Rotational isomerism in 2,4,6-tri-tert-butylanilides

Article abstract of DOI:10.1016/j.tet.2012.11.096

Z-Rotamers of several 2,4,6-tri-tert-butylanilides slowly isomerize at rt in CDCl₃ to E-rotamers, yielding equilibrium mixtures of Z- and E-rotamers after standing for 1 week. The equilibrium ratios between the anilide rotamers in the solution

Full text of DOI:10.1016/j.tet.2012.11.096

Tetrahedron 69 (2013) 1013e1016
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Rotational isomerism in 2,4,6-tri-tert-butylanilides
*
Nobutaka Ototake, Isao Takahashi, Shiori Tsukagoshi, Tatsuki Maeda, Osamu Kitagawa
Department of Applied Chemistry, Shibaura Institute of Technology, 3-7-5 Toyosu, Kohto-ku, Tokyo 135-8548, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 October 2012
Received in revised form 27 November 2012
Accepted 28 November 2012
Available online 6 December 2012
Z-Rotamers of several 2,4,6-tri-tert-butylanilides slowly isomerize at rt in CDCl3 to E-rotamers, yielding
equilibrium mixtures of Z- and E-rotamers after standing for 1 week. The equilibrium ratios between the
anilide rotamers in the solution depend strongly on the bulkiness of the acyl substituents as well as the
formation of intramolecular hydrogen bond. Heating equilibrium mixtures in the solid state produced
complete isomerization to the Z-rotamer.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Anilides
Amides
Rotamers
Isomerization
Hydrogen bonding
1. Introduction
2,6-di-substituted anilides is considerably higher than in other
ordinary secondary amides (Z-rotamers of secondary amides are
Since an amide C(O)eN bond has relatively high rotational
barrier because of the double bond character, in unsymmetrical
amides, the rotational isomers are often observed by means of NMR
spectra. It is well known that in acyclic secondary amides, the Z-
rotamer is preferred to the E-rotamer.1 For example, acetanilide
(R1¼Me, R2¼Ph) exists almost completely as the Z-rotamer (Eq. 1).
This Z-rotamer preference can be explained by the destabilization
of the E-rotamer by the steric repulsion between the R1 substituent
on the acyl group and the R2 substituent on the nitrogen atom.1
generally favored by roughly 2 kcal/mol relative to the E-rotam-
ers).1,3 Moreover, it has been reported that E-rotamers of 2,6-di-
substituted anilides form complexes with N2O and CO2 by hydro-
gen bonding and electrostatic interactions.4 However, in spite of
these interesting properties of 2,6-di-substituted anilides, no re-
ports have been published of the systematic investigations in-
volving anilide substrates other than 2,6-disubstituted acetanilides
(R1¼Me, Eq. 2). Also, rational explanation for the equilibrium ratio
of the resulting rotamer mixtures and investigation of the solvent
effect on isomerization has not been described.
R1
O
H
H
R1
R2
N
O
N
R2 ≠ H
R2
R2
R2
(2)
R3
R3
Z-rotamer
E-rotamer
On the other hand, Kessler and Rieker found that 2,6-
R1 = Me, R2 = Me, R3 = H (Z/E = 2.8, ΔG≠ = 18.3 kcal/mol)
R1 = Me, R2 = R3 = t-Bu (Z/E = 1.3, ΔG≠ = 24.2 kcal/mol)
disubstituted anilides exist as the mixtures of Z- and E-rotamers
(D
Gs around CeN bond in Z-rotamer¼24.2 kcal/mol), and the
Recently, we reported the highly selective stereodivergent
synthesis of Z- and E-rotamers of various N-allylated 2,4,6-tri-tert-
butylanilides II through Pd-catalyzed N-allylation of NH-anilides I
(Eq. 3).5 In N-alkylated 2,4,6-tri-tert-butylanilide derivatives, the
rotational isomers Z-II and E-II can easily be isolated at room
proportion of E-rotamer increases with the bulkiness of the ortho-
substituent (2,6-dimethylacetanilide: Z/E¼2.8, 2,4,6-tri-tert-butyl-
acetanilide: Z/E¼1.3, Eq. 2).2 The proportion of E-rotamer in these
temperature (
D
Gs¼27e28 kcal/mol). Furthermore, in a thermal
* Corresponding author. Tel.: þ81 3 5859 8161; fax: þ81 3 5859 8101; e-mail
address: kitagawa@shibaura-it.ac.jp (O. Kitagawa).
isomerization experiment, it was found that E-rotamers E-II are
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.096

