Temperature coefficient of NH chemical shifts of thioamides and amides in relation to structure

Article abstract of DOI:10.1016/j.molstruc.2004.01.006

NH chemical shift temperature coefficients have been measured in a large series of N-substituted-3-piperidinethiopropionamides in which the N?N distances are short but of varied length, as well as in a couple of the corresponding amides and in some simpler amides and thioamides. Geometries are calculated by means of ab initio DFT methods. The N-substituted-3- piperidinethiopropionamides show in most cases strong intramolecular N-H?N hydrogen bonds according to IR spectra and ab initio calculations. For compounds with rather short N?N distances the S=C-N-H moiety is non-planar. Dihedral angles as small as 160° are found. The NH chemical shift coefficients measured in non-polar solvents in all the N-substituted-3-piperidinethiopropionamides are more negative (-8 to -17ppb/K) than in non-hydrogen bonded thioamides. For the latter in non-polar solvents like CDCl₃ and toluene the temperature coefficients are as small as -1 to -4ppb/K. The large negative effects can be related not only to the non-planarity of the thioamide group in a way that the more pronounced the non-planarity the more negative the temperature coefficients, but also to strong hydrogen bonding and the fact that the acceptor is a nitrogen. For similar amides with non-planar amide groups and nitrogen acceptor large negative temperature coefficients are likewise seen. In polar solvents like DMF the effects in simple thioamides are uniform and close to -6ppb/K, whereas in the more complex compound like 4p(t) the temperature coefficient is close to 0. An essential feature of measuring temperature coefficients of compounds without strong intramolecular hydrogen bonds in non-polar solvents and at low temperatures is to keep the concentration low enough to avoid dimerisation.

Full text of DOI:10.1016/j.molstruc.2004.01.006

Journal of Molecular Structure 700 (2004) 91–103
www.elsevier.com/locate/molstruc
Temperature coefficient of NH chemical shifts of thioamides
and amides in relation to structure
a
Jacek G. Sosnicki , Poul Erik Hansen
b, ,1
*
´
a
´
Institute of Chemistry and Environmental Protection, Technical University of Szczecin, Aleja Piastow 42, 71065 Szczecin, Poland
bDepartment of Life Sciences and Chemistry, Roskilde University, P.O. Box 260, DK-4000 Roskilde, Denmark
Received 12 November 2003; revised 6 January 2004; accepted 8 January 2004
Abstract
NH chemical shift temperature coefficients have been measured in a large series of N-substituted-3-piperidinethiopropionamides in which
the N· · ·N distances are short but of varied length, as well as in a couple of the corresponding amides and in some simpler amides and
thioamides. Geometries are calculated by means of ab initio DFT methods. The N-substituted-3-piperidinethiopropionamides show in most
cases strong intramolecular N–H· · ·N hydrogen bonds according to IR spectra and ab initio calculations. For compounds with rather short
N· · ·N distances the SyC–N–H moiety is non-planar. Dihedral angles as small as 1608 are found. The NH chemical shift coefficients
measured in non-polar solvents in all the N-substituted-3-piperidinethiopropionamides are more negative (28 to 217 ppb/K) than in non-
hydrogen bonded thioamides. For the latter in non-polar solvents like CDCl3 and toluene the temperature coefficients are as small as 21 to
24 ppb/K. The large negative effects can be related not only to the non-planarity of the thioamide group in a way that the more pronounced
the non-planarity the more negative the temperature coefficients, but also to strong hydrogen bonding and the fact that the acceptor is a
nitrogen. For similar amides with non-planar amide groups and nitrogen acceptor large negative temperature coefficients are likewise seen. In
polar solvents like DMF the effects in simple thioamides are uniform and close to 26 ppb/K, whereas in the more complex compound like
4p(t) the temperature coefficient is close to 0. An essential feature of measuring temperature coefficients of compounds without strong
intramolecular hydrogen bonds in non-polar solvents and at low temperatures is to keep the concentration low enough to avoid dimerisation.
q 2004 Elsevier B.V. All rights reserved.
Keywords: NH chemical shifts; NH temperature coefficients; Intramolecular hydrogen bonding; Ab initio calculations; Thioamides; Amides
1. Introduction
extensive investigations of amides and peptides in non-polar
solvents and demonstrated that equilibrium between inter
and intramolecular hydrogen bonding or dimerisations
could give both small and large temperature coefficients
depending on the DH of the two hydrogen bonded states.
These authors decided upon a value of 25 ppb/K in non-
polar solvents for an ideal intramolecularly hydrogen
bonded amide, whereas for compounds with no hydrogen
bond they found values of approx. 22 ppb/K. They point to
the necessity of keeping the concentration low, typically
below 2 mg/ml for small amides as dimerisation otherwise
could lead to wrong results (see below).
NH chemical shifts of amides as a function of
temperature have attracted much attention as a monitor of
hydrogen bonding [1–18]. Coefficients more positive than
24 to 25 ppb/K have especially in protein structure work
been taken as evidence for intramolecular hydrogen
bonding [3–8]. The effects in proteins were originally
related to solvent access [1–3]. More recently it has been
pointed out that conformational changes may play an
important role [5,6]. In order to make predictions more
reliable a combination of parameters have been suggested
[4], but the temperature coefficients are so far not fully
understood. Gellman et al. [14–18] have performed very
Temperature coefficients of thioamides have been
investigated in a couple of cases [10,11]. In the present
study a number of intramolecularly hydrogen bonded N-
substituted-3-piperidine, morpholine thiopropionamides
[19] have been investigated. Structures of all the compounds
are calculated using ab initio DFT methods [20–22].
As reference non-hydrogen bonded thioamides are also
*
Corresponding author. Tel.: þ45 46742432; fax: þ45 46743011.
´
E-mail addresses: sosnicki@ps.pl (J.G. Sosnicki), poulerik@ruc.dk
(P.E. Hansen).
1
Fax: þ45-4674301.
0022-2860/$ - see front matter q 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2004.01.006

´
J.G. Sosnicki, P.E. Hansen / Journal of Molecular Structure 700 (2004) 91–103
92
studied. In addition, a couple of strongly hindered cyclic
amides similar to the thioamides are investigated together
with ortho-substituted naphthalenes with azo and acetamido
groups.
to strong intramolecular hydrogen bonding and nitrogen as
the hydrogen bond acceptor and to compare these results
with those of simple amides with only possibility of
intermolecular hydrogen bonding and finally with amides
and thioamides in which the acceptor is an oxygen atom
(Fig. 1). Furthermore, the type of acceptor, sp2 hybridised
The idea is to study NH temperature coefficients in a
series of thioamides and amides covering a range from weak
Fig. 1. Investigated compounds.

