Nonplanar structures of thioamides derived from 7-azabicyclo[2.2.1]heptane. Electronically tunable planarity of thioamides

Article abstract of DOI:10.1021/jo801996b

X-ray crystallographic analysis showed that N-thiobenzoyl-7-azabicyclo[2.2. 1]heptane displays marked nonplanarity of the thioamide (1a, α = 167.1° and |τ| = 11.2°) as compared with the corresponding monocyclic pyrrolidine thioamide (2a, α = 174.7° and |τ

Full text of DOI:10.1021/jo801996b

Nonplanar Structures of Thioamides Derived from
7-Azabicyclo[2.2.1]heptane. Electronically Tunable Planarity of
Thioamides
Tetsuharu Hori,† Yuko Otani,† Masatoshi Kawahata,‡ Kentaro Yamaguchi,‡ and
Tomohiko Ohwada*,†
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, 7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan, and Department of Pharmaceutical Sciences at Kagawa Campus, Tokushima
Bunri UniVersity, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan
ohwada@mol.f.u-tokyo.ac.jp
ReceiVed September 11, 2008
X-ray crystallographic analysis showed that N-thiobenzoyl-7-azabicyclo[2.2.1]heptane displays marked
nonplanarity of the thioamide (1a, R ) 167.1° and |τ| ) 11.2°) as compared with the corresponding
monocyclic pyrrolidine thioamide (2a, R ) 174.7° and |τ| ) 3.9°). In a series of para-substituted or
unsubstituted thioaroyl-7-azabicyclo[2.2.1]heptanes (1a-1h), the planarity of the thioamide depended
significantly on the electronic nature of the substituent; for example, in the p-nitro-substituted compound,
planarity was substantially restored (1h, R ) 175.2° and |τ| ) 0.1°). In solution, increasing electron-
withdrawing character of the aromatic substituent was associated with a larger rotational barrier of the
1
bicyclic thioamides, as determined by means of variable-temperature H NMR spectroscopy and line
shape analysis. The reduced rotational barrier, that is, reduced enthalpy of activation (∆Hq) for thioamide
rotation, of 1a as compared with that of 2a in nitrobenzene-d5 is consistent with the postulate that 1a
assumes a nonplanar thioamide structure in solution. These results indicate that the planarity of thioamides
based on 7-azabicyclo[2.2.1]heptane is controlled by electronic factors in the solid phase and in solution.
Introduction
this feature is a greater contribution of the dipolar canonical
structure (B) in the resonance structures (Scheme 1),3-5 because
C(2p)-S(3p) overlap in a thioamide bond is less effective than
C(2p)-O(2p) overlap in an amide bond. Peptides containing
thioamide bonds have been utilized as probes of local peptide
secondary structures, but introduction of a thioamide group into
a peptide linkage can have apparently contradictory effects; for
Although thioamides are analogues of amides, experimental
and theoretical studies have shown that they differ from each
other in many respects; the longer CdS bond and weaker
hydrogen-bond-accepting ability of thioamides electronically and
sterically influence neighboring groups. Also, thioamides display
much higher rotational barriers about the N-C(S) bond than
amides do.1,2 Thus, thioamides have a stronger preference for
planar structure than amides.3a An accepted interpretation of
(3) (a) Wiberg, K. B.; Rablen, P. R. J. Am. Chem. Soc. 1995, 117, 2201–
2209. (b) Lauvergnat, D.; Hiberty, P. C. J. Am. Chem. Soc. 1997, 119, 9478–
9482.
(4) For a counter-example to the resonance effect, see: Laidig, K. E.;
Cameron, L. M. J. Am. Chem. Soc. 1996, 118, 1737–1742.
(5) Galabov, B.; Ilieva, S.; Hadjieva, B.; Dinchova, E. J. Phys. Chem. A
2003, 107, 5854–5861.
† The University of Tokyo.
‡ Tokushima Bunri University.
(1) Sandstro¨m, J. J. Phys. Chem. 1967, 71, 2318–2325.
(2) Neuman, R. C., Jr.; Jonas, V. J. Phys. Chem. 1971, 75, 3532–3536.
9102 J. Org. Chem. 2008, 73, 9102–9108
10.1021/jo801996b CCC: $40.75 2008 American Chemical Society
Published on Web 10/24/2008

Nonplanar Structures of Thioamides
FIGURE 1. Thioamides in this study.
SCHEME 1. Resonance Structures of Amide and
Thioamide
example, peptide conformations are maintained6,7 or destabilized8,9
due to high rotational barriers and weaker hydrogen bonding.
While thioamides show a strong preference for planar structure,
little has been reported about their deviation from planarity. This
is an important issue in relation to the structural features of
peptides containing thioamide bonds.
Bicyclic 7-azabicyclo[2.2.1]heptane amides have intrinsically
nonplanar structures in the solid phase and in solution.10,11 Thus,
it is of considerable interest to know whether nonplanar
thioamides can be generated from this bicyclic skeleton. In this
study, the planarity of solid and solution structures of thioamide
derivatives of bicyclic 7-azabicyclo[2.2.1]heptane and related
amines was investigated. We found that in a series of para-
substituted or unsubstituted thioaroyl-7-azabicyclo[2.2.1]heptanes
the planarity of the thioamide can be tuned by altering the
electronic nature of the substituent.
FIGURE 2. ORTEP diagrams of 1a, 1b, and 1h showing the thermal
ellipsoids at 30% probability. a Two kinds of molecules are contained
in a unit cell.
SCHEME 2. Synthesis of Bicyclic, Monocyclic, and Acyclic
Thioamides
Results and Discussion
Crystal Structures of Thioamides. Various para-substituted
or unsubstituted N-thiobenzamides of bicyclic (1a-1h), mono-
cyclic (2a-2h), and acyclic (3a) amines were synthesized
by thioxylation with Lawesson’s reagent of the corresponding
aroyl amides, which were synthesized by acylation of amines
with suitable aroyl chlorides11 (Figure 1 and Scheme 2).
