Three-center intramolecular hydrogen bonding in oxamide derivatives. NMR and X-ray diffraction study

Article abstract of DOI:10.1039/a704640e

This contribution describes the synthesis and structural investigation of the symmetric and non-symmetric oxamides N,N′-bis(2-hydroxyphenyl)oxamide 1, N,N′-bis(5-tert-butyl-2-hydroxyphenyl)-oxamide 2, N,N′-bis(3,5-dimethyl-2-hydroxyphenyl)oxamide 3, N,N′-bis(2-hydroxybenzyl)oxamide 4, N,N′-diphenethyloxamide 5, N-(2-hydroxyphenyl)-N′-(2-methoxyphenyl)oxamide 6, N-(2-hydroxy-phenyl)-N′-phenethyloxamide 7, (1S,2R)-(-)-N-(2-hydroxyphenylcarbamoylcarbonyl)norephedrine 8, (1R,2S)-(-)-N-(2-hydroxyphenylcarbamoylcarbonyl) 9, ethyl N-(2-hydroxyphenyl)oxalamate 10 and ethyl N-(2-methoxyphenyl)oxalamate 11. The structures were established by ¹H, ¹³C, ¹⁵N and variable temperature NMR spectroscopy. Compounds 1-4 and 6-11 are stabilized by intramolecular three-center hydrogen bonding between the amide proton and two oxygen atoms. The ¹H NMR Δδ/ΔT value of the amide proton correlates with the ¹⁵N NMR chemical shift. The X-ray diffraction molecular structures of 1 and 11 showed a planar conformation with trans configuration in the solid state, corresponding to the preferred conformation found in solution.

Full text of DOI:10.1039/a704640e

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Three-center intramolecular hydrogen bonding in oxamide derivatives.
NMR and X-ray diffraction study
F. J. Martínez-Martínez,*,a I. I. Padilla-Martínez,a M. A. Brito,a E. D. Geniz,a
R. C. Rojas,a J. B. R. Saavedra,a H. Höpfl,b M. Tlahuextlc and R. Contrerasc
a Departamento de Química, Unidad Profesional Interdisciplinaria de Biotecnología, Instituto
Politécnico Nacional, Av. Acueducto s/n, Barrio la Laguna Ticomán, México DF 07340,
México
b Departamento de Química, Universidad Autónoma del Estado de Morelos,
Av. Universidad No. 1001, Col. Chamilpa, Cuernvaca Morelos, 62210, México
c Departamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto
Politécnico Nacional, Apartado Postal 14–740, México DF 07000, México
This contribution describes the synthesis and structural investigation of the symmetric and non-
symmetric oxamides N,NЈ-bis(2-hydroxyphenyl)oxamide 1, N,NЈ-bis(5-tert-butyl-2-hydroxyphenyl)-
oxamide 2, N,NЈ-bis(3,5-dimethyl-2-hydroxyphenyl)oxamide 3, N,NЈ-bis(2-hydroxybenzyl)oxamide 4,
N,NЈ-diphenethyloxamide 5, N-(2-hydroxyphenyl)-NЈ-(2-methoxyphenyl)oxamide 6, N-(2-hydroxy-
phenyl)-NЈ-phenethyloxamide 7, (1S,2R)-(؊)-N-(2-hydroxyphenylcarbamoylcarbonyl)norephedrine 8,
(1R,2S)-(؊)-N-(2-hydroxyphenylcarbamoylcarbonyl) 9, ethyl N-(2-hydroxyphenyl)oxalamate 10 and
ethyl N-(2-methoxyphenyl)oxalamate 11. The structures were established by 1H, 13C, 15N and variable
temperature NMR spectroscopy. Compounds 1–4 and 6–11 are stabilized by intramolecular three-center
hydrogen bonding between the amide proton and two oxygen atoms. The 1H NMR Ää/ÄT value of the
amide proton correlates with the 15N NMR chemical shift. The X-ray diffraction molecular structures
of 1 and 11 showed a planar conformation with trans configuration in the solid state, corresponding to
the preferred conformation found in solution.
Introduction
Results and discussion
The concept of intermolecular and intramolecular hydrogen
bonding was originally used to explain physical properties of
organic compounds and the formation of molecular aggre-
gates.1,2 Hydrogen bonding is relevant in the conformation of
proteins and biochemical systems.3–5
Several methods have been developed to study the conform-
ation and hydrogen bonding of peptides and proteins.6 One of
the most used is the study of N᎐H by NMR spectroscopy.
Small molecules have been extensively used to model the
specific hydrogen bonding interactions found in bigger bio-
chemical systems.7 Oxamides provide a simple model to study
peptide bonds, particularly the hydrogen bonding interactions
that give rise to molecular recognition processes such host–
guest interactions. Amide groups generally adopt a trans con-
figuration which facilitates linear chain networks suitable to
form important supramolecular structures.8,9
NMR Spectroscopy
The conformational study in solution of the oxamides 1–11 was
carried out using 1H, 13C and 15N NMR spectroscopy. The 13
NMR spectra of compounds 1–5 showed one half of the total
carbon atoms because of the symmetry plane (Table 1). The
oxamide carbon chemical shifts of 1–11 were in the character-
istic range of this group (154.3–159.7 ppm)13 disregarding some
π conjugation through the OC᎐CO bond.