´
J.G. Sosnicki, P.E. Hansen / Journal of Molecular Structure 700 (2004) 91–103
93
oxygen or nitrogen or sp3 hybridised nitrogen is covered by
the above-mentioned compounds.
[24], 15 [11], 16, 17 and 18 [11], 19 and 20 [25] are
described elsewhere. Compound 14 was purchased from
Aldrich, Weinheim, Germany.
2. Experimental
2.1. 3-(4-Methylpiperidin-1-yl)-3,N-
diphenylthiopropionamide (2apme)
Theoretical calculations. The molecular geometries were
optimised using the GAUSSIAN98 suite of programs [20] and
B3LYP Density Functional Theory (DFT) [21,22] and the 6-
31G* basis set.
Pale yellow solid, mp 108–111 8C from acetonitrile. dH
(400.1 MHz, 300 K, CDCl3) 0.90 (3H, d, J ¼ 5:9 Hz, 7-
CH3eq), 1.18 (1H, qd, J ¼ 11:2; 3.9 Hz, H-8ax), 1.20–1.25
(1H, m, H-7ax), 1.32 (1H, qd, J ¼ 11:2; 3.8 Hz, H-6ax),
1.62–1.75 (2H, m, H-6eq, H-8eq), 1.78 (1H, td, J ¼ 11:2;
2.4 Hz, H-9ax), 2.31 (1H, td, J ¼ 11:3; 2.7 Hz, H-5ax), 2.96
(1H, brd, J ¼ ca. 11.5 Hz, H-5eq), 3.12 (1H, brd, J ¼ ca.
11.5 Hz, H-9eq), 3.17 (1H, dd, J ¼ 17:3; 2.2 Hz, H-2eq),
3.66 (1H, dd, J ¼ 17:3; 12.1 Hz, H-2ax), 4.15 (1H, dd, J ¼
12:1; 2.2 Hz, H-3ax), 7.13 (2H, dd, J ¼ 7:5; 1.3 Hz, 2 £ H-
200), 7.24 (1H, dt, J ¼ 7:4; 1.0 Hz, H-40), 7.27–7.38 (3H, m,
2 £ H-300, H-40), 7.42 (2H, t, J ¼ 8:3 Hz, 2 £ H-30), 7.88
(2H, dd, J ¼ 8:3; 1.1 Hz, 2 £ H-20), 13.75 (1H, brs, NH).
dH (400.1 MHz, 300 K, C6D6) 0.68 (3H, s, 7-CH3eq),
0.66–0.77 (1H, m, H-7ax), 0.88 (1H, qd, J ¼ ca. 11.8,
3.7 Hz, H-8ax), 1.08 (1H, qd, J ¼ ca. 11.8, 4.0 Hz, H-6ax),
1.20–1.31 (2H, m, H-8eq, H-6eq), 1.32 (1H, td, J ¼ 11:7;
2.3 Hz, H-9ax), 1.84 (1H, td, J ¼ 11:7; 2.4 Hz, H-5ax), 2.28
(1H, brd, J ¼ ca. 11.7 Hz, H-5eq), 2.52 (1H, brd, J ¼ ca.
11.3 Hz, H-9eq), 3.22 (1H, dd, J ¼ 17:0; 2.3 Hz, H-2eq),
3.39 (1H, dd, J ¼ 17:0; 12.0 Hz, H-2ax), 3.65 (1H, dd, J ¼
12:0; 2.3 Hz, H-3ax), 6.69–6.73 (2H, m, 2 £ H-200), 6.99
(1H, tt, J ¼ 7:4; 1.0 Hz, H-40), 7.08–7.11 (3H, m, 2 £ H-300,
H-400), 7.22–7.26 (2H, m, 2 £ H-30), 8.35 (2H, dd, J ¼ 8:7;
1.0 Hz, 2 £ H-20), 13.39 (s, 1H, NH); [Found: C, 74.62; H,
7,75; N, 8.37; S, 9.36. C21H26N2S requires C, 74.51; H,
7.74; N, 8.28; S, 9.47%]; nmax(KBr pellet) 2944, 2920, 2730
br, 1594, 1562, 1492, 1380, 756, 740, 708 cm21; GCMS-
decomposition (retro-Michael addition).
Experiments. Melting points were determined on a
Boetius hot stage apparatus and are uncorrected. Infrared
spectra were taken with a Specord M80 instrument. Mass
spectra (70 eV) were recorded with a HP 6890 (Hewlett-
Packard) GCMS spectrometer equipped with a mass
detector HP 5973. Elemental analyses were performed on
EuroEA 3000 series, EuroVector CHNS-O Elemental
Analyser.
1
NMR. H, 13C NMR spectroscopic measurements were
performed on a Bruker DPX 400 spectrometer equipped
with a 5 mm 1H/BB-inverse probehead, operating at
400.13 and 100.62 MHz with a digital resolution of 0.12
1
and 0.97 Hz per point for H and 13C, respectively, or on
a Bruker AC 250 or a Varian Mercury 300 instrument
primarily using CDCl3 as solvent. Low temperature
spectra were recorded in CDCl3, CD2Cl2 or in toluene-
d8. TMS was used as internal reference in all
measurements. Two-dimensional spectra were acquired
using standard Bruker software. Heteronuclear
1
correlation (13C, H COSY) was optimised for a coupling
145 Hz. In 1H, 1H NOESY experiment (2apme, C6D6)
the mixing time of 0.6 s was applied. Enhanced
resolution spectra were obtained by Lorentzian to
Gaussian transformation (LB ¼ 22.5, GB ¼ 0.64) using
Bruker software for PC.
Compounds. Compounds 1–7 were synthesized by
addition of amines to corresponding a,b-unsaturated
thioamides according to the method described earlier [19].
Yield and the reaction conditions of new compounds are
presented in Table 1. Compounds 8 [23], 11 [11], 12 and 13
2.2. N-(4-chlorophenyl)-3-morpholin-4-yl-3-
phenylthiopropionamide (2amCl)
Table 1
Yields and reaction conditions of new compounds
Aminea/solvent Molar ratio
to amine
Temperature (8C) Product yield (%)
(ratio of
Pale yellow solid, mp 133–137 8C from acetonitrile. dH
(400.1 MHz, rt, CDCl3) 2.48 (2H, brs, CH2N), 2.70–2.78
(2H, m, CH2N), 3.21 (1H, dd, J ¼ 17:1; 2.7 Hz, H-2eq), 3.64
(1H, dd, J ¼ 17:1; 11.3 Hz, H-2ax), 3.70–3.83 (4H, m,
2 £ CH2O), 4.11 (1H, dd, J ¼ 11:3; 2.7 Hz, H-3ax), 7.14
(2H, dd, J ¼ 7:9; 2.9 Hz, 2 £ H-200), 7.33–7.41 (5H, m,
C6H4Cl, C6H5), 7.81 (2H, d, J ¼ 8:8 Hz, 2 £ H-20), 13.06
(1H, s, NH); [Found: C, 63.02; H, 5,91; N, 7.30; S, 8.89.
C19H21ClN2OS requires C, 63.23; H, 5.86; N, 7.76; S,
8.88%]; nmax(KBr pellet) 2888, 2750 br, 1608, 1556, 1490,
1388, 1116, 776, 760, 740, 710 cm21; GCMS-decompo-
sition (retro-Michael addition).
of thioamide (reaction time)
diastereoisomers)
p/Neat
1:10
1:8
20 (6 h)
2apme, 82
2amCl, 90
2apNO2, 64
m/Neat
20 (1 d)
p/Methanol
1:20
20 (0.5 h) then
210 (0.5 h)
20 (1.5 h) then
210 (3 d)
20 (2 d)
p/Neat
1:3
3am, 80
m/Neat
p/Neat
p/Neat
1:10
1:10
1:8
5ap(t), 70, (50:50)
5am(c), 74, (50:50)
7ap, 86
20 (3 d)
20
a
p, piperidine; m, morpholine.