Crystal structures of some of the thioamides were elucidated
by X-ray crystallography (Figure 2 and Figures S1-S9 in
Supporting Information). Selected structural parameters are
shown in Table 1.
The planarity of thioamide nitrogen can be represented in
terms of three angle parameters, θ, R and τ, the definitions of
which are shown in Figure 3: θ is the sum of the three valence
angles around the nitrogen atom (θ ) a + b + c); the hinge
angle R is the angle between the N-C(S) bond and the plane
(6) Miwa, J. H.; Pallivathucal, L.; Gowda, S.; Lee, K. E. Org. Lett. 2002, 4,
4655–4657.
(7) Sherman, D. B.; Spatola, A. F. J. Am. Chem. Soc. 1990, 112, 433–441.
(8) Artis, D. R.; Lipton, M. A. J. Am. Chem. Soc. 1998, 120, 12200–12206.
(9) Reiner, A.; Wildemann, D.; Fischer, G.; Kiefhaber, T. J. Am. Chem. Soc.
2008, 130, 8079–8084.
(10) Ohwada, T.; Achiwa, T.; Okamoto, I.; Shudo, K. Tetrahedron Lett. 1998,
39, 865–868.
(11) Otani, Y.; Nagae, O.; Naruse, Y.; Inagaki, S.; Ohno, M.; Yamaguchi,
K.; Yamamoto, G.; Uchiyama, M.; Ohwada, T. J. Am. Chem. Soc. 2003, 125,
15191–15199.
defined by the nitrogen atom, R1, and R2; and the twist angle
|τ| is the absolute value of the mean of two torsion angles,
ω1(R3CNR2) and ω2(SCNR1) (|τ| ) 1/2|ω1+ω2|).12 Values of θ,
R, and τ of the ideal planar thioamide are 360°, 180°, and 0°,
respectively. The former two values will decrease and the third
(12) Winkler, F. K.; Dunitz, J. D. J. Mol. Biol. 1971, 59, 169–182.
J. Org. Chem. Vol. 73, No. 22, 2008 9103

Hori et al.
TABLE 1. Selected Crystal Structural Data of Thioamidesa
a (deg) θ (deg) R (deg) |τ| (deg) N-C(X) bond (Å)
CHART 1
R
1ab
H
97.8(2) 357.6(2) 167.3 11.0(3)
98.0(1) 357.5(2) 167.1 11.2(3)
1.324(2)
1.323(2)
1.339(2)
1.339(5)
1.332(5)
1.322(2)
1.331(2)
1.312(2)
1.325(2)
1.324(2)
1.324(2)
1.319(2)
1.318(2)
1.333(2)
1.356(3)
1.354(4)
1.350(4)
1.345(3)
1b N(CH3)2 97.1(1) 350.1(1) 154.0 14.6(2)
1db CH3
97.6(3) 353.9(3) 159.7 12.1(6)
97.3(3) 355.7(3) 163.2 8.6(6)
98.2(1) 358.7(1) 170.6 12.6(2)
1e
1f
Cl
COOMe 97.8(1) 352.7(1) 157.7
of the substituent on the aroyl group. The intrinsic nonplanarity
of the corresponding bicyclic amide (such as 4a and 4h) was
proposed to be attributable to both angle strain around the
nitrogen atom (i.e., angle a) and 1,3-allylic strain between the
bridgehead hydrogens and the oxygen atom or the phenyl ring.11
In the case of the present bicyclic thioamides (1), similar
structural features may also favor the observed nonplanar
structures, because the C-N bond of the thioamides is
shortened, as compared with that of the corresponding amides
(see Table 1), imposing 1,3-allylic strain.
9.6(2)
0.1(2)
3.9(3)
5.5(2)
5.8(2)
1.3(2)
2.0(2)
9.2(2)
1h NO2
2a
2c
2d CH3
2g CN
2h NO2
98.6(1) 359.7(1) 175.2
111.1(1) 359.7(2) 174.7
111.2(1) 359.9(1) 176.7
111.1(1) 359.5(1) 173.4
111.3(1) 359.7(1) 174.8
111.0(1) 359.5(1) 173.7
113.7(1) 359.7(1) 174.5
H
OMe
3a
H
H
4ac
97.2(2) 349.5(2) 153.2 15.5(3)
96.9(2) 347.1(3) 150.2 13.0(5)
4hb,c NO2
97.8(2) 350.1(3) 153.8
111.5(2) 359.2(2) 171.3
6.9(5)
3.0(3)
5cc OMe
On the other hand, the acyclic thioamide 3a displayed
significant twisting around the thioamide bond, while nitrogen-
pyramidalization was insignificant (R ) 174.5° and |τ| ) 9.2°).
Solution Structures of Thioamides. To estimate the N-C(S)
double bond character of thioamides in solution, rotational
barriers with respect to the thioamide bond, i.e., the free energy
of activation (∆Gq), were evaluated by variable-temperature 1H
NMR spectroscopy in nitrobenzene-d5 (ε ) 35.6 at 20 °C) and
o-dichlorobenzene-d4 (ε ) 10.1 at 20 °C) at 25 mM.14,15 In
variable-temperature NMR experiments, temperatures were
calibrated by a standard method using an ethylene glycol.14,16
Upon elevation of the temperature, the bridgehead proton signals
(Ha and Hb in Chart 1) or the exo-proton signals (Hc and Hd)
in the case of bicyclic thioamides and the R-proton signals (He
and Hf) in the case of monocyclic and acyclic thioamides
broadened and then coalesced. The rate constant kc and the
a Standard deviations are shown in parentheses. b Two kinds of
molecules are contained in a unit cell. c Data from ref 11.
FIGURE 3. Definition of angle parameters.
value will increase as the thioamide functionality deviates from
planarity to a greater extent.