C
The 1H NMR chemical shifts of compounds 1–11 in
[2H6]DMSO (DMSO = dimethyl sulfoxide) are shown in Table
2. The chemical shift of the N᎐H hydrogen lies between 8.4 and
11.0 ppm for 1–3 and 5–11. The signals of the aryl hydrogens
appeared in two regions, the H4–H6 hydrogens were found
between 6.83–7.70 ppm and the signals at high frequencies
(7.73–8.17 ppm) were assigned to H3 hydrogens which are
deshielded by the carbonyl group10 (vide infra).
We have previously found by solution NMR that the pre-
ferred conformation of compound 1 is planar, involving three-
center-hydrogen bonding (bifurcated).10 Therefore, we were
interested in finding other examples of this conformation by
varying the ring substituents (2, 3), the effect of five- or six-
membered ring formation (4), or aromatic versus aliphatic
groups in symmetric (5) and non-symmetric oxamides (6–11).
In this work a method based on the temperature dependence of
amide NH hydrogen chemical shift11,12 has been used to study
the intramolecular hydrogen bonding interactions in eleven
oxamide derivatives, as model compounds. Thus compounds 1–
11 were prepared and hydrogen bonding interactions analyzed
by 1H, 13C and 15N variable temperature NMR in solution. It is
shown that a three-center intramolecular hydrogen bonding
interaction is the common pattern of all oxamides 1–11. The
molecular structure of 1 and 11 confirmed the same conform-
ational preference in the solid state and in solution.
The 1H NMR chemical shift dependence on the temperature
gave support to the role of intramolecular three-center hydro-
gen bonding in stabilizing the planar conformation. Due to
intramolecular hydrogen bonding formation in oxamides 1–11,
a small value of ∆δ/δT for the NH hydrogen is expected in a
polar solvent.11 The 1H NMR ∆δ/δT experiments were done in
[2H6]DMSO at 30–150 ЊC with increments of 10 ЊC. The ∆δ/δT
values are shown in Table 3.
The chemical shifts of NHA signals in compounds 1–3 and
6–11 showed a small variation with the temperature (∆δ/δT
from Ϫ0.5 to Ϫ2.2 ppb KϪ1). It is known that the ∆δ/δT values
of the NH hydrogen are directly related to the proton mobil-
ity.14 Thus, these small ∆δ/δT values can be explained by the
formation of a three-center hydrogen bond shown schematic-
ally for compounds 1, 4 and 8. The bonding interaction of the
NHA moiety is stabilized by two five-membered chelate rings
and favors a planar conformation and trans configuration of
J. Chem. Soc., Perkin Trans. 2, 1998
401

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Table 1 13C NMR chemical shifts of compounds 1–11 in ppm (in [2H6]DMSO)
Comp.
C-1
C-2
C-3
C-4
C-5
C-6
C-7
C-8
1a
2b
147.2
144.7
142.9
132.0
137.4
149.0
146.8
146.8
146.8
147.5
149.3
124.5
124.1
125.2
135.7
128.4
125.6
124.8
124.8
124.8
124.7
125.5
119.8
116.6
118.5
121.4
128.4
119.7
119.2
119.2
119.3
120.8
120.6
119.3
144.5
128.3
128.1
126.5
119.2
119.1
119.1
119.2
119.1
120.5
125.4
121.9
122.5
124.7
128.4
125.8
126.1
124.9
125.0
125.5
125.6
115.1
114.4
125.5
127.7
128.4
115.1
114.8
114.8
114.9
115.1
111.2
156.9
156.9
157.3
157.8
159.7
156.8
156.9
156.9
157.0
154.3
154.7
3c
4d
5e
6f
157.1
159.5
158.6
158.9
160.5
160.5
7g
8h
9i
10j
11k
a Data taken from ref. 8. b Ar᎐C 31.2, Ar᎐C᎐CH3 33.8 ppm. c C4-CH3 20.4, C6᎐CH3 16.3 ppm. d Ar᎐CH2᎐O 62.6 ppm. e N᎐CH2 39.8, Ar᎐CH2 32.7
ppm. f ClЈ 149.0, C2Ј 125.4, C3Ј 119.8, C4Ј 120.5, C5Ј 125.5, C6Ј 111.2, OMe 55.9 ppm. g N᎐CH2 40.6, Ar᎐CH2 34.3, phenyl: ipso 138.9, ortho 128.5,
i
meta 128.2, para 124.9 ppm. h N᎐CH 51.3, HO᎐CH 73.7, C᎐CH3 14.6, phenyl: ipso 142.8, ortho 126.1, meta 127.7, para 126.8 ppm. N᎐CH 51.4,
HOCH 74.1, C᎐CH3 17.2, phenyl: ipso 142.9, ortho 126.3, meta 127.9, para 127.0 ppm. j O᎐CH2 62.6, C᎐CH3 13.7 ppm. k O᎐CH2 62.6, C᎐CH3 13.7,
OCH3 55.8 ppm.
