7.8 Hz), 10.81 (br
s, 1H) ppm; 13C-NMR δ 26.87 (q), 38.71 (s), 68.06 (t), 81.76 (s), 90.64
(s), 111.3 (d), 121.1 (d), 127.9 (d), 128.2 (d), 128.4 (d), 137.0 (s), 138.7
(d), 139.8 (s), 163.2 (s), 178.9 (s) ppm; IR (film) ν 2976, 2234, 1712
cm-1; mass spectrum (m/z, rel intensity) 295 (4) [M•+], 252 (3), 225
(10), 145 (33), 91 (100), 65 (26) amu.
Anal. Calcd for C11H11NO3 (205.2): C, 64.38; H, 5.40; N, 6.83.
Found: C, 64.15; H, 5.38; N, 6.49.
Acknowledgment. We thank the National Institutes of
Health (HD-17779) for support of this research and the National
Science Foundation (DIR-9102893 and CHE 9214294) for funds
to purchase the mass spectrometer and 500 MHz NMR
spectrometer used in this study. We thank Mr. Lew Cary for
assistance with the NMR measurements and Prof. Dr. Armin
de Meijere (University of Go¨ttingen) for determining the vapor
pressure osmometric molecular weight of 1 in CHCl3. We thank
Prof. Daniel Nogales (Northwest Nazarene College) for pre-
1
liminary H-NMR studies of 1, and Prof. K. N. Trueblood
(UCLA) for support for crystallographic studies. Paul Wash is
an R. C. Fuson Graduate Fellow.
Supporting Information Available: Listings of positional
and displacement parameters and bond distances, angles and
torsion angles for the crystal structure of 1 (2 pages). See any
current masthead page for ordering and Internet access
instructions.
Anal. Calcd for C18H17NO3 (295.3): C, 73.20; H, 5.80; N, 4.74.
Found: C, 73.00; H, 5.78; N, 4.71.
JA963416E