As shown in Table 1, thioamides with a bicyclic skeleton
(1a-b and 1d-f, except 1h) were substantially both nitrogen-
pyramidal and twisted, as compared with monocyclic (2a, 2c-d
and 2g-h) and acyclic (3a) thioamides; the R value of those
bicyclic thioamides ranged from 154.0° to 170.6° and the |τ|
value ranged from 8.6° to 14.6°, whereas those of the mono-
cyclic thioamides were close to the values of planar structures
(R from 173.4° to 176.7° and |τ| from 1.3° to 5.8°). In the case
of the corresponding bicyclic amides (such as 4a and 4h),
nonplanarity of the amide functionality was also observed, but
the aromatic substituent effects on the planarity were insignifi-
cant, e.g., R values of 153.0° (4a, R ) H) and 150.2° and 153.8°
(average 152.0°) (4h, R ) NO2) (see Table 1). N-Aroyl bicyclic
amides took nitrogen-pyramidalized amide structures, irrespec-
tive of the aromatic substituent.11 In contrast, an electronic effect
of the aromatic substituent (R) on thioamide planarity was
obvious in the case of the bicyclic thioamides, i.e., the degree
of planarity represented in terms of R is in the order 1h (R )
NO2) > 1e (R ) Cl) > 1a (R ) H) > 1d (R ) CH3) > 1b (R
) N(CH3)2). 1h (R ) NO2) takes a nearly planar structure,
whereas 1b (R ) NMe2) takes a significantly nitrogen-
pyramidalized structure (Figure 2). This trend is consistent with
the idea that an electron-withdrawing group tends to restore
nitrogen planarity, except for 1f (R ) COOMe).13 This recovery
of nitrogen planarity coincided with shortening of the C-N bond
of these thioamides, probably due to an increase of N-C(S)
double bond character. Such a phenomenon was not seen among
the monocyclic thioamides (2) (e.g., R value 174.7° (2a, R )
H); 173.7° (2h, R ) NO2)), or among bicyclic amides (4) (Vide
ante) (Table 1). Thus, it appears that the planarity of bicyclic
thioamides can be controlled by varying the electronic nature
barriers to rotation (∆Gq ) about the C-N bond in the
c
thioamides were therefore obtained by the coalescence method
on the basis of the difference in chemical shifts (∆ν in Hz) of
these two exchanging signals at 21 °C and their coalescence
temperature (Tc). It was confirmed that the magnitudes of the
∆Gq values obtained from the coalescence of the bridgehead
c
proton signals and those from the exo-proton signals were in
good agreement (e.g., in the case of 1c, the values of ∆Gqc from
bridgehead proton signals and from exo-proton signals were 19.6
and 19.7 kcal/mol, respectively).
The rotational barriers (∆Gq ) of N-thiobenzoyl derivatives
c
1a, 2a, and 3a in nitrobenzene-d5 were 20.7, 20.2 and 18.6 kcal/
mol, respectively (Table 2). The ∆Gqc values of the thioamides
are larger than those of the corresponding amides (e.g., 4a, 15.3
and 5a, 16.9 kcal/mol, respectively), which is consistent with
the general trend.1,2 There is a good linear relationship in the
Hammett plot between the magnitude of ∆Gqc and σp+ values17
(r ) 0.98, F+ ) 1.15 (1a-1h) and r ) 0.99 and F+ ) 1.41
(2a-2h), see Figure S10 in Supporting Information); the
substituent on the benzene ring showed a significant electronic
effect on the rotational barrier (∆Gq) of the thioamides. A similar
linear relationship was found in the cases of the corresponding
(14) Stewart, W. E.; Siddall, T. H., III. Chem. ReV. 1970, 70, 517–551.
(15) Oki, M. Applications of Dynamic NMR Spectroscopy to Organic
Chemistry; VCH Publishers: Deerfield, 1985; Vol. 4.
(16) Ammann, C.; Meier, P.; Merbach, A. E. J. Magn. Reson. 1982, 46,
319–321.
(17) Hansch, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991, 91, 165–195.
(18) Regression coefficients (r) and regression slopes (F+) of corresponding
amides are as follows (see ref 11): r ) 0.98, F+ ) 0.61 for 4 and r ) 0.99 and
F+ ) 0.82 for 5.
(13) This is due to high-density packing of 1f with a Z-value of 8 and an
aromatic stacking distance of 3.4 Å.
9104 J. Org. Chem. Vol. 73, No. 22, 2008

Nonplanar Structures of Thioamides
TABLE 2. Experimental Data and Barriers for Thioamide Bond
TABLE 3. Estimated Rate Constants for Thioamide Bond
Rotation Obtained from Line Shape Analysis of the Spectra in
Nitrobenzene-d5 and o-Dichlorobenzene-d4
Rotation Obtained by the Coalescence Method in Nitrobenzene-d5
a
q
compound
R
Tc (°C)
∆ν (Hz)
∆Gc
T (K)
k (Hz)
T (K)
nitrobenzene-d5
66.36 3a
k (Hz)
T (K)
k (Hz)
1ab
H
H
148
(141)
128
157
174
178
149
148
143
158
(149)
96
130
148
154
169
168
171
123
(111)
68.0
(99.3)
382.6
442.1
491.1
497.4
44.9
20.7
1ab c
(20.0)
18.3
19.6
20.3
20.5
21.1
21.0
21.3
20.2
(19.6)
17.4
18.9
19.7
20.0
20.8
20.7
20.9
18.6
(18.0)
,
1b
1c
1d
1e
N(CH3)2
OMe
CH3
Cl
COOMe
CN
NO2
H
H
N(CH3)2
OMe
CH3
Cl
COOMe
CN
NO2
H
H
1a
1b
1c
1d
1e
1f
399
410
421
431
442
453
363
373
382
392
401
410
363
375
387
399
412
423
389
399
409
420
429
438
393
408
419
428
438
449
403
413
420
422
431
442
403
413
421
430
441
453
399
410
420
430
441
453
54.87 2a
397
406
414
422
430
437
346
355
363
372
379
386
375
382
389
397
406
414
382
392
401
409
417
426
393
401
409
417
426
434
403
412
420
429
438
448
399
408
416
424
433
441
399
408
417
427
436
446
362
372
381
390
400
409
49.33
93.85
102.06
173.74
308.33
529.01
896.63
99.02 2b
172.82
296.39
490.10
837.17
1409.35
38.49 2c
55.98
120.31
191.78
331.31
555.88
58.99 2d
90.26
148.92
247.46
407.11
676.48
52.06 2e
119.31
194.91
313.85
548.30
864.39
58.02 2f
84.68
115.01
125.07
189.13
295.88
58.21 2g
91.76
109.33
192.46
318.20
489.99
704.00
83.78
162.67
281.70
483.68
722.78
1166.80
55.26
100.69
166.01
302.48
551.16
908.70
40.35
188.52
314.96
553.94
950.26
1fb
1gb
1hb
2a
2ac
2b
2c
49.3
24.4
238.6
(274.5)
171.5
198.0
224.1
214.8
211.5
219.9
212.4
192.5
(215.4)
2d
2e
2f
2g
2h
3a
3ac
a Values in kcal mol-1. The error of the coalescence temperature is
76.31
(1.0 °C and therefore the error of ∆Gq is (0.05 kcal mol-1 b Values
.