O
H
N
H
H
O
R1
O
N
O
N
8
N
H
R2
7
OH
HA
O
HA
HA
N
O
O
O
6
3
HO
O
O
O
HO
5
4
1
N
N
N
O
Me
Ph
HA
HA
HB
2
1 R1 = R2
=
2 R1 = R2
=
HO
O
H
H
HO
1
4
8
HO
4 R1 = R2
=
3 R1 = R2
=
two nearer oxygen atoms, because of the presence of six-
membered rings formed by intramolecular hydrogen bonding.
The signals for NHA in 5 and NHB in 7–9 showed a large low-
frequency shift with increasing temperature (∆δ/δT > Ϫ4.1 ppb
Ϫ1). These NH protons form only a simple intramolecular
5 R1 = R2
=
K
hydrogen bond.
The 15N NMR spectra showed typical values for an oxamide
group (Table 3).15 In the NHA or NHB groups which showed
intramolecular three-center hydrogen bonding by 1H NMR, the
15N chemical shift appeared at low frequencies (ca. Ϫ263 to
Ϫ266 ppm) and those with more mobility were observed at high
frequencies (ca. Ϫ258 to Ϫ260 ppm). The 15
6
6′
3′
HO
MeO
5
5′
4′
1
1′
2′
4
2
6 R1
=
R2
=
3
N chemical shift of
HO
the phenolic oxamides 1–3 and 6–11 depends on the N᎐H
mobility as is shown by the linear correlation found between the
∆δ/∆T (1H) and the δ(15N) of the oxamide nitrogen (Fig. 1)
described by eqn. (1).
7 R1
=
R2
=
HO
CH3
Ph
∆δ/∆T(1H) = 106.9 ( 9.5) ϩ 0.40 ( 0.04)δ(15N);
n = 11, r = 0.97 (1)
R2
=
8 R1
=
HO
HO
HO
X-Ray diffraction analysis
CH3
Ph
The oxamide 1 and the oxalyl 11 compounds may exist in two
conformations, cis and trans,10 differentiated by the relative
positions of the carbonyl group. The X-ray molecular structure
of 1 and 11 was determined in order to provide an insight into
the role that hydrogen bonding plays in the molecular conform-
ation of the aromatic oxamides in the solid state. The X-ray
molecular structure of 1 and 11 showed the same conformation
found in solution by NMR spectroscopy.
R2
=
8 R1
=
OR
H
N
O
O
The selected bond lengths and bond angles are shown in
Tables 4 and 5 and the molecular structure in Figs. 2 and 3 for
compounds 1 and 11, respectively. The oxamide group in com-
pound 1 has the structure of two independently amides dis-
regarding a π conjugation across the central C᎐C bond as is
shown by the oxalyl OC᎐CO average bond length value of
1.541(5) Å (1.53 Å in other examples).16 The structures showed
O
10 R = H
11 R = Me
the oxamides 1–3 and 6–11. Compound 4 showed a slight
increase in the ∆δ/∆T absolute value (Ϫ3.4 ppb KϪ1) probably
due to the weaker interaction of the N᎐H hydrogen with the
402
J. Chem. Soc., Perkin Trans. 2, 1998

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Table 2 1H NMR chemical shifts of compounds 1–11 in ppm (in [2H6]DMSO)
Comp.
H-3
H-4
6.89
H-5
H-6
NHA
NHB
OH
1a
2b
8.13
8.24
7.73
8.07
7.06
7.05
6.76
7.36
7.00
6.88
9.82
9.86
10.05
11.01
8.69
9.90
9.73
9.69
9.73
9.63
9.70
10.43
10.19
8.97
3c
4d
7.17
7.17–7.35
7.02
6.83
6.83
6.85
6.84
7.02
7.34
5.83
5e
6f
8.17
8.12
8.09
8.12
7.98
8.08
7.20
6.99
6.99
6.99
7.02
7.20
7.15
6.92
6.92
6.95
6.94
7.13
9.88
9.16
8.71
8.46
10.42
10.37
10.24
10.36
10.26
7g
8h
9i
10j
11k
a Data taken from ref. 8. b But 1.26 ppm. c C4-Me 2.15, C6-Me 2.21 ppm. d ᎐CH2᎐ 4.64 ppm. e Ar᎐CH2᎐ 2.79, ᎐CH2᎐N 3.38 ppm. f Second ring H3Ј
8.12, H4Ј 6.89, H5Ј 7.05, H6Ј 6.97, OMe 3.92 ppm. g N᎐CH2᎐ 3.43, Ar᎐CH2᎐ 2.83, ArH 7.17–7.33 ppm. h N᎐CH 4.02, N᎐C᎐CH3 1.09, Ar᎐CH 4.70,
C᎐OH, 5.6 ArH 7.18–7.37 ppm. i N᎐CH 4.04, N᎐C᎐CH3 1.09, Ar᎐CH 4.66, C᎐OH 5.6 ArH 7.15–7.35 ppm. j O᎐CH2 4.31, C᎐CH3, 1.32 ppm.
k O᎐CH2 4.34, C᎐CH3, 1.35 ppm.