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94
2.3. N-(4-nitrophenyl)-3-phenyl-3-piperidin-1-yl-
thiopropionamide (2apNO2)
from n-hexane:ethyl acetate. dH (400.1 MHz, 300 K,
CDCl3) 1.40 (3H, d, J ¼ 6:7 Hz, CH3), 2.48–2.65 (4H, m,
2 £ CH2N), 3.40 (1H, q, J ¼ 6:7 Hz, H-2), 3.71–3.79 (5H,
m, H-3, 2 £ CH2O), 7.15–7.31 (6H, m, 3-C6H5, N-C6H5),
7.34 (2H, t, J ¼ 7:6 Hz, 2 £ H-30), 7.46 (2H, d, J ¼ 7:7 Hz,
2 £ H-20), 11.25 (1H, brs, NH); nmax(KBr pellet) 3428 br,
3216 br, 2956, 2816, 596, 1496, 1412, 1288, 1106, 862, 756,
704 cm21; [Found: C, 70.57; H, 7,25; N, 8.22; S, 9.23.
C20H24N2OS requires C, 70.55; H, 7.10; N, 8.23; S, 9.42%];
m=z (EI, 70 eV) 340 (1, Mþ), 307 (5), 252 (2), 176 (100), 117
(8), 91 (8), 17 (5).
Pale yellow solid, mp 163–166 8C from acetonitrile. dH
(400.1 MHz, rt, CDCl3) 1.45 (2H, brs, CH2), 1.70 (4H, brs,
2 £ CH2), 2.40 (2H, brs, CH2N), 2.75 (2H, brs, CH2N), 3.18
(1H, dd, J ¼ 17:3; 1.7 Hz, H-2eq), 3.67 (1H, dd, J ¼ 17:3;
12.3 Hz, H-2ax), 4.15 (1H, brd, J ¼ ca. 10.9 Hz, H-3ax), 7.13
(2H, brd, J ¼ ca. 6.0 Hz, 2 £ H-200), 7.25–7.42 (3H, m,
2 £ H-300, H-400), 8.19 (2H, d, J ¼ 9:1 Hz, C6H4NO2), 8.29
(2H, d, J ¼ 9:1 Hz, C6H4NO2), 14.40 (1H, brs, NH); [Found:
C, 64.92; H, 6,34; N, 11.40; S, 8.77. C20H23N3O2S requires
C, 65.01; H, 6.27; N, 11.37; S, 8.68%]; nmax(KBr pellet)
2.7. N-phenyl-3-piperidin-1-yl-butyramide (7ap)
2936, 2650 br, 1584, 1514, 1336, 1110, 854, 744, 706 cm21
GCMS-decomposition (retro-Michael addition).
;
Pale yellow solid, mp 105–107 8C from n-hexane:ethyl
acetate. dH (400.1 MHz, 300 K, CDCl3) 1.02 (3H, d,
J ¼ 6:6 Hz, CH3), 1.47–1.78 (6H, m CH2-6, CH2-7, CH2-
9), 2.48 (2H, brs, CH2N), 2.75–2.84 (2H, m, CH2N), 2.88
(1H, dd, J ¼ 17:4; 2.6 Hz, H-2eq), 3.02 (1H, dd, J ¼ 17:4;
11.0 Hz, H-2ax), 3.15–3.27 (1H, m, H-3ax), 7.21 (1H, t,
J ¼ 7:5 Hz, C6H5), 7.39 (2H, t, J ¼ 8:2 Hz, C6H5), 7.83
(2H, dd, J ¼ 8:7; 1.1 Hz, C6H5), 13.89 (1H, brs, NH);
[Found: C, 68.75; H, 8.52; N, 10.51; S, 12.15. C15H22N2S
requires C, 68.65; H, 8.45; N, 10.68; S, 12.22%]; nmax(KBr
pellet) 2932, 2650 br, 1596, 1570, 1428, 1402, 736,
692 cm21; GCMS-decomposition (retro-Michael addition).
Amides: 9amCl and 10ap(t) were obtained from
corresponding thioamides by using method described by
Papadopoulos [26] with some modifications.
2.4. 2-Methyl-3-morpholin-4-yl-N-phenylthiopropionamide
(3am)
Pale yellow solid, mp 97–98 8C from n-hexane: ethyl
acetate. dH (400.1 MHz, 300 K, CDCl3) 1.41 (3H, d,
J ¼ 6:9 Hz, CH3), 2.49–2.57 (2H, m, CH2N), 2.59 (1H,
dd, J ¼ 13:0; 3.3 Hz, H-3eq), 2.71–2.79 (2H, m, CH2N),
2.76 (1H, dd, J ¼ 13:0; 10.2 Hz, H-3ax), 2.85–2.94 (1H, m,
H-2ax), 3.72–3.82 (4H, m, 2CH2O), 7.22 (1H, t, J ¼ 7:4; H-
40), 7.37–7.41 (m, 2H, 2 £ H-30), 7.75 (2H, dd, J ¼ 8:7;
1.2 Hz, 2 £ H-20), 12.44 (1H, brs, NH); [Found: C, 63.29; H,
7,57; N, 10.42; S, 12.04. C14H20N2OS requires C, 63.60; H,
7.62; N, 10.60; S, 12.13%]; nmax(KBr pellet) ca. 2700 br,
1592, 1568, 1492, 1404, 1366, 1292, 1116, 860, 716 cm21
;
General procedure. To the homogenous mixture, result-
ing from 0.23 g (5.7 mmol) of NaOH (pellets) and 0.1 g
(0.33 mmol) of thioamide and 8 cm3 99.8% ethanol,
0.7 cm3 of H2O2 (30%) was added at room temperature.
After 20 min further 0.7 cm3 of H2O2 was added and the
mixture was kept at room temperature for an additional
20 min. In this time the small amounts of the products
precipitated. Finally the resulting mixture was acidified with
diluted HCl causing the gas evolution and the solid
dissolving. After 10 min the mixture was slightly alkalised
with solid NaOH and was left overnight to precipitate
yielding white solid.
m=z (EI, 70 eV) 264 (7), 231 (13), 100 (100), 77 (8).
2.5. trans-2-Methyl-3,N-diphenyl-3-piperidin-1-yl-
thiopropionamide [5ap(t)]
This compound was obtained after fractional crystal-
lization of the mixture of diastereoisomers from methanol:
water. White solid, mp 163–166 8C from methanol:water.
dH (400.1 MHz, 300 K, CDCl3) 1.31 (3H, d, J ¼ 6:9 Hz,
CH3), 1.36 (2H, brs, CH2-7), 1.51–1.71 (4H, m, CH2-6,
CH2-8), 2.33–2.70 (4H, m, CH2-5, CH2-9), 3.37–3.48 (1H,
m, H-2ax), 3.89 (1H, d, J ¼ 10:7 Hz, H-3ax), 7.16 (2H, brd,
J ¼ ca. 6.7 Hz, 2 £ H-200), 7.23–7.30 (1H, m, H-40), 7.31–
7.48 (5H, m, 3-C6H5, N-C6H5), 7.75 (2H, dd, J ¼ 8:6;
1.2 Hz, 2 £ H-20), 13.89 (1H, brs, NH); [Found: C, 74.63; H,
7,64; N, 8.38; S, 9.57. C21H26N2S requires C, 74.51; H,
7.74; N, 8.28; S, 9.47%]; nmax(KBr pellet) 3240, 2932, ca.
2750 br, 1490, 1416, 764, 704 cm21; m=z (EI, 70 eV) 338 (1,
Mþ), 305 (8), 177 (5), 174 (100), 91 (12), 77 (5).
2.8. N-(4-chlorophenyl)-3-morpholin-4-yl-3-phenyl-
propionamide (9amCl)
Yield 76%. White solid, mp 204–206 8C from n-
hexane:ethyl acetate. dH (400.1 MHz, rt, CDCl3) 2.48 (2H,
brs, CH2N), 2.55 (1H, dd, J ¼ 16:7; 3.2 Hz, H-2eq), 2.62–
2.72 (2H, m, CH2N), 3.19 (1H, dd, J ¼ 16:7; 11.2 Hz, H-
2ax), 3.70–3.85 (4H, m, 2 £ CH2O), 4.01 (1H, dd, J ¼ 11:2;
3.2 Hz, H-3ax), 7.15 (2H, brd, J ¼ 7:8 Hz, 2 £ H-200), 7.25–
7.40 (5H, m, C6H4Cl, C6H5), 7.52 (2H, d, J ¼ 8:7 Hz,
2 £ H-20), 10.95 (1H, s, NH); [Found: C, 65.96; H, 6.28; N,
8.06. C19H21ClN2O2 requires C, 66.18; H, 6.14; N, 8.12%];
2.6. cis-2-Methyl-3-morpholin-4-yl-3,N-
diphenylthiopropionamide [5am(c)]
This compound was obtained after fractional crystal-
lization of the mixture of diastereoisomers from n-
hexane:ethyl acetate. Pale yellow solid, mp 193–196 8C
n
max(KBr pellet) 3440 br, 2888, 1680, 1592, 1544, 1492,