c
144.77
244.16
400.14
622.80
61.65
were obtained from the coalescence of exo-proton signals, because the
coalescence temperature for bridgehead proton signals exceeds 180 °C.
c Values in parentheses were obtained in o-dichlorobenzene-d4.
97.42
bicyclic amides (4) and the corresponding monocyclic amides
(5), both having much smaller regression slopes.18 Thus, while
a more electron-withdrawing group tends to increases the amide/
thioamide rotational barriers, the dependency of the magnitude
of the rotational barriers on the electronic nature of the
substituent is more significant in the case of the thioamides as
compared with the corresponding amides.
166.11
266.62
412.50
646.11
67.24
93.84
145.25
243.47
431.99
706.73
43.18
The free energy of activation (∆Gq), and its components, the
enthalpy of activation (∆Hq) and the entropy of activation (∆Sq)
were also obtained experimentally by line shape analysis (Table
4). Rate constants were obtained at six different temperatures
(Table 3), and then activation parameters ∆Gq, ∆Hq and ∆Sq
were obtained by least-squares analysis of the Eyring plots (see
Figure S11 in Supporting Information).
1g
1h
76.14
124.22
197.29
312.65
533.43
50.57 2h
85.22
118.31
198.22
319.58
474.38
127.39
208.86
333.31
498.71
37.78
The magnitude of ∆Gq, especially at higher temperature (at
64.65
150 °C; ∆Gq150 °C), was in good agreement with that of ∆G‡
c
107.52
182.18
308.73
498.71
because the coalescence temperatures (Tc) of the thioamides
ranged between 96-180 °C in this study, and the average value
is around 150 °C. Since the magnitude of ∆Sq is affected by
several factors, such as solvation upon thioamide rotation,19 the
∆Hq value is likely a more appropriate index to estimate the
energetic cost of rotation of thioamides, i.e., the N-C(S) double
bond character, in this case. Indeed, the consistently large
negative ∆Sq term contributes to the increase of the barrier (∆Gq
o-dichlorobenzene-d4
1a
413
420
427
434
440
444
142.88 2a
385
393
401
409
417
426
38.94 3a
358
367
376
385
393
401
77.19
149.69
281.60
454.62
738.80
1182.73
213.10
334.29
551.16
789.47
961.44
67.65
132.60
241.64
414.32
640.37
and probably ∆Gq ) in the cases of the bicyclic thioamides.
c
Experimentally, on the basis of the observed ∆Hq values for
thioamide rotation, the energetic costs of rotation of the bicyclic
thioamides (1a-1h) were smaller than those of the correspond-
ing monocycles (2a-2h), particularly in nitrobenzene (Table
4).20 Furthermore, the rotational barrier (∆Hq) of an acyclic
thioamide, N,N-dimethylthiobenzamide (3a), is definitely smaller
than that of monocyclic 2a in both solvents.21 This small
rotational barrier (∆Hq) of 3a can be interpreted in terms of
twisting of the thioamide bond arising from 1,3-allylic strain
between methyl hydrogens and the sulfur atom or the phenyl
ring, which was observed in the solid-state structure of 3a (see
Table 1). Twisting of the thioamide bond leads to destabilization
of the ground-state structure and therefore reduction of the
(19) Olsen, R. A.; Liu, L.; Ghaderi, N.; Johns, A.; Hatcher, M. E.; Mueller,
L. J. J. Am. Chem. Soc. 2003, 125, 10125–10132.
(20) The fact that the negative entropic contribution is larger in more polar
nitrobenzene than in o-dichlorobenzene can be partially explained in terms of
enhanced solvation of thioamides, especially of the bicyclic thioamides, upon
rotation. As for solvent effects on thioamide rotation, see: Wiberg, K. B.; Rush,
D. J. J. Am. Chem. Soc. 2001, 123, 2038–2046.
(21) This observation is consistent with a previous study of the corresponding
amides, i.e., monocyclic and acyclic amides. (a) Pinto, B. M.; Grindley, T. B.;
Szarek, W. A. Magn. Reson. Chem. 1986, 24, 323–331. (b) Suarez, C.; Nicholas,
E. J.; Bowman, M. R. J. Phys. Chem. A 2003, 107, 3024–3029.
J. Org. Chem. Vol. 73, No. 22, 2008 9105

Hori et al.