Table 3 Temperature dependence (∆δ/∆T in ppb KϪ1) and 15N chem-
ical shifts (ppm) of compounds 1–11
Table 4 Selected bond lengths (Å), bond angles (Њ) and torsion angles
(Њ) of 1
Comp.
Ϫ∆δ/∆T NHA Ϫ∆δ/∆t NHB
δ
15N NHA
δ
15N NHB
Interatomic bond lengths/Å
O(10)᎐C(1)
1.357(3)
1.219(3)
1.395(3)
1.382(3)
1.415(3)
1.336(3)
C(1)᎐C(6)
C(3)᎐C(4)
C(4)᎐C(5)
C(6)᎐C(5)
C(7)᎐C(7A)
1.376(3)
1.384(4)
1.379(3)
1.377(3)
1.541(5)
1
2
0.5
1.2
1.5
3.4
5.2
1.1
1.1
1.1
1.2
2.0
2.2
Ϫ266.0
Ϫ263.9
Ϫ263.8
Ϫ258.9
Ϫ264.6
Ϫ264.0
O(9)᎐C(7)
C(1)᎐C(2)
C(2)᎐C(3)
C(2)᎐N(9)
C(7)᎐N(9)
3
4
5
6
1.1
5.8
4.6
4.1
Ϫ265.0
7
Bond angles (Њ)
8
Ϫ265.1
Ϫ265.2
Ϫ260.7
Ϫ262.5
Ϫ256.9
Ϫ260.6
9
C(1)᎐C(2)᎐O(10)
C(2)᎐C(3)᎐C(4)
C(3)᎐C(2)᎐N(9)
C(3)᎐C(4)᎐C(5)
C(6)᎐C(5)᎐C(4)
O(7)᎐C(7)᎐C(7A)
C(7)᎐N(9)᎐C(2)
N(9)᎐C(7)᎐C(7A)
115.6(2)
119.4(2)
125.3(2)
120.6(2)
120.1(2)
121.7(2)
128.5(2)
112.0(2)
O(10)᎐C(1)᎐C(6)
C(6)᎐C(1)᎐C(2)
C(3)᎐C(2)᎐C(1)
C(1)᎐C(2)᎐N(9)
C(1)᎐C(6)᎐C(5)
O(8)᎐C(7)᎐N(9)
N(12)᎐C(7)᎐O(13)
124.1(2)
120.3(2)
119.7(2)
115.1(2)
119.9(2)
126.3(2)
127.2(3)
10
11
Torsion angles (Њ)
O(10)᎐C(1)᎐C(2)᎐N(9)
C(1)᎐C(2)᎐N(9)᎐C(7)
C(7A)᎐C(7)᎐N(9)᎐C(2)
1.9
Ϫ174.7
179.8
C(3)᎐C(2)᎐N(9)᎐C(7)
O(8)᎐C(7)᎐N(9)᎐C(2) Ϫ0.31
5.1
Fig. 1 ∆δ/∆T 1H NMR vs. δ(15N) NMR plot for 1–11 compounds
[eqn. (1)]. NHB of oxamide 9 is out of correlation probably due to steric
effects.
a OC᎐CO torsion angle value of 180.0(2)Њ for a trans con-
formation in contrast with other oxamides which show a tor-
sional angle between 90Њ and 115Њ.16 The oxalyl 11 presents the
same characteristic values, 1.541(4) Å for the C᎐C bond and
Ϫ170.0(2)Њ for the OC᎐CO torsion angle.
The planar conformation of 1 and 11 is stabilized by a three-
center (bifurcated) intramolecular hydrogen interaction
between the N᎐H amide hydrogen with two oxygen atoms.
Both hydrogen bond lengths with values of [N(9)᎐H(91) ؒ ؒ ؒ
O(10)᎐H = 2.172(2) Å] and [N(9)᎐H(91) ؒ ؒ ؒ O(8a) = 2.138(2) Å]
for oxamide 1 (Fig. 2) and [N(12)᎐H(121) ؒ ؒ ؒ O(15)᎐Me =
2.15(3) Å] and [N(12)᎐H(121) ؒ ؒ ؒ O(14) = 2.22(3) Å] for 11
(Fig. 3) are below the sum of the van der Waals radii of hydro-
gen (rVDW = 1.20 Å) and oxygen (rVDW = 1.50 Å)17 in both com-
pounds. The arrangement of the three atoms involved in the
intramolecular interaction O ؒ ؒ ؒ H ؒ ؒ ؒ O is almost colinear
Fig. 2 The molecular structure of 1 showing the three-center hydrogen
bonding interaction [N(9)᎐H(91) ؒ ؒ ؒ O(10)᎐H = 2.172(2) Å] and
[N(9)᎐H(91) ؒ ؒ ؒ O(8a) = 2.138(2) Å]
with the angle O(10) ؒ ؒ ؒ H(91) ؒ ؒ ؒ O(8a) being 149.8(2)Њ in
oxamide 1. This intramolecular hydrogen bond in both com-
pounds forms an arrangement of two five-membered chelate
rings in agreement with Hamilton et al. who reported similar
structures stabilized by intramolecular three-center hydrogen
J. Chem. Soc., Perkin Trans. 2, 1998
403

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Table 5 Selected bond lengths (Å), bond angles (Њ) and torsion angles
(Њ) of 11
molecules the full planar arrangement observed in the solid
state. This structure is strong enough to be the predominant
form in solution as was found by NMR spectroscopy.10 There-
fore it is confirmed that in the solid state compound 1 and 11
have the same conformation as in solution.