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J.G. Sosnicki, P.E. Hansen / Journal of Molecular Structure 700 (2004) 91–103
95
1116, 828, 784, 748, 712 cm21; m=z (EI, 70 eV) 344 (4, Mþ),
285 (9), 257 (10), 176 (100), 131 (47), 103 (22), 86 (64).
For simple amides like 14 and 22 we find temperature
coefficients of 25 and 23 ppb/K. This can be compared to
the value of 22.5 and 23.5 ppb/K found for N-methyla-
cetamide in CD2Cl2 and CD3CN [18]. However, using
DMF-d4 forming strong hydrogen bonds to the solute the
temperature coefficient for the simple thioamides like 12, 13
in DMF are typically 26 to 28 ppb/K similar to those
found in 15e(c) and 15e(t). For 4ap(t), 2bep and 2bem the
temperature coefficients change to 24 and 22 ppb/K in
DMF-d8 (Table 2). Martinez-Martinez et al. [12] investi-
gated oxamides and simpler amides in DMSO and found
temperature coefficients between 20.5 and 25.9 ppb/K.
Thioamides with a NH group forming a hydrogen bond
to oxygen have previously been investigated in 16k, 17k
and 18 [11]. For 16k the temperature coefficient was
24 ppb/K, for 17k only 22.6 ppb/K and for 18 22 ppb/K,
all very close to zero and all in non-polar solvents.
2.9. 2-Piperidin-1-yl-cyclohexanecarboxylic acid
phenylamide [10ap(t)]
Yield 75%. White solid, mp 153–157 8C from n-
hexane:ethyl acetate. dH (400.1 MHz, rt, CDCl3): 1.10–
1.35 (3H, m, CH H-7, H-13ax, H-10ax), 1.45–1.90 (9H, m,
CH2-6, CHH-7, CH2-8, CH2-11, CH2-12), 1.97 (1H, br s, H-
13eq), 2.32 (1H, td, J ¼ 11:3; 4.0 Hz, H-2ax), 2.51 (2H, br s,
CH2N), 2.57–2.70 (2H, m, H-10eq, H-3ax), 2.78–2.88 (2H,
m, CH2N), 7.05 (1H, t, J ¼ 7:4 Hz, C6H5), 7.26–7.34 (2H,
m, C6H5), 7.61 (2H, d, J ¼ 7:8 Hz, C6H5), 12.58 (1H, br s,
NH). [Found: C, 75.60; H, 9.22; N, 9.66. C18H26N2O
requires C, 75.48; H, 9.15; N, 9.78%]; nmax(KBr pellet)
3284, 3216, 2932, 2872, 2796, 1654, 1604, 1544, 1442, 760,
744, 692 cm21; m=z (EI, 70 eV) 286 (41, Mþ), 194 (7), 166
(16), 124 (100), 84 (35).
Intramolecularly hydrogen bonded amides are exempli-
fied by 19–21 giving temperature coefficients of 21, 23
and 24.8 ppb/K (Table 2). 20 shows a linear behaviour at
low concentrations, which at a concentration of 4.4 mM it
becomes non-linear.
3. Results
3.1. OH temperature coefficient
The temperature coefficients of non-intramolecularly
hydrogen bonded compounds have been measured at
concentrations of 2 mg/ml. In case higher concentrations
are used then the plot vs. temperature usually becomes non-
linear so an internal check is present. In non-polar solvents
like CDCl3 and toluene we find very small and negative
temperature coefficients 21 to 24 ppb/K for simple
thioamides like 11, 15e(c) and 15e(t). In the series of N-
substituted-3-piperidinethiopropionamides the effects are
seen to range from 28.5 to 217 ppb/K in non-hydrogen
bonding solvents with the more negative ones observed for
4ap(t), 4am(t), 5ap(t), 5am(t) and 4bep(t). For the
morpholine derivatives the temperature coefficients are
normally more negative than for the corresponding
piperidine derivatives (see Table 2). For the compounds
2ap . 2am the numerical order of the temperature
coefficient is as shown. Differences are also seen for aniline
(a) and benzyl (be) derivatives, but these are much less
systematic and they are most likely related to structure (see
later). For the weakly hydrogen bonded compounds like 8
the temperature coefficient is 27.5 pp/K (Table 2).
A couple of the present compounds have OH groups. For
11 the temperature coefficient is 24 in CDCl3 and
27 ppb/K in toluene and close to zero in 15e(c) and
15e(t). For 11 and 15e(c) the temperature coefficient is
uniform in the temperature interval irrespective of the
concentration, but this is not the case for 15e(t), which
decreases numerically at high concentration at low
temperature.
3.2. Structure assignment
The formation of quasi-heterocyclic ring due to intra-
molecular NH· · ·N hydrogen bonding is observed for
compounds described in this work. The same fact was
noticed in the case of derivatives described earlier [19].
Based on coupling constants between protons at C-2 and C-
3 the quasi-axial and -equatorial positions of the protons
were assigned. A more detailed analysis of 2apme based on
1D and 2D (1H, 1H NOESY) 1H and 13C spectra allowed to
1
It is noteworthy for compounds 1–10 that in most
cases the change in the NH chemical shifts are uniform
in the measured temperature interval (Fig. 2). One
exception is 5am(c) in which the change with tempera-
ture is decreasing due to conformational averaging (see
later).
assign all H and 13C signals and estimate conformation of
quasi-heterocyclic and 4-methylpiperidine rings and their
orientation to each other. The NMR analysis performed in
C6D6 was facilitated as 4-methylpiperidine exhibited no
exchange process at room temperature and most of signals
did not overlap. Based on conformational analysis derived
from JHH couplings and the NOE effects (Fig. 3) the chair
shape of piperidine ring with equatorially substituted
nitrogen atom was recognized as well as the perpendicular
orientation of quasi-heterocyclic ring in relation to piper-
idine one. This picture correlates well with the calculated
structure (Fig. 3) and that obtained from X-ray studies [27].
The temperature coefficients do not vary significantly
with the solvent as long as this is not strongly hydrogen
bonding as seen for 2ap in CDCl3 and THF-d8 and for
4ap(t) in toluene-d8 (see Table 2). For the sterically
hindered amides 9amCl and 10ap(t) we again find large
negative values, 212 and 29 ppb/K, respectively.