TABLE 4. Experimental Rotational Barriers of Thioamides Obtained by Line Shape Analysisa
b
b
b
c
R
∆Gq
∆Gq
∆Hq
∆Sq
25 °C
150 °C
1a
1ad
1b
1c
1d
1e
H
H
19.8 ( 0.5
(20.8 ( 1.0)
17.7 ( 0.4
17.8 ( 1.0
19.0 ( 1.0
19.3 ( 0.4
18.9 ( 0.5
19.3 ( 0.6
18.9 ( 0.7
20.1 ( 0.6
(20.4 ( 0.9)
17.2 ( 0.3
19.6 ( 0.4
19.8 ( 0.3
19.7 ( 0.4
20.0 ( 1.3
20.3 ( 0.3
20.2 ( 0.4
18.4 ( 0.5
(17.8 ( 0.2)
20.6 ( 0.6
(20.3 ( 1.1)
18.5 ( 0.5
19.8 ( 1.1
20.2 ( 1.1
20.4 ( 0.5
20.9 ( 0.6
20.9 ( 0.7
20.9 ( 0.8
20.2 ( 0.6
(19.7 ( 1.0)
17.5 ( 0.4
18.8 ( 0.5
19.8 ( 0.3
20.1 ( 0.4
20.7 ( 1.5
20.6 ( 0.4
20.8 ( 0.5
18.7 ( 0.5
(18.1 ( 0.3)
17.8 ( 0.3
(21.8 ( 0.6)
16.0 ( 0.2
13.2 ( 0.5
15.9 ( 0.6
16.7 ( 0.3
14.1 ( 0.3
15.4 ( 0.4
14.3 ( 0.4
19.9 ( 0.3
(21.9 ( 0.5)
16.7 ( 0.2
21.6 ( 0.2
19.7 ( 0.2
18.7 ( 0.2
18.5 ( 0.8
19.6 ( 0.2
18.6 ( 0.2
17.8 ( 0.3
(17.1 ( 0.1)
-6.7 ( 0.7
(3.5 ( 1.3)
-6.0 ( 0.6
-15.6 ( 1.4
-10.2 ( 1.4
-8.7 ( 0.6
-16.1 ( 0.7
-13.0 ( 0.9
-15.6 ( 0.9
-0.8 ( 0.8
(5.2 ( 1.2)
-1.9 ( 0.4
6.5 ( 0.6
N(CH3)2
OMe
CH3
Cl
COOMe
CN
NO2
H
H
N(CH3)2
OMe
CH3
Cl
COOMe
CN
NO2
H
H
1f
1g
1h
2a
2ad
2b
2c
2d
2e
2f
2g
2h
3a
3ad
0.0 ( 0.4
-3.3 ( 0.5
-5.2 ( 1.8
-2.4 ( 0.5
-5.2 ( 0.5
-2.1 ( 0.7
(-2.3 ( 0.3)
a Parameters were obtained from unbiased estimates of the standard deviations of least-squares parameters and are reported at the 95% confidence
b
level. Values were obtained in nitrobenzene-d5 unless otherwise noted. Values in kcal mol-1
were obtained in o-dichlorobenzene-d4.
.
c Values in eu (cal mol-1 K-1). d Values in parentheses
rotational barrier. The present structural arguments are consistent
with the minimum energy structures of 1a, 2a, and 3a, which
were obtained by calculation with DFT methods (see Table S1
in Supporting Information). While there is a tendency that the
degrees of nitrogen-pyramidalization of the calculated structures
are consistently larger than those of the solid-state structures,11
1a showed significant nonplanarity (R ) 158.1° and |τ| ) 13.2°)
as compared with 2a (R ) 171.5° and |τ| ) 7.3°), and the twist
angle of 3a (|τ| ) 13.0°) was as large as that of 1a (see Table
S4 in Supporting Information). Also, the calculated rotational
barriers (∆Hq)22 of these thioamides in PCM models (ꢀ ) 35.6,
equivalent to nitrobenzene) showed that the rotational barriers
(∆Hq) of the bicyclic thioamides (1) are consistently smaller
than those of the monocyclic thioamides (2) (Table S2 in
Supporting Information). Calculated ∆Hq values of the bicyclic
thioamides (1) showed a good linear relationship with σp+ values
of the substituents (Figure S12).23 Therefore, our findings are
experimentally and theoretically consistent with the postulate
that the structures of the bicyclic thioamides also show more
significant nonplanarity than those of monocyclic thioamides
in solution, and the degree of planarity depends on the electronic
nature of the substituent.
pyramidalizes nitrogen and decreases the contribution from
resonance B (increasing A and D). Strongly electron-
withdrawing substituents (R) at the para position destabilize
resonance D (increasing A and B), thereby increasing
planarity. The difference between bicyclic amides and
thioamides may be due to the difference between the relative
proportions of resonance B in the overall resonance hybrid
structures.5,24
Conclusions
In summary, X-ray crystallographic study of some N-thioaroyl
derivatives of secondary amines showed that thioamide deriva-
tives of bicyclic 7-azabicyclo[2.2.1]heptane take significantly
more nonplanar structures, as compared to the corresponding
monocyclic thioamides. The magnitude of enthalpy of activation
(∆Hq) for rotation about the N-C(S) bond, which was derived
from dynamic NMR spectroscopy, showed reduced N-C(S)
bond order in the bicyclic thioamides (1a-1h) and the acyclic
thioamide 3a, which is consistent with more nonplanar thioa-
mide structures in solution. Therefore, nonplanar thioamides can
be derived from the bicyclic 7-azabicyclo[2.2.1]heptane skel-
eton. On the basis of the substituent effects on the crystal
structures and the magnitude of rotational barriers of the relevant
bicyclic thioamides, the planarity of these compounds depends
significantly on the electronic nature of the substituent, both in
the solid phase and in solution.