Interatomic bond lengths/Å
N(12)᎐C(2)
1.411(3)
1.316(3)
1.213(3)
1.358(3)
1.403(4)
1.379(4)
1.362(5)
1.541(4)
N(12)᎐C(7)
O(9)᎐C(10)
O(14)᎐C(8)
O(15)᎐C(16)
C(1)᎐C(6)
C(3)᎐C(4)
C(5)᎐C(6)
1.348(3)
1.464(3)
1.195(3)
1.426(4)
1.384(4)
1.387(4)
1.385(5)
1.490(5)
O(9)᎐C(8)
O(13)᎐C(7)
O(15)᎐C(1)
C(1)᎐C(2)
C(2)᎐C(3)
C(4)᎐C(5)
C(7)᎐C(8)
Conclusions
The present NMR and crystallographic studies have shown
that compounds 1–11 have the same conformation in the solid
state and in solution. The planar structure of 1–3, 6, 10 and 11
compounds is stabilized by an intramolecular three-center
hydrogen bond forming two five-membered rings. In com-
pound 4 the hydrogen bond forms two six-membered rings; this
arrangement is less strong than the five-membered one. Also
worth noting is the stability difference with the hydrogen bond-
ing in compound 5 where three coordinated hydrogen bonding
is not possible. In the non-symmetric oxamines 7–9 only the
phenolic part of the molecule presents strong three-centered
C(10)᎐C(11)
Bond angles (Њ)
C(2)᎐N(12)᎐C(7)
C(1)᎐O(15)᎐C(16)
O(15)᎐C(1)᎐C(6)
N(12)᎐C(2)᎐C(1)
C(1)᎐C(2)᎐C(3)
C(3)᎐C(4)᎐C(5)
C(1)᎐C(6)᎐C(5)
N(12)᎐C(7)᎐C(8)
O(9)᎐C(8)᎐O(14)
O(14)᎐C(8)᎐C(7)
128.8(2)
118.0(2)
125.5(3)
115.6(2)
119.9(3)
120.6(3)
119.3(3)
109.7(2)
125.7(3)
123.0(2)
C(8)᎐O(9)᎐C(10)
O(15)᎐C(1)᎐C(2)
C(2)᎐C(1)᎐C(6)
N(12)᎐C(2)᎐C(3)
C(2)᎐C(3)᎐C(4)
C(4)᎐C(5)᎐C(6)
N(12)᎐C(7)᎐O(13)
O(13)᎐C(7)᎐C(8)
O(9)᎐C(8)᎐C(7)
O(9)᎐C(10)᎐C(11)
114.9(2)
114.7(2)
119.8(3)
124.4(3)
119.5(3)
120.9(3)
127.2(3)
123.1(3)
111.3(2)
106.1(3)
1
hydrogen bonding. The role of variable temperature H NMR
studies as a tool in the study of hydrogen bonding has been
confirmed.
The three-center hydrogen bonding interaction is favored by
formation of at least two coplanar rings (five- or six-membered
rings). This planar structure is stable enough to remain the
principal conformer in solution.
Torsion angles (Њ)
O(14)᎐C(8)᎐C(7)᎐O(13) Ϫ170.2 H(121)᎐N(12)᎐C(2)᎐C(1) Ϫ7.6
H(121)᎐N(12)᎐C(7)᎐C(8)
O(14)᎐C(8)᎐C(7)᎐N(12)
6.4 H(31)᎐C(3)᎐C(2)᎐N(12)
8.7 O(13)᎐C(7)᎐N(12)᎐C(2)
2.0
1.7
Experimental
All solvents were freshly distilled and dried before use accord-
ing to established procedures. Melting points were measured
on a Gallenkamp apparatus and are uncorrected. The IR
spectra were recorded in KBr discs using a Perkin-Elmer 16F
PC IR spectrophotometer. Elemental analyses were per-
formed in a Fisons Instruments EA 1108 elemental analyzer
CHNS-0. The NMR spectra were obtained on a JEOL GXS-
1
270 spectrometer in [2H6]DMSO solution. H and 13C NMR
spectra were measured with SiMe4 as internal reference. Vari-
able temperature experiments were performed with a temper-
ature controller to keep the temperature constant within 0.3 ЊC.
A microprogram was used to change the temperature auto-
matically in fixed increments, with a delay of 5 min for tem-
perature stabilization. Each spectrum was obtained with 32
scans.