´
J.G. Sosnicki, P.E. Hansen / Journal of Molecular Structure 700 (2004) 91–103
96
Table 2
NH temperature coefficients, NH chemical shifts and NH stretching frequencies and ab initio calculated bond length and bond angles
nNHa (cm21
)
dNH (ppm)b
Solvent
˚
RN–H (A)
˚
RN· · ·N (A)
Compound
DNH/T (ppb/K)
Angle SyC–N–H
1ap
2ap
29
174.5
177.9
1.0302
1.0326
2.876
2.855
–
13.44
13.77
13.70
12.94
14.30
13.06
13.37
12.44
14.51
14.02
11.57
12.75
13.72
11.04
12.98
12.33
13.86
12.00
11.05g
11.28
10.55
12.9
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
Toluene-d8
DMF-d4
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
DMF-d4
CDCl3
DMF-d4
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
DMF-d4
DMF-d4
CDCl3
CDCl3
DMF-d4
DMF-d4
CDCl3
DMF-d4
CDCl3
CDCl3
CDCl3
CD2Cl2
CD2Cl2
CDCl3
CDCl3
CDCl3
28.8
28.3
210
2750
2apmec
2am
177.9
176.9
177.9
173.4
173.7
160.6
–
1.0298
1.0348
1.0311
1.0294
1.0280
1.0301
–
2.876
2.846
2.866
2.857
2.867
2.799
–
2apNO2
2amCl
3ap
29
210.6
211
2680
2780
2790
2790
2630
–
3am
212.5
214
4ap(t)
4ap(t)
4ap(t)
4am(t)
5ap(t)
5am(c)d,e
6ap(t)
6am(t)
7ap
211.3
22.0
217
–
–
–
–
161.2
170.8
1.0289
1.0310
2.804
2.804
2700
2740
3377f
216.3
28
210
174.6
174.5
177.3
179.8
1.0283
1.0269
1.0307
1.0285
2.927
2.942
2.875
2.823
28.8
29
2750
2bep
2bep
2bem
2bem
4bep(t)
4bep(c)
6bep(t)
6bem
7bem
8
28.7
24
2780
2900
210.4
24
215
177.2
1.0207
2.844
164.4
179.8
172.2
172.9
175.6
176.4
175.2
175.1
1.0308
1.0315
1.0268
1.0260
1.0265
1.0233
1.0254
1.0278
2.759
2.772
2.896
2.906
2.851
2.867
2.884
2.801
–
28.6
210
–
12.95
11.36
10.68
11.63
11.51
10.88
12.58
11.14
9.94, 10.25
9.16, 9.22
7.20
–
210.6
28.8
27.5
212.2
29.3
22
26 and 27i
25.8 and 28i
25
3160h
–
9amCl
10ap(t)
11d
2970
2800
12
13d
14d
15k
Non-linear
26
26
173.7
–
1.0216
–
2.827
–
10.99
11.48
12.07k
8.24l
11.33k
8.32l
15k
–
–
15e(t)j
15e(t)
15e(c)
15e(c)
16km
17km
18m
173.4
–
1.0131
–
22
26
173.5
–
1.0139
–
–
22 to 24
24
172.7
172.0
173.6
180.0
159.3
1.0230
1.0240
1.0315
1.0232
1.0217
2.762
2.708
2.586
2.870
2.690
10.34
11.25
13.97
9.69
22.6
22
21
19m
20
21d
22d
23
24.8
23
8.16
13.00
7.73k
a
Almost all resonances are very broad.
At 300 K.
b
c
d
e
f
Structure not calculated. Assumed to be similar to 2ap.
Structure not calculated.
Exists as a mixture of a closed and an open form.
Open form.
g
h
i
Measured at 273 K. j broad at 298 K. Measured at 273 K.
Sharp resonance.
Assigned to the H(Z) proton.
j
Assignment according to Ref. [11].
Broad at 298 K. Measured at 273 K.
Broad at 298 K. Measured at 213 K.
Data taken from Ref. [11].
k
l
m

´
J.G. Sosnicki, P.E. Hansen / Journal of Molecular Structure 700 (2004) 91–103
97
Fig. 4. Plot of 3J(H-2ax,H-3ax) (Hz) vs. temperature (K) for selected
compounds.
Fig. 2. Plot of NH chemical shifts vs. temperature (K) for selected
compounds in CDCl3.
3.3. Coupling constants and structural implications
the trans coupling goes up slightly as the temperature is
lowered, whereas for others the coupling constant remains
constant (Fig. 4).
3J(H-2,H-3). This coupling constant at ambient tempera-
ture in CDCl3 is typically between 10.4 and 12.1 Hz for the
trans coupling and 2.2 and 2.8 Hz for gauche coupling for
2ap, 2am, 2apme, 2bep, 3ap, 5ap(t), 7ap, 9amCl and
10ap(t). For 3am it is 10.29 and 3.37 Hz and for 2bem
11.17 and 3.14 Hz (similar to those shown in Ref. [19]). For
4ap(t) no coupling could be measured because of overlap at
3.4. Ab initio calculations
Structure calculation. Ab initio calculations of the
B3LYP DFT type [20–22] have been performed to obtain
optimised geometries. The structures calculated with
respect to N· · ·N distances are similar to those obtained
from PM3 calculations [28] (see below) except that N· · ·N
3
ambient temperature. At 240 K J(H-2, H-3) couplings of
10.4 and 3.3 Hz could be measured, showing a trans
structure. For 1ap the couplings could be calculated from
the AA0XX0 system as 4.7 and 6.6 Hz showing an
equilibrating structure. For 5am(c) the two coupling
constants are identical, 7.35 Hz measured at 250–
220 K. At higher temperature overlap prevents measure-
ment. For 2bep dissolved in DMF the coupling constants are
7.3 and 7.5 Hz showing that this compound is no longer
forming an intramolecular hydrogen bond. This is also
confirmed from the NH chemical shifts. A similar pattern is
seen in DMSO for 4ap(t).
˚
distances systematically are 0.01 A shorter in the semi
empirical calculations apparently caused by shorter H· · ·H
distances between H-20, H-60 of the N-phenyl ring and H-
6,H-8ax in the PM3 calculations, thereby leading to a
slightly more compact structure. This distance is short as is
seen from NOESY spectra (Fig. 3). This finding lends
support to the search for optimal structures using semi-
empirical PM3 methods [28]. This has been useful in order
to search the conformational space in order not to end up in
local minima.
Important for the following discussion is the temperature
variation of 3J(H-2,H-3). For a number of compounds
An important feature is the acidity of the NH group. This
is greatly enhanced by the phenyl ring in derivatives of
aniline type. The NH bond is found to be largely coplanar
with the benzene ring in these compounds. An additional
factor is the hybridisation of the thioamide nitrogen. In a
number of key compounds the SyC–N–H dihedral angle
is found to be considerably less than 1808 (see below). The
˚
N–H bond length is calculated to be close to 1.03 A
illustrating the hydrogen bond formation. This is seen in
contrast to simple non-hydrogen bonded compounds like
N-phenylthioacetamide in which the N–H bond length is
˚
calculated as 1.01 A.
For 7bem two structures (one with the methyl group at
C-3 equatorial, relative to the six-membered hydrogen bond
ring) and one with the methyl group axial are found to have
very similar energies with the latter 5.5 kJ of lower energy.
However, this conformation was not found in the first
Fig. 3. Calculated (ab initio) structure of 2apme together with a structure
estimated from NOESY constraints.