The data found here is consistent with the idea that the relative
contributions from resonance B versus resonance D control the
planarity of the nitrogen. Only resonance B requires the nitrogen
to be planar (pyramidalization and twisting will destabilize
the CdN bond). Tying the nitrogen into a bicyclic structure
(22) ∆H is equal to the difference of potential energy E plus RT, zero-point
energy, and the thermal corrections. Thus, it is well accepted that ∆Hq is
approximately equal to ∆E (which is obtained by calculation) along the reaction
coordinate. See: Houk, K. N.; Li, Y.; Evanseck, J. D. Angew. Chem., Int. Ed.
Engl. 1992, 31, 682–708.
(23) The planarity (in terms of R value) of the calculated structures of the
thioamides was also dependent on the electron-withdrawing nature of the aromatic
substituents. In the case of the bicyclic thioamides 1: 1h (R ) NO2) 160.7° >
1g (R ) CN) 160.1° > 1f (R ) COOMe) 159.8° > 1e (R ) Cl) 158.8° > 1a
(R ) H) ≈ 1d (R ) CH3) 158.1° > 1c (R ) OMe) 157.2° > 1b (R ) N(CH3)2)
156.0°. In the case of the monocyclic 2: 2h (R ) NO2) 172.5° > 2g (R ) CN)
≈ 2f (R ) COOMe) 172.0° > 2e (R ) Cl) 171.3° ≈ 2a (R ) H) 171.5° ≈ 2d
(R ) CH3) 171.2° > 2c (R ) OMe) 170.3° > 2b (R ) N(CH3)2) 169.5°. The
dependency of 2 was smaller than that of 1, which was consistent with the trend
found in the crystal structures. See Table S1 in Supporting Information.
Experimental Section
1. Synthetic Methods. General Procedure. N-Thiobenzoyl-7-
azabicyclo[2.2.1]heptane (1a). A solution of N-benzoyl-7-azabi-
(24) We thank an anonymous reviewer for valuable comment about the
contribution of resonance structure D.
9106 J. Org. Chem. Vol. 73, No. 22, 2008

Nonplanar Structures of Thioamides
cyclo[2.2.1]heptane 3a (262 mg, 1.30 mmol) and Lawesson’s
reagent (299 mg, 0.739 mmol) in dry toluene (25 mL) was refluxed
for 3 h under Ar. The solvent was evaporated and the residue was
flash-chromatographed (n-hexane/CH2Cl2 ) 2:3) to give 1a (197
mg, 70%) as a yellow solid. Mp: 112.1-113.0 °C (yellow cubes,
recrystallized from CH2Cl2/n-hexane). 1H NMR (CDCl3, 400 MHz):
δ 7.43-7.40 (2H, m), 7.38-7.31 (3H, m), 5.34 (1H, t, J ) 5.0
Hz), 4.17 (1H, t, J ) 5.0 Hz), 2.16-2.08 (2H, m), 1.95-1.87 (2H,
m), 1.67-1.57 (4H, m). 13C NMR (CDCl3, 100 MHz): δ 194.0,
142.7, 129.3, 128.1, 126.4, 61.0, 59.0, 29.9, 27.5. Anal. Calcd for
C13H15NS: C, 71.84; H, 6.96; N, 6.44. Found: C, 71.83; H, 6.97;
N, 6.36.
Compound 1b. Mp: 165.0-166.5 °C (orange cubes, recrystal-
lized from CH2Cl2/n-hexane). 1H NMR (CDCl3, 400 MHz): δ 7.45
(2H, d, J ) 8.8 Hz), 6.62 (2H, d, J ) 8.8 Hz), 5.30 (1H, t, J ) 5.0
Hz), 4.40 (1H, t, J ) 4.8 Hz), 3.00 (6H, s), 2.13-2.09 (2H, m),
1.96-1.90 (2H, m), 1.63-1.52 (4H, m). 13C NMR (CDCl3, 100
MHz): δ 194.9, 151.6, 130.1, 129.2, 110.6, 61.5, 59.4, 40.2, 30.0,
27.5. Anal. Calcd for C15H20N2S: C, 69.19; H, 7.74; N, 10.76.
Found: C, 69.11; H, 7.81; N, 10.63.
Compound 1c. Mp: 127.2-128.4 °C (yellow needles, recrystal-
lized from CH2Cl2/n-hexane). 1H NMR (CDCl3, 400 MHz): δ 7.43
(2H, d, J ) 8.8 Hz), 6.85 (2H, d, J ) 8.8 Hz), 5.31 (1H, t, J ) 5.2
Hz), 4.28 (1H, t, J ) 4.8 Hz), 3.83 (3H, s), 2.15-2.05 (2H, m),
1.94-1.86 (2H, m), 1.65-1.55 (4H, m). 13C NMR (CDCl3, 100
MHz): δ 194.2, 160.7, 135.2, 128.7, 113.2, 61.3, 59.3, 55.4, 30.0,
27.5. Anal. Calcd for C14H17NOS: C, 67.98; H, 6.93; N, 5.66.
Found: C, 68.16; H, 6.87; N, 5.66.
Compound 1d. Mp: 131.6-133.0 °C (yellow needles, recrystal-
lized from CH2Cl2/n-hexane). 1H NMR (CDCl3, 400 MHz): δ 7.33
(2H, d, J ) 8.4 Hz), 7.14 (2H, d, J ) 8.4 Hz), 5.33 (1H, t, J ) 5.0
Hz), 4.23 (1H, t, J ) 4.8 Hz), 2.36 (3H, s), 2.15-2.08 (2H, m),
1.94-1.87 (2H, m), 1.66-1.54 (4H, m). 13C NMR (CDCl3, 100
MHz): δ 194.3, 139.9, 139.6, 128.7, 126.7, 61.1, 59.1, 29.9, 27.5,
21.2. Anal. Calcd for C14H17NS: C, 72.68; H, 7.41; N, 6.05. Found:
C, 72.84; H, 7.47; N, 6.09.