15N NMR spectra were obtained with neat nitromethane as
standard set to 0 ppm. All signals are upfield from nitro-
methane and chemical shifts are negative. 15N spectra were
recorded at 27.25 MHz using a multinuclear 5 mm probe and
approximately 0.3 mmol of each compound was dissolved in
0.5 cm3 of [2H6]DMSO. The refocused INEPT pulse sequence
was used to detect the 15N signal. The values of tD were set to
1
2.7 ms in instances where the average J(15N–1H) value was 93
Hz (tD = 1/4, 1J(15N–1H). A spectral width of 16 400 Hz with a
digital resolution of 0.5 Hz was used; the pulse delay was 5 s
with an acquisition time of 0.999 s.
Fig. 3 The molecular structure of 11 showing the three-center hydro-
gen bonding interaction [N(12)᎐H(121) ؒ ؒ ؒ O(15)᎐Me = 2.15(3) Å] and
[N(12)᎐H(121) ؒ ؒ ؒ O(14) = 2.22(3) Å]
The X-ray diffraction studies were performed on an Enraf-
Nonius CAD4 diffractometer (λMoKα = 0.710 69 A, mono-
chromator: graphite, T = 293 K, ω-2θ scan). Cell parameters
were determined by least squares refinement on diffract-
ometer angles for 24 automatically centred reflections.
Absorption correction was not necessary; corrections
were made for Lorentz and polarization effects. Solution
and refinement: direct methods (SHELXS-86) for struc-
ture solution. The CRYSTALS (version 9, 1994)19 and
SHELXL (Sheldrick)20 software packages were used for
refinement and data output. All hydrogen atoms were found
and refined in the case of structure 11; in the case of structure
1 hydrogen atoms were refined as riding atoms. Structure 1 has
a C2 axis and structure 11 has no symmetry axes. No inter-
molecular hydrogen bonding interactions were found in either
bonding forming one five-(N ؒ ؒ ؒ H = 2.20–2.22 Å) and one six-
membered ring (NH ؒ ؒ ؒ OC = 1.62–2.00 Å).18
Molecular structures of 1 and 11 showed that the carbonyl
amide group N᎐CO is in an endo conformation, pointing
towards the aromatic ring and in the plane of the molecule with
values of the angles O(8)᎐C(7)᎐N(9)᎐C(2) of Ϫ0.3(4)Њ and
O(13)᎐C(7)᎐N(12)᎐C(2) of 1.72(2)Њ. This conformation favours
the formation of a second intramolecular hydrogen interaction
between C(7)᎐O(8) ؒ ؒ ؒ H(31)᎐C(3) [2.216(2) Å] in 1 and
C(3)᎐H(3) ؒ ؒ ؒ O(13)–C(7) [2.35(3) Å] in 11, forming a six-
membered ring in each molecule.
The combined effect of the three-center hydrogen bond
O ؒ ؒ ؒ H ؒ ؒ ؒ O and the simpler one NH ؒ ؒ ؒ OC confers on these
404
J. Chem. Soc., Perkin Trans. 2, 1998

View Article Online
Table 6 Crystallographic data of compounds 1 and 11 at room temperature
Compound
1a
11b
Formula
C14H12N2O4
272.2
P21/n
C11H13NO4
223.23
P1
0.30 × 0.39 × 0.42
8.2168(5)
11.3201(5)
12.3648(5)
80.245(4)
81.839(4)
81.666(4)
1113.4(1)
4
0.095
1.33
Fw/g molϪ1
¯
Space group
Crystal size/mm3
0.28 × 0.27 × 0.15
5.289(10)
5.316(10)
21.495(4)
90.00(3)
92.81(3)
90.00(3)
603.6(2)
2
a/Å
b/Å
c/Å
α/Њ
β/Њ
γ’/Њ
V/Å3
Z
Linear abs. coeff./µ mmϪ1
0.112
1.50
Dc/g cmϪ3
θ limits/Њ
2–24
2–27
Octants collected
No. of data collected
No. of unique data collected
No. of unique data used
Intensity variation (σ)
R
0, 6; Ϫ6, 6; Ϫ24, 24
1775
940
726 [(F) > 4σ(F)]
>4
0.0415
0.1143
0.675
91
Ϫ0.28
Ϫ10, 0; Ϫ14, 14; Ϫ15, 15
5202
4311
3125 [Fo > 3σ(Fo)]
>3
0.0430
0.0440 w = 1/σ2
1.17
368
Ϫ0.21
0.17
Rw
Goodness of fit s
No. of variables
∆ρmin/e AϪ3
∆ρmax/e AϪ3
0.24
a Program for structure solution and refinement: SHELXL (1993).20 b Program for structure solution and refinement: CRYSTALS.19
structures 1 or 11. The experimental parameters are listed in
Table 6.†
(1.032 g, 8.13 mmol, 0.5 equiv.) at 25 ЊC. After stirring for
an additional 1 h at 25 ЊC, the solid was removed and washed
with 95% ethanol to give 4 (2.24 g, 92.1%) as a white solid.
νmax(KBr)/cmϪ1 3470, 1682, 1592, 1558, 1526, 1456, 1302, 1260,
1188, 1014, 748, 668 and 500 (Found: C, 63.74; H, 5.52; N, 9.17.
Calc. for C16H16N2O4: C, 64.00; H, 5.30; N, 9.30%); mp 206–
208 ЊC.