´
J.G. Sosnicki, P.E. Hansen / Journal of Molecular Structure 700 (2004) 91–103
98
Table 3
Calculated 1H nuclear shielding tensor elements and isotropic shielding
Compounds XX
YY
ZZ
Isotropic shielding
2apNO2
2am
6.9
22.3
23.3
23.0
23.2
23.5
23.0
23.6
21.6
24.8
24.6
24.5
25.8
25.9
23.0
31.5
31.2
31.5
31.3
31.2
31.7
31.7
31.6
32.2
32.0
32.2
32.1
29.0
34.0
20.2
20.9
20.8
20.8
21.00
20.4
20.9
21.6
22.7
21.8
21.9
23.3
21.4
22.6
8.0
7.7
2amCl
4ap(t)
4am(t)
5ap(t)
7ap
7.8
8.3
7.1
7.8
2bep
2bem
4bep(c)
4bep(t)
6bep
8
11.7
11.1
8.9
9.4
11.9
9.4
Fig. 6. IR spectrum of 10ap(t) measured in CDCl3 solution.
9amCl
12
15k
10.8
21.8, 20.7 23.9, 25.9 32.2, 32.9 26.0, 26.5
3.5. Infrared spectra
12.7
17.5
18.1
10.9
9.2
26.3
28.3
28.8
26.1
25.8
23.1
26.2
25.6
28.4
30.8
29.0
28.1
28.0
29.6
30.6
29.2
22.5
25.2
25.3
21.7
21.0
19.5
23.4
20.9
15e(t)
15e(c)
16k
IR data have been obtained in CDCl3 and in addition in
CD2Cl2 in order to gauge the hydrogen bond states of these
compounds. As seen from Fig. 5 (4am(t)) and Fig. 6
(10ap(t)) bands due to NH stretching are broad and shifted
strongly towards lower wave numbers (Table 2). For 5am(c)
two bands are observed due to an open (3377 cm21) and a
hydrogen bonded case (,2800 cm21). For all other
compounds this is not so.
17k
18
5.7
19
20
13.2
7.9
attempt. For 8 the calculations oscillated between two very
similar low energy structures.
1H nuclear shielding tensors. 1H nuclear shielding
tensors of the NH protons are given in Table 3. The values
for the N-substituted-3-piperidinethiopropionamides of
aniline type show a small change in the smallest tensor
value related to the change in the N· · ·N distance.
Derivatives of benzyl type fall in between. However,
going to compounds like 15k, 16k, 17k, 18, 19 and 20 the
tensor elements are changed considerably. The smallest
tensor element is increasing for these again related to the
N· · ·N distance, but the two other tensor elements are now
much more alike giving a cylindrical type of shielding
surface. This change in the tensor elements reflects also the
influence of the acceptor atom.
4. Discussion
The discussion will be divided according to compounds
and their hydrogen bond patterns, strength and solvent type.
The hydrogen bonds are of intra or intermolecular type. The
hydrogen bond strength is of course best given by the
hydrogen bond energy, but as this is not known, the heavy
atom distance can be used as a measure of hydrogen bond
strength [29]. The heavy atom distances are in all cases
calculated by the DFT method as given in Table 2. In a
number of cases they have also been determined by X-ray
[27]. The results not only show good correlation, but also
˚
that the calculated ones generally are 0.1 A longer than
those determined by X-ray.
The simple thioamides at so low concentration that even
intermolecular hydrogen bonds are no longer important
show small negative temperature coefficients in non-polar
solvents. Examples are 11 and 15e(c and t). The temperature
coefficients are of the order of 22 ppb/K. For simple amides
the effects can be slightly larger, e.g. 25 ppb/K as seen for
14, but in this case conformational effects of the methoxy
group cannot be ruled out. The thioamides of N-substituted-
3-piperidine or morpholine type studied in the present case
show NH temperature coefficients more negative than
27.5 ppb/K and for compounds such as 4ap(t), 4am(t),
5ap(t) and 4bep(t) very negative temperature coefficients
are found. The same is true for the corresponding amides
9amCl and 10ap(t). All these compounds are characterised
Fig. 5. IR spectrum of 4am(t) measured in CDCl3 solution.