Compound 1e. Mp: 157.8-159.0 °C (yellow cubes, recrystallized
from CH2Cl2/n-hexane). 1H NMR (CDCl3, 400 MHz): δ 7.37 (2H,
d, J ) 8.4 Hz), 7.32 (2H, d, J ) 8.4 Hz), 5.31 (1H, t, J ) 5.2 Hz),
4.16 (1H, t, J ) 4.8 Hz), 2.15-2.08 (2H, m), 1.93-1.88 (2H, m),
1.67-1.55 (4H, m). 13C NMR (CDCl3, 100 MHz): δ 192.7, 141.0,
135.3, 128.3, 127.9, 61.2, 59.1, 29.9, 27.5. Anal. Calcd for
C13H14ClNS: C, 62.02; H, 5.60; N, 5.56. Found: C, 62.06; H, 5.59;
N, 5.60.
Compound 1f. Mp: 132.2-133.4 °C (yellow plates, recrystallized
from CH2Cl2/n-hexane). 1H NMR (CDCl3, 400 MHz): δ 8.02 (2H,
d, J ) 8.4 Hz), 7.46 (2H, d, J ) 8.4 Hz), 5.34 (1H, t, J ) 4.8 Hz),
4.08 (1H, t, J ) 5.0 Hz), 3.93 (3H, s), 2.16-2.08 (2H, m),
1.93-1.87 (2H, m), 1.68-1.55 (4H, m). 13C NMR (CDCl3, 100
MHz): δ 192.6, 166.3, 146.5, 130.5, 129.5, 126.3, 61.1, 59.0, 52.2,
29.9, 27.5. Anal. Calcd for C15H17NO2S: C, 65.43; H, 6.22; N, 5.09.
Found: C, 65.28; H, 6.32; N, 5.01.
Compound 1g. Mp: 194.6-195.5 °C (yellow cubes, recrystal-
lized from AcOEt/n-hexane). 1H NMR (CDCl3, 400 MHz): δ 7.65
(2H, d, J ) 8.0 Hz), 7.49 (2H, d, J ) 8.0 Hz), 5.32 (1H, t, J ) 5.0
Hz), 4.05 (1H, t, J ) 4.8 Hz), 2.15-2.09 (2H, m), 1.93-1.87 (2H,
m), 1.70-1.58 (4H, m). 13C NMR (CDCl3, 100 MHz): δ 191.1,
146.3, 132.0, 126.9, 118.1, 112.6, 61.2, 59.1, 29.8, 27.4. Anal. Calcd
for C14H14N2S: C, 69.39; H, 5.82; N, 11.56. Found: C, 69.51; H,
5.95; N, 11.46.
Compound 1h. Mp: 216.3-217.2 °C (yellow cubes, recrystal-
lized from AcOEt). 1H NMR (CDCl3, 400 MHz): δ 8.22 (2H, d, J
) 8.8 Hz), 7.54 (2H, d, J ) 8.8 Hz), 5.34 (1H, t, J ) 5.0 Hz), 4.05
(1H, t, J ) 4.8 Hz), 2.17-2.10 (2H, m), 1.94-1.88 (2H, m),
1.71-1.59 (4H, m). 13C NMR (CDCl3, 100 MHz): δ 190.9, 148.0,
147.8, 127.2, 123.6, 61.3, 59.1, 29.9, 27.5. Anal. Calcd for
C13H14N2O2S: C, 59.52; H, 5.38; N, 10.68. Found: C, 59.47; H,
5.40; N, 10.61.
Compound 2a. Mp: 73.0-73.8 °C (pale yellow plates, recrystal-
lized from CH2Cl2/n-hexane). 1H NMR (CDCl3, 400 MHz): δ
7.37-7.30 (5H, m), 3.97 (2H, t, J ) 7.2 Hz), 3.46 (2H, t, J ) 6.8
Hz), 2.11-2.04 (2H, m), 1.99-1.93 (2H, m). 13C NMR (CDCl3,
100 MHz): δ 197.1, 143.9, 128.6, 128.2, 125.5, 53.7, 53.3, 26.4,
24.5. Anal. Calcd for C11H13NS: C, 69.07; H, 6.85; N, 7.32. Found:
C, 68.99; H, 6.79; N, 7.24.
Compound 2b. Mp: 113.2-114.5 °C (yellow needles, recrystal-
lized from CH2Cl2/n-hexane). 1H NMR (CDCl3, 400 MHz): δ 7.39
(2H, d, J ) 8.8 Hz), 6.62 (2H, d, J ) 8.8 Hz), 3.98 (2H, t, J ) 7.0
Hz), 3.62 (2H, t, J ) 6.8 Hz), 2.98 (6H, s), 2.10-2.03 (2H, m),
1.98-1.91 (2H, m). 13C NMR (CDCl3, 100 MHz): δ 197.7, 151.0,
131.5, 128.1, 110.9, 54.2, 53.9, 40.2, 26.6, 24.7. Anal. Calcd for
C13H18N2S: C, 66.62; H, 7.74; N, 11.95. Found: C, 66.80; H, 7.78;
N, 11.81.
Compound 2c. Mp: 111.0-112.5 °C (colorless needles, recrys-
1
tallized from CH2Cl2/n-hexane). H NMR (CDCl3, 400 MHz): δ
7.37 (2H, d, J ) 9.0 Hz), 6.86 (2H, d, J ) 9.0 Hz), 3.97 (2H, t, J
) 7.0 Hz), 3.82 (3H, s), 3.53 (2H, t, J ) 6.6 Hz), 2.10-2.04 (2H,
m), 2.00-1.95 (2H, m). 13C NMR (CDCl3, 100 MHz): δ 197.1,
160.0, 136.4, 127.7, 113.4, 55.3, 53.9, 53.7, 26.5, 24.7. Anal. Calcd
for C12H15NOS: C, 65.12; H, 6.83; N, 6.33. Found: C, 65.06; H,
6.98; N, 6.27.