N,NЈ-Bis(2-hydroxyphenyl)oxamide 1
Compound 1 was prepared as reported.10
N,NЈ-Bis(5-tert-butyl-2-hydroxyphenyl)oxamide 2
2-Amino-4-tert-butylphenol (2.0 g, 12.10 mmol) in tetrahydro-
furan (THF) (20 ml) was treated dropwise under vigorous stir-
ring with oxalyl chloride (0.769 g, 6.06 mmol, 0.5 equiv.) at
25 ЊC. After stirring for an additional 1 h at 25 ЊC, the solid was
removed and washed with 95% ethanol to give 2 (1.27 g, 56.6%)
as beige solid. νmax(KBr)/cmϪ1 3358, 1654, 1558, 1540, 1458,
1362, 1264, 1122, 820, 668 and 472 (Found: C, 68.35; H, 7.26;
N, 7.27. Calc. for C22H28N2O4: C, 68.75; H, 7.29; N, 7. 29%); mp
288–289 ЊC.
N,NЈ-Diphenethyloxamide 5
Phenethylamine (2.0 g, 16.52 mmol) in CH2Cl2 (10 ml) and
triethylamine (0.82 g, 1.14 ml) were treated dropwise under
vigorous stirring with oxalyl chloride (1.049 g, 8.26 mmol, 0.5
equiv.) at 25 ЊC. After stirring for an additional 2 g at 25 ЊC, the
solid was filtered and washed with water (20 ml) to give 5 (2.1 g,
86.0%) as white solid. νmax(KBr)/cmϪ1, 3305, 1653, 1520, 1495,
1224, 1189, 740 and 697 (Found: C, 72.94; H, 7.22; N, 9.97.
Calc. for C18H20N2O2: C, 72.94; H, 6.80, N 9.45%), mp 184–
185 ЊC.
N,NЈ-Bis(3,5-dimethyl-2-hydroxyphenyl)oxamide 3
6-Amino-2,4-dimethylphenol (2.0 g, 14.59 mmol) in THF (20
ml) was treated dropwise under vigorous stirring with oxalyl
chloride (0.926 g, 7.29 mmol, 0.5 equiv.) at 25 ЊC. After stirring
for an additional 1 h at 25 ЊC, the solid was removed and
washed with 95% ethanol to give 3 (2.1 g, 87.8%) as a beige
solid. νmax(KBr)/cmϪ1 3488, 1670, 1654, 1558, 1540, 1458, 1420,
1338, 1208, 1026, 668 and 506 (Found: C, 65.11; H, 5.97; N,
8.27. Calc. for C18H20N2O4: C, 65.85; H, 6.09; N, 8.53%); mp
262–264 ЊC.
N-(2-Hydroxyphenyl)-NЈ-(2-methoxyphenyl)oxamide 6
Ethyl N-(2-hydroxyphenyl)oxalamate 10 (1.0 g, 4.78 mmol) in
THF (10 ml) was treated under vigorous stirring with ortho-
anisidine (0.587 g, 4.78 mmol) at 25 ЊC. After refluxing for
18 h, the solid was filtered and washed with THF (2 ml) to
give 6 (0.72 g, 52.2%) as a beige solid. νmax(KBr)/cmϪ1
3370, 3314, 1670, 1615, 1596, 1528, 1457, 1287, 1196, 1100,
1018, 744, 696 and 512 (Found: C, 63.39; H, 5.23; N, 9.68.
Calc. for C15H14N2O4: C, 62.93; H, 4.92; N, 9.78%); mp 230–
231 ЊC.
N,NЈ-Bis(2-hydroxybenzyl)oxamide 4
2-Aminobenzyl alcohol (2.0 g, 16.26 mmol) in THF (15 ml) was
treated dropwise under vigorous stirring with oxalyl chloride
N-(2-Hydroxyphenyl)-NЈ-phenethyloxamide 7
The oxalamate 10 (1.0 g, 4.78 mmol) in THF (10 ml) was
treated under vigorous stirring with phenylethylamine (0.578 g,
4.78 mmol) at 25 ЊC. After refluxing for 18 h, the solid was
filtered and washed with THF (2 ml) to give 7 (0.82 g, 60.7%) as
white solid. νmax(KBr)/cmϪ1, 3314, 3148, 1663, 1597, 1527, 1457,
1361, 1281, 1104, 747, 698 and 529 (Found: C, 68.01; H, 5.98;
N, 10.09. Calc. for C16H16N2O3: C, 67.59; H, 5.67; N, 9.85%);
mp 183–185 ЊC.
† Full crystallographic details, excluding structure factor tables, have
been deposited at the Cambridge Crystallographic Data Centre
(CCDC). For details of the deposition scheme, see ‘Instructions for
Authors’, J. Chem. Soc., Perkin Trans. 2, available via the RSC Web
pages (http://chemistry.rsc.org/rsc/plpifa.htm). Any request to the
CCDC for this material should quote the full literature citation and the
reference number 188/114.