Table 4
13C chemical shifts (ppm) of all compounds, obtained at 300 K (upper) and 210 K (lower) in CDCl3 solution unless stated otherwise
Compound
C-1
C-2
C-3
C-5
C-9
C-6
C-8
C-7
C-10
C-20
C-30
C-40
C-100
C-200
C-600
C-300
C-500
C-400
Other
1ap
2ap
2am
201.8
201.6
201.3
201.0
200.9
200.6
201.3
200.9
201.1
201.0
201.1
203.2
203.1
202.1
201.0
201.7
200.8
206.8
206.7
206.7
206.5
207.3
206.9
206.4
206.5
201.5
201.2
202.1
56.3
55.7
46.2
44.5
46.6
44.6
46.4
47.5
44.7
46.5
44.9
46.7
45.7
44.0
42.3
44.5
44.2
41.9
39.7
42.4
40.1
46.1
43.9
47.6
46.3
48.4
47.0
48.0
42.2
40.8
67.7
66.8
67.1
66.6
67.3
66.9
66.4
67.6
66.8
67.5
66.8
67.6
66.7
67.7
66.6
63.9
63.2
63.7
63.0
74.1
73.1
74.4
74.9
58.8
58.3
58.7
53.5
52.9
49.4a
52.9
48.7
51.3
52.5a
52.3a
52.4
48.7
51.5
49.1a
52.9
49.2
52.7
44.7
51.1
54.1
55.3
53.3
54.1
49.7a
52.3
51.2
51.9
48.4a
52.2
48.0
26.1
24.1
23.7
24.1
23.7
–
139.6
138.7
139.6
138.6
139.3
138.3
139.6
140.9
138.6
137.8
137.1
145.2
144.9
136.6
135.5
136.5
135.5
139.9
139.0
139.5
138.8
139.9
139.1
138.9
138.2
139.6
138.6
136.6
122.3
122.4
122.7
122.8
122.7
122.7
122.7
122.2
122.8
123.9
123.9
121.9
122.0
128.8b
129.0b
128.7b
129.1b
122.8
123.1
122.9
123.1
123.7
123.8
123.7
123.8
122.7
122.6
128.8b
128.7
128.8
128.8
128.9a
128.4
128.2a
128.8
129.0
128.9
128.6b
128.5
128.6
128.6
128.9b
128.9b
129.0b
129.1b
128.7
128.8
128.8
128.9
128.8
129.0
128.3
128.2
128.8
128.7
128.7b
125.9
126.2
126.1
126.4a
126.3
126.5a
126.1
125.8
126.3a
131.3
131.1
144.4
143.8
128.0b
128.3b
128.5b
128.9b
125.8
126.1
126.2
126.3
126.3
126.5
126.5
126.8
126.0
126.0
127.9
–
–
–
–
–
25.8
26.4
26.4
67.7
67.0b
35.0
35.1
34.7
67.1
67.1
26.5
26.6
25.6
24.9
66.5
66.1
26.1
26.1
66.9
66.9
26.3
26.2
67.2
67.1
26.4
26.3
25.5
–
–
–
–
–
134.8
133.5
134.6
133.0
134.9
135.4
133.6
134.4
133.0
134.2
133.4
135.0
133.7
134.8
132.9
–
128.6
128.7a
128.6
128.5a
128.6
128.9
128.5a
128.5b
128.3
128.3
128.1
128.5b
128.4b
128.2b
128.5b
–
128.1
128.0
128.9
129.0
128.1
128.1
128.0a
128.5b
128.4
124.8
124.8
128.0b
128.3b
128.3b
128.3b
–
128.0
128.0a
128.3
128.3a
128.0
127.9
128.0a
129.0b
129.0
128.3
128.3
128.0b
127.9b
127.8b
128.2b
–
–
44.1
25.6
–
–
43.8
44.6
44.5
43.6
66.8b
34.4
34.6
33.9
–
–
2apme
C6D6
30.6
21.8
30.4
–
21.7
22.1
–
2amCl
220 K
2apNO2
230 K
2bep
44.0
44.3
43.9
43.5
51.3
51.0
45.0
48.9
42.9
66.9
25.8
–
–
24.0
23.7
23.9
23.4
–
–
–
50.7
51.0
50.7
50.9
19.2
18.9
19.3
19.0
21.6
21.8
18.9
19.1
12.8
12.6
50.5
12.6
50.7
12.5
50.6
12.9
50.7
12.7
–
2bem
3ap
66.0
25.5
66.7
25.5
66.9
25.5
–
24.0
23.6
–
–
–
–
–
3am
–
–
–
–
–
–
–
–
–
5ap(t)
5am(c)
7ap
24.0
23.5
–
134.4
133.3
135.3
134.4
–
129.2a
131.2b
129.5
128.2
128.2b
128.9
128.8
–
127.8a
127.8
127.9
127.8
–
126.6b
128.1b
–
br. ca 129.1
24.4
24.0
24.2
–
–
–
–
–
–
7bep
220 K
7bem
–
–
–
201.5
201.8
201.0
45.1
46.0
44.6
58.3
58.4
58.0
52.3
47.6
50.9
42.9
25.0
66.5
66.2
25.0
23.9
–
135.8
136.6
135.7
128.9
128.8
128.1
128.2
128.5
–
–
–
–
–
–
–
–
–
128.7b
128.9b
129.0b
129.0b
–
–
42.9
44.2
66.0
67.1
–
9amCl
220 K
169.6
170.0
37.5
36.1
65.8
65.0
49.0
51.6
67.2
67.2
–
–
137.9
136.7
120.7
120.4
128.4b
128.4
128.7
128.4
–
–
129.0b
129.0
128.5b
128.3
128.3
128.3
–
Compound
C-1
C-2
C-3
C-5
C-9
C-6
C-8
C-7
C-10
C-11
C-12
C-13
C-10
C-20
C-30
C-40
Other
4ap(t)
220 K
4am(t)
207.0
206.8
207.1
50.4
48.6
52.5
67.6
67.2
67.0
48.3
51.3
47.8
26.4
26.4
67.3
24.4b
24.0b
–
34.9
34.5
35.0
26.6b
26.3b
26.4
25.6b
25.1b
25.4
23.7
23.3
23.8
139.9
139.9
139.4
123.7
123.8
123.9
128.7
128.9
128.9
126.0
126.3
126.4
–
–
–
44.4
25.7
(continued on next page)

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100
by strong intramolecular hydrogen bonding judged from a
N· · ·N distance as found in Table 2, by the fact that the
acceptor is a sp3 hybridised nitrogen with a non-planar
SyC–N–H bond.
For thioamides with intramolecular hydrogen bonds in
which the acceptor is oxygen, the picture is akin to that
described for intermolecular hydrogen bonds to a polar
solvent (see later). The shorter the N· · ·N distance the less
negative the temperature coefficients as seen from the series
of thioamides 16–18 and for the amides 19–21 something
similar is seen.
In polar solvents like DMF, compounds that form only
moderately strong hydrogen bonds to the solvent give
temperature coefficients of 26 to 28 ppb/K (examples are
12, 13 and 15e(c and t). For the compounds 2bep, 2bem and
4ap(t) the temperature coefficients are however only 24,
24 and 22 ppb/K, respectively. We will return to this
point.
4.1. Structural features
One possibility to be considered with strongly hydrogen
bonded thioamides is the possibility of tautomerism. This
has been observed in a couple of cases [11,23]. This can be
ruled out judging from the very small changes in the C-1 and
C-2 carbon chemical shifts (Table 4). Another possibility
has been pointed out by Muller and Reiter [30] that very low
frequency vibrations may be important in strongly hydrogen
bonded systems. This could lead to a high frequency shift.
However, frequency calculations using the DFT ab initio
calculations do not suggest that the present compounds have
strong low frequency vibrations.
Conformational changes have been pointed out as a
potential source of the temperature coefficients [5,14–18].
The thioamides are clearly flexible. However, the overall
conformational changes are very moderate as seen from the
small changes in the H–H coupling constant with
temperature (Fig. 4). Compounds like 4ap(t), 4am(t),
5ap(t), 4bep(t) and 10ap(t) do not show changes at all
and furthermore, for the remaining compounds these
changes stop as the temperature is reaching a temperature
typical for each compound. This indicates that these small
changes are not the origin of the temperature coefficients as
these vary uniformly throughout the temperature interval
with exception of 5am(c). In this case the drop in the
temperature coefficient (see Table 2) is due to the compound
being an equilibrating mixture of hydrogen bonded and an
open form (Scheme 1). This is, judging from the 1H
chemical shifts, not the case for the remaining compounds.
For some of the compounds the phenyl ring rotation is
slowed down at very low temperatures [31] but this is not
reflected in the temperature coefficient either, as the
temperature coefficients vary uniformly. The IR spectra
reveal that all intramolecularly hydrogen bonded com-
pounds 1–7, 9 and 10, except 5am(c), do not exist in the
open form (Scheme 1). Overall structural changes can thus