Compound 2d. Mp: 72.5-73.8 °C (yellow needles, recrystallized
from CH2Cl2/n-hexane). 1H NMR (CDCl3, 400 MHz): δ 7.27 (2H,
d, J ) 8.0 Hz), 7.15 (2H, d, J ) 8.0 Hz), 3.97 (2H, t, J ) 7.0 Hz),
3.49 (2H, t, J ) 6.8 Hz), 2.34 (3H, s), 2.11-2.04 (2H, m),
1.99-1.92 (2H, m). 13C NMR (CDCl3, 100 MHz): δ 197.5, 141.2,
138.8, 128.8, 125.7, 53.8, 53.4, 26.4, 24.6, 21.2. Anal. Calcd for
C12H15NS: C, 70.20; H, 7.36; N, 6.82. Found: C, 70.21; H, 7.36;
N, 6.84.
Compound 2e. Mp: 95.7-96.8 °C (yellow cubes, recrystallized
from CH2Cl2/n-hexane). 1H NMR (CDCl3, 400 MHz): δ 7.32 (4H,
s), 3.96 (2H, t, J ) 7.0 Hz), 3.46 (2H, t, J ) 6.8 Hz), 2.11-2.05
(2H, m), 2.00-1.95 (2H, m). 13C NMR (CDCl3, 100 MHz): δ 195.8,
142.2, 134.7, 128.5, 127.1, 53.8, 53.5, 26.5, 24.6. Anal. Calcd for
C11H12ClNS: C, 58.53; H, 5.36; N, 6.20. Found: C, 58.41; H, 5.49;
N, 6.16.
Compound 2f. Mp: 120.3-121.8 °C (yellow needles, recrystal-
lized from AcOEt/n-hexane). 1H NMR (CDCl3, 400 MHz): δ 8.03
(2H, d, J ) 8.4 Hz), 7.41 (2H, d, J ) 8.4 Hz), 3.97 (2H, t, J ) 7.0
Hz), 3.92 (3H, s), 3.42 (2H, t, J ) 6.8 Hz), 2.13-2.06 (2H, m),
2.02-1.95 (2H, m). 13C NMR (CDCl3, 100 MHz): δ 195.8, 166.4,
147.8, 130.1, 129.8, 125.6, 53.6, 53.3, 52.2, 26.4, 24.5. Anal. Calcd
for C13H15NO2S: C, 62.62; H, 6.06; N, 5.62. Found: C, 62.61; H,
6.09; N, 5.54.
Compound 2g. Mp: 151.4-152.2 °C (yellow cubes, recrystal-
lized from CH2Cl2/n-hexane). 1H NMR (CDCl3, 400 MHz): δ 7.65
(2H, d, J ) 8.8 Hz), 7.44 (2H, d, J ) 8.8 Hz), 3.95 (2H, t, J ) 7.0
Hz), 3.41 (2H, t, J ) 6.8 Hz), 2.14-2.06 (2H, m), 2.04-1.97 (2H,
m). 13C NMR (CDCl3, 100 MHz): δ 194.4, 147.6, 132.3, 126.3,
118.2, 112.2, 53.6, 53.3, 26.5, 24.5. Anal. Calcd for C12H12N2S:
C, 66.63; H, 5.59; N, 12.95. Found: C, 66.68; H, 5.86; N, 12.93.
Compound 2h. Mp: 155.2-156.1 °C (yellow plates, recrystal-
lized from CH2Cl2/n-hexane). 1H NMR (CDCl3, 400 MHz): δ 8.23
(2H, d, J ) 8.8 Hz), 7.51 (2H, d, J ) 8.8 Hz), 3.98 (2H, t, J ) 7.0
Hz), 3.43 (2H, t, J ) 6.6 Hz), 2.15-2.08 (2H, m), 2.06-1.99 (2H,
m). 13C NMR (CDCl3, 100 MHz): δ 194.0, 149.3, 147.4, 126.5,
123.8, 53.6, 53.3, 26.5, 24.5. Anal. Calcd for C11H12N2O2S: C,
55.91; H, 5.12; N, 11.86. Found: C, 55.91; H, 5.15; N, 11.86.
Compound 3a. Mp: 66.0-66.8 °C (yellow cubes, recrystallized
from CH2Cl2/n-hexane). 1H NMR (CDCl3, 400 MHz): δ 7.37-7.28
(5H, m), 3.60 (3H, s), 3.16 (3H, s). 13C NMR (CDCl3, 100 MHz):
δ 201.1, 143.2, 128.5, 128.2, 125.6, 44.0, 43.1. Anal. Calcd for
C9H11NS: C, 65.41; H, 6.71; N, 8.48. Found: C, 65.43; H, 6.75; N,
8.37.
2. Dynamic NMR. In variable-temperature NMR experiments,
temperatures were calibrated by a standard method using ethylene
glycol.14,16
J. Org. Chem. Vol. 73, No. 22, 2008 9107

Hori et al.
Line shape analysis was carried out with a program, DNMR
(Bruker Biospin) and was performed by iterative matching of
simulated spectra with the experimental spectra.
X-ray Crystallographic Analysis. Data collections were per-
formed using a CCD area detector diffractometer with Mo KR
radiation in a w-scan mode (l ) 0.71073 Å). The structure was
solved by direct methods and refined by full-matrix least-squares
refinements based on F2. All hydrogen atoms were anisotropically
refined. Hydrogen atoms were added geometrically and refined with
a riding model. Structure solutions were performed with the
SHELXS-97 and SHELXL-97.25
Acknowledgment. This work was supported by a Grant-in-
Aid for Scientific Research from the Japan Society for the
Promotion of Science.
Supporting Information Available: 1H and 13C NMR
spectra, crystallographic data in CIF format, figures showing
dynamic NMR, and details of calculations. This material is
available free of charge via the Internet at http://pubs.acs.org.
(25) Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112–122.
JO801996B
9108 J. Org. Chem. Vol. 73, No. 22, 2008