J. Chem. Soc., Perkin Trans. 2, 1998
405

View Article Online
N-(2-Hydroxyphenylcarbamoylcarbonyl)-(1S,2R)-(؊)-
norephedrine 8
Acknowledgements
This work was supported by CONACYT-México. M. T. and
E. G. thank CONACYT-México for scholarships, Dr Armando
Ariza-Castolo for some of the 15N NMR spectra and Dr Noráh
Barba-Behrens for the elemental analysis facilities.
The oxalamate 10 (1.0 g, 4.78 mmol) in anhydrous ethanol (20
ml) was treated dropwise under vigorous stirring with (1S,2R)-
(Ϫ)-norephedrine (0.721 g, 4.78 mmol) at 25 ЊC. After refluxing
for 12 h, the solvent was removed under vacuum. Recrystalliz-
ation from ethyl acetate gave 8 (0.915 g, 61.8%) as a beige solid.
νmax(KBr)/cmϪ1 3383, 1670, 1560, 1522, 1458,1386, 1258, 1104,
1044, 750, 702 and 518 (Found: C, 65.13; H, 5.80; N, 8.76. Calc.
for C17H18N2O4: C, 64.96; H, 5.76; N, 8.90%); mp 154–156 ЊC.
References
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N-(2-Hydroxyphenylcarbamoylcarbonyl)-(1R,2S)-(؊)-
norephedrine 9
The oxalamate 10 (1.0 g, 4.78 mmol) in anhydrous ethanol (20
ml) was treated dropwise under vigorous stirring with (1R,2S)-
(Ϫ)-norephedrine (0.721 g, 4.78 mmol) at 25 ЊC. After refluxing
for 5 h, the solvent was removed under vacuum. Recrystalliz-
ation from ethyl acetate gave 9 (0.7 g, 47.3%) as a beige solid,
νmax(KBr)/cmϪ1 3304, 1652, 1600, 1524, 1456, 1480, 1384, 1240,
1102, 1042, 756, 696 and 518 (Found: C, 65.47; H, 5.88; N, 9.01.
Calc. for C17H18N2O4: C, 64.96; H, 5.76; N, 8.90%); mp 202–
203 ЊC.
9 C. B. Aakeröy and K. R. Seddon, Chem. Soc. Rev., 1993, 397.
10 F. J. Matínez-Martínez, A. Ariza-Castolo, H. Tlahuext,
M. Tlahuextl and R. Contreras, J. Chem. Soc., Perkin Trans 2, 1993,
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Ethyl N-(2-hydroxyphenyl)oxalamate 10
11 G. P. Dado and S. H. Gellman, J. Am. Chem. Soc., 1994, 116, 1054.
12 S. H. Gellman, B. R. Adam and G. P. Dado, J. Am. Chem. Soc.,
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13 S. Provera, C. Marchioro, S. Davailli and N. Case, Magn. Reson.
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14 H. Kessler, Angew. Chem., Int. Ed. Engl., 1982, 21, 2177.
15 G. A. Webb, Ann. Rep. NMR Spectrosc., 1981, 113, 112.
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P. Strazzolini, Tetrahedron, 1993, 49, 10 609.
17 J. E. Huheey, Inorganic Chemistry, Harper International SI edn.,
1983, p. 258.
o-Aminophenol (2.0 g, 18.34 mmol) in THF (25 ml) was treated
dropwise under vigorous stirring with ethyl oxalyl chloride
(2.49 g, 18.8 mmol, 1.0 equiv.) at 5 ЊC. After stirring for an
additional 1 h at 25 ЊC the solid was filtered. Recrystallization
from ethyl acetate gave 10 (2.75 g, 71.9%) as a beige solid.
νmax(KBr)/cmϪ1: 3362, 1654, 1596, 1544, 1464, 1350, 1292,
1106, 1026, 752, 744 and 504 (Found: C, 57.90; H, 5.54; N, 6.96.
Calc. for C10H11NO4: C, 57.41; H, 5.30; N, 6.69%); mp 179–
181 ЊC.
18 Y. Hamuro, S. J. Geib and A. D. Hamilton, Angew. Chem., Int. Ed.
Engl., 1994, 33, 446.
19 D. J. Watkin, J. R. Carruthers and P. W. Betteridge, CRYSTALS, An
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20 G. W. Sheldrick, SHELXTL 93, University of Göttingen, 1993.
Ethyl N-(2-methoxyphenyl)oxalamate 11
o-Anisidine (2.0 g, 16.26 mmol) in THF (10 ml) was treated
dropwise under vigorous stirring with ethyl oxalyl chloride
(2.21 g, 16.26 mmol, 1 equiv.) at 5 ЊC. After stirring for an
additional 1 h at 25 ЊC, the solid was filtered and washed with
water (50 ml) and dried in vacuum to give 11 (2.48 g, 68.9%) as
beige solid. νmax(KBr)/cmϪ1 3378, 1704, 1534, 1463, 1296, 1168,
1018, 936 and 754 (Found: C, 59.65; H, 6.22; N, 6.63. Calc. for
C11H13NO4: C, 59.18; H, 5.87; N, 6.27%); mp 82–83 ЊC.
Paper 7/04640E
Received 1st July 1997
Accepted 15th October 1997
406
J. Chem. Soc., Perkin Trans. 2, 1998