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J.G. Sosnicki, P.E. Hansen / Journal of Molecular Structure 700 (2004) 91–103
101
Scheme 1. H bonded (closed) and non-H bonded opened form of 5am(c).
in almost all cases be excluded for the group of N-
substituted-3-piperidinethiopropionamides.
An interesting feature is that for some of the present
thioamides 4ap(t), 4am(t), 5ap(t) and 4bep(t) the SyC–
N–H dihedral angle is considerably smaller than 1808
(Table 2). It can be seen that the more negative temperature
coefficients are found in compounds with large deviations
from planarity. A plot is shown in Fig. 7. From this plot it is
also seen that the temperature coefficients are more negative
for morpholine than for piperidine derivatives. A possible
mechanism could then be a change in the SyC–N–H
dihedral angle upon temperature change. If this is the case,
one would expect a change in some of the chemical shifts of
the neighbour carbons. For the CyS carbon the changes with
temperature are close to null (Table 4). For C-2 small
changes with temperature are seen and they correlate
weakly for thioamides with substituents at C-2 with
the NH temperature coefficients (Fig. 8). The twist of the
SyC–N–H bond has effects on the N–H bond lengths. The
larger the twist the shorter the N–H bond length. However,
no direct correlation is seen between N–H bond lengths and
the temperature coefficients. A comparison of data for the
four compounds: 2ap, 4bep(t), 5ap(t) and 4ap(t) all with
similar RNH bond length show again a dramatic increase in
the temperature coefficient with non-planarity (see Table 2).
Another interesting pair of compounds is 4bep(t) and
4bep(c) as they have very different temperature coefficients
but the NH and N· · ·N distances are fairly similar. The main
difference lies in the SyC–N–H dihedral angles, which is
much smaller for 4bep(t) than for 4bep(c) corroborating
Fig. 8. Plot of NH temperature coefficients vs. DdC-2.
the suggestion that this is an important factor for the NH
chemical shift temperature coefficients.
The temperature coefficients for corresponding benzyl
and aniline derivatives are not significantly different (see
Table 2), whereas for 2ap and 2am the coefficients increase
in this order although the RN· · ·N distances and twist angles
are similar. In this case the electric field effects from the
hetero atom are different.
Also interesting is that the amides 9amCl and 10ap(t)
(oxygen analogues of 2amCl and 4ap(t)) show large
negative temperature coefficients and have OyC–N–H
dihedral angels smaller than 1808 (Table 2).
Much of the current thinking regarding temperature
coefficients is based on solvent interactions as the cause of
negative temperature coefficient and also recently that
conformational effects may play a role [5,14–18]. Llinas
and Klein [3] studied temperature coefficients in a broad
range of solvents, trifluoroacetic acid, chloroform, water,
dimethylsulfoxide, dimethylformamide and pyridine and
stated “the temperature coefficient affords an excellent
criterion to determine the extent of exposure of the NH
group, whatever the solvent”. In the present study
tetrahydrofuran, methylene chloride and toluene have
been included. This will of course explain the close to
zero effects seen for simple thioamides in non-polar solvents
as no interaction with solvent takes place.
The temperature coefficients found for thioamides with
intramolecular hydrogen bonds to a sp2 hybridised oxygen
represented by 15k, 16k, 17k and 18 give a different picture
than the thioamides and amides in which the acceptor is a
nitrogen. Basically the stronger the hydrogen bond the less
negative the temperature coefficient and the magnitudes are
apparently not related to the non-planarity of the SyC–N–
H group (Table 2). The results of Gellman et al. [14–18]
that intramolecularly hydrogen bonded peptides show a
temperature coefficient of 25 ppb/K in non-polar solvents
is on the high side.
Fig. 7. Plot of NH temperature coefficients vs. torsion angle XyC–N–H
(X ¼ S, O).

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J.G. Sosnicki, P.E. Hansen / Journal of Molecular Structure 700 (2004) 91–103
102
4.2. Other effects
amides and thioamides without intramolecular hydrogen
bonds is based on data obtained at sufficiently low
concentration to avoid dimerisation seen as non-linearity
of the dNH vs. T plot. A very distinct case in which an
equilibrium exists between a closed and an open form is that
of 5am(c). In non-polar solvents simple amides and
thioamides give small temperature coefficients. This can
be understood as no interactions take place. In solvents that
can form hydrogen bonds such as water, DMF or DMSO the
interaction may increase in strength at lower temperature
thus leading to a high frequency shift. For intramolecularly
hydrogen bonded compounds with a rigid structure and an
optimal hydrogen bond geometry cooling will not modify
the hydrogen bond to any great extent and the temperature
coefficient will be small (see 18 and 19). For compounds
with intramolecular hydrogen bonds but of a flexible nature
such as the small peptides described by Gellman et al.
[13–18] the situation is similar to that found for
intermolecular interactions.
The results obtained for 4ap(t), 2bep and 2bem in DMF
deserve discussion. The very small temperature coefficients
22 to 24 ppb/K are unusual as these compounds do not
form intramolecular hydrogen bonds in DMF according to
their NH chemical shifts (Table 2). Small values were also
obtained by Martinez-Martinez et al. [12] for N,N0-bis[(2-
hydroxy)phenyl]oxamides. These authors ascribe the small
temperature coefficients to intramolecular hydrogen bond-
ing. However, this is difficult to envisage as both possible
hydrogen bonds only involve five-membered rings. We
would like to suggest that repulsive protection from solvent
is at play. The two oxygens at each end prevent the SyO end
of the DMSO to get close due to simple electrostatic
repulsion.
For the present compounds a similar mechanism could be
at play assuming that the change in the hydrogen bond
pattern and the following NH chemical shifts arise solely
from the change in the solvent dielectric constant and not
from specific interactions with the solvent.
For intramolecularly hydrogen bonded compounds with
steric constraints leading, e.g. to non-planar amide or
thioamide moieties and a nitrogen as acceptor such as 1–10
and hence with less than optimal hydrogen bond geometry a
lowering of the temperature may cause the formation of a
stronger hydrogen bond through geometry optimisation and
therefore a strong high frequency shift. This situation is akin
to ortho-hydroxy acyl aromatics in which steric perturbation
prevents full conjugation of the acyl moiety with the
aromatic ring. For those cases deuteriation of e.g. the acetyl
group leads to optimisation of the hydrogen bond and to a
high frequency shift of the OH proton [32]. For those
compounds in which the acceptor is an sp2 hybridised
oxygen, such as 15k–17k, 19 and 21 the temperature
coefficients are not so negative despite the fact that the
SyC–N–H or OyC–N–H angles are quite far from 1808 in
some cases. This can possibly be related to a combination of
less rearrangement at low temperature and to the finding that
the NH nuclear shielding tensor is much less asymmetric in
these cases (Table 3).
4.3. Non-linearity of NH chemical shifts with temperature
Non-linearity is strongly seen for 5am(c). The IR
spectrum as well as the 3J(H-2,H-3) couplings show
unambiguously that the compound exists as a mixture of a
hydrogen bonded and an open form (Scheme 1).
The strong non-linearity of the temperature coefficient of
11 at high concentrations points to extensive dimer
formation. The CyS group is involved in a reasonably
strong hydrogen bond with the OH group. This then
suggests that the dimer formation occurs as a N–H· · ·N
hydrogen bond. As none of the other chemical shifts are
very temperature sensitive we can rule out aggregation in
general.
At high concentration also the NH chemical shifts of 15
are non-linear in CDCl3 and toluene. This is especially true
for the NH proton of 15e(t), whereas the NH proton of
15e(c) is much more linear. Such studies can in a simple
manner tell about the tendency for dimer formation, but also
give structural details of how this is occurring.
Observation of NH temperature coefficients in non-polar
solvents can be categorized as follows. Small coefficients
point either to strong intramolecular hydrogen bonding or to
intermolecular hydrogen bonding. In the latter case an
increase in concentration most likely will lead to non-
linearity.
The intramolecularly hydrogen bonded compounds show
much less tendency to non-linearity (Fig. 2).
As mentioned, the temperature coefficients are more
negative for morpholines than for piperidines. This indicates
that the potential also plays a role. The finding that
temperature coefficients are different for 12 and 13 also
shows that substitution to a smaller degree plays a role. This
was less obvious for 2ap and 2apNO2 (Table 2).
Large negative temperature coefficients point to strong
intramolecular hydrogen bonding in which the hydrogen
bond is distorted.
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