1014
N. Ototake et al. / Tetrahedron 69 (2013) 1013e1016
Table 1
thermodynamically more stable than Z-rotamers Z-II, and that the
thermodynamic stability of the rotamers depends strongly on the
bulkiness of the acyl substituent (R¼Me: E/Z¼10.1, R¼Et: E/Z¼6.0,
R¼cyclohexyl: E/Z¼1.4).5 Our study on N-alkylated 2,4,6-tri-tert-
butylanilide chemistry5e7 excited our interest in the isomerization
between rotamers of 2,4,6-tri-tert-butyl-NH-anilides.
Solvent effect on the isomerization of 1aa
O
R
R
allyl
allyl
O
t-Bu
R
t-Bu
N
NH
O
t-Bu
N
Entry
Solvent
Z-1a/E-1ab
t-Bu
t-Bu
t-Bu
1
2
3
4
5
6
CDCl3
Toluene
THF
CH3CO2Et
C2H5OH
CH3OH
1.5
1.5
4.4
5.4
9.5
(3)
I
t-Bu
t-Bu
(separable)
E-II
Z-II
(separable)
t-Bu
12.5
a
1a (10 mg) in each solvent (1 mL) was stood for 1 week at rt, and after evapo-
ration of solvent, the 1H NMR of 1a was measured in CDCl3.
R = Me, Et, i-Pr, CH3-CH=CH, Ar, COOMe etc.
(ΔG≠ of II = 27-28 kcal/mol)
b
The ratio was determined by 400 MHz 1H NMR.
in MeOH, entries 5 and 6). Thus, the equilibrium ratio of the anilide
rotamers was significantly affected by solvent polarity.3,9
In this paper, we report on the thermodynamic isomerization
between the rotamers of various 2,4,6-tri-tert-butylanilides (sec-
ondary amides). The equilibrium ratio between the anilide Z- and E-
rotamers in solution was found to be remarkably sensitive to the
bulkiness of the acyl substituent and the formation of an intra-
molecular hydrogen bond. Furthermore, heating the equilibrium
mixtures in the solid state led to complete isomerization to the Z-
rotamer. The effect of the acyl substituent on the isomerization is
also considered.
The isomerization of various 2,4,6-tri-tert-butylanilides 1beh
was also examined at rt in CDCl3 (Table 2). The proportion of E-
rotamer in propionanilide 1b decreased slightly in comparison with
that in acetanilide 1a, and in this case, the equilibrium ratio was Z/
E¼2.8/1 (entry 2). In cyclohexane carboxanilide 1c, no E-rotamer
was detected (entry 3). Rudkevich et al. previously reported that N-
octanoyl-2,4,6-tri-tert-butylaniline gave an equilibrium ratio of Z/
E¼8/1 after standing at rt in CDCl3.4 Rudkevich’s results and ours
indicate a good correlation between the Z/E ratio and the bulkiness
of the acyl group. That is, the proportion of E-rotamer decreased
with increasing bulkiness of the acyl group (Fig. 1).
2. Results and discussion
We previously reported the synthesis of various 2,4,6-tri-tert-
butylanilides 1 (precursors of N-allylated anilides II) through the
reaction of 2,4,6-tri-tert-butylaniline with the corresponding acid
chloride in the presence of NaH (Eq. 4).5 In the all acylation re-
actions, Z-rotamer Z-1 was obtained as the sole isomer. However, in
some anilide products, a slow isomerization to E-rotamer at rt was
observed by 1H NMR, while, in other anilides, such isomerization
did not proceed at all. We became interested in the effect of the acyl
substituent on the isomerization between anilide rotamers.
Table 2
Equilibrium ratios of rotamers of various anilides 1aeha
Entry
1
R
Z-1/E-1b
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Me
Et
1.5
2.8
>50
1.4
6.1
>50
>50
>50
Cyclohexyl
(E)-CH3CH]CH
Thiophene-2-yl
4-BrC6H4
Furan-2-yl
COOMe
1g
1h
a
After each compound 1 (0.03 mmol) remained dissolved in CDCl3 (1 mL) for 1
week at rt, 1H NMR of 1 was measured.
b
The ratio was determined by 400 MHz 1H NMR.
n-octyl cyclohexyl
>50
Me
Et
R
(Z/E)
~ 1.5
2.8
8
First, we investigated the solvent effect on the isomerization of
acetanilide 1a. When Z-1a (10 mg) was stood for 1 week at rt in
various solvents (1 mL), the equilibrium mixtures of Z- and E-
rotamers were obtained.8 The equilibrium ratios were determined
by means of 1H NMR in CDCl3 after evaporation of solvent. These
results are shown in Table 1. In CDCl3 and toluene, the rotamer
mixtures showed Z/E¼1.5 (entries 1 and 2). The proportion of E-
rotamer decreased with the increasing solvent polarity. Z/E ratios in
THF and ethyl acetate were 4.4 and 5.4, respectively (entries 3 and
4). In protic solvents, such as EtOH and MeOH, a further decrease in
the E-rotamer proportion was observed (Z/E¼9.5 in EtOH, Z/E¼12.5
high
low
small
Z/E
large
bulkiness
Fig. 1. Relationship between rotamer ratios and acyl group bulkiness.
These results may be rationalized as follows (Fig. 2). The anilide
E-rotamer is destabilized by the steric repulsion between the ortho-
tert-butylphenyl group and acyl substituent R, while in the Z-
rotamer, there is destabilization due to the ne
p repulsion between
the lone pair of carbonyl oxygen and the -electrons of the twisted
p

N. Ototake et al. / Tetrahedron 69 (2013) 1013e1016
1015
low field shift was observed for the NH-hydrogen of 1h, which
indicates the formation of a hydrogen bond (Fig. 3).
The stereochemistries of anilide rotamers were determined
based on chemical shifts in 1H NMR spectra. In general, hydrogens
on the acyl group in the E-rotamer appeared at higher field than
those on the Z-rotamer because of the anisotropy effect due to the
tert-butylphenyl group possessing a large twist angle. For example,
for the a-hydrogens in E-1a,b,d and the C-3 hydrogen on thiophene
Fig. 2. Visualizing the isomerization between anilide rotamers.
in E-1e, high field shifts of
Experimental section).
d
¼0.6e1.1 ppm were observed (see
tert-butylphenyl group.10 The relative magnitude of these two de-
stabilization factors would possibly determine the Z/E ratio of the
rotamers. Anilides having a hindering acyl group exist almost
completely as the Z-rotamer, because the steric repulsion in the E-
rotamer results in a larger destabilization than the nep repulsion in
the Z-rotamer. Meanwhile, in anilides having a less hindering acyl
group, since the destabilization due to the steric repulsion in the E-
The equilibrium ratios of 1a,b,d,e in CDCl3 were also maintained
while in the solid state. When the solid obtained by evaporating the
equilibrium mixtures of 1a,b,d,e in CDCl3 was dissolved in CDCl3
again and the 1H NMR was measured, no detectable change of the
equilibrium ratios was observed (Scheme 1). In contrast, when the
equilibrium mixtures of 1a,b,d,e were heated in the solid state
(100 ꢀC, 20 h), complete isomerization to the Z-rotamer was ob-
served in all cases. Thus, the thermodynamic behavior of anilide
rotamers in the solid state was found to be different from that in
solution.
rotamer is close to that due to the nep repulsion in the Z-rotamer,
equilibrium mixtures include both rotamers in varying proportion.
A correlation between the Z/E ratio and the bulkiness of the acyl
group was also found in anilide derivatives bearing an unsaturated
acyl group. Less hindered crotonanilide 1d gave the rotamer mix-
tures with Z/E¼1.4/1 (entry 4). In thiophene-2-yl carboxanilide 1e,
a decrease in the proportion of E-rotamer was observed in com-
parison with 1d (Z/E¼6.1/1, entry 5). p-Bromobenzanilide 1f bear-
ing a relatively large acyl group exists almost completely as the Z-
rotamer (entry 6).
Furan-2-yl carboxanilide 1g favored the Z-rotamer with a ratio
of Z/E¼>50 (entry 7). The higher Z-rotamer preference in 1g than
that in 1e cannot be rationalized based on simple steric factors
involving the acyl group because the furanyl group is slightly less
hindered than the thiophenyl group. However, this might be ex-
plainable based on the formation of an intramolecular hydrogen
bond. In the Z-rotamer of 1g with a furanyl group, intramolecular
hydrogen bonding between the NH-hydrogen and the oxygen in
the furan ring is possible. Stabilization by this hydrogen bonding
might increase the energenic favorability of the Z-rotamer. Indeed,
in 1H NMR spectra in CDCl3, the NH-hydrogen of 1g appeared at
a lower field by 0.4 ppm than that of thiophene-2-yl carboxanilide
1e, which does not form a hydrogen bond (Fig. 3). The stabilization
of the Z-rotamer by the intramolecular hydrogen bonding is also
supported by the behavior of anilide 1h with an ester group. That is,
anilide 1h, which can form an intramolecular hydrogen bond be-
tween the NH-hydrogen and the carbonyl oxygen of the ester
group, exists almost completely as the Z-rotamer. A remarkably,
Scheme 1. Thermodynamic behavior of 1a,b,d,e in the solid state.
3. Conclusion
We found that the isomerization between the rotamers of 2,4,6-
tri-tert-butylanilides is significantly influenced by the bulkiness of
the acyl substituent. Anilides having a small acyl substituent, such
as acetyl, propionyl, and crotonoyl groups give the equilibrium
mixtures that include substantial amount of Z- and E-rotamers,
while anilides having a large acyl substituent exist almost exclu-
sively as Z-rotamers. The Z-rotamer preference was also increased
by the formation of an intramolecular hydrogen bond. Heating the
rotamer mixtures in the solid state produced the complete isom-
erization to the Z-rotamer. These results describe a new structural
property of 2,4,6-tri-tert-butylanilides.
4. Experimental section
4.1. General techniques
1H and 13C NMR spectra were recorded on a 300 MHz spec-
trometer. In 1H and 13C NMR spectra, chemical shifts were
expressed in d (parts per million) downfield from CHCl3 (7.26 ppm)
and CDCl3 (77.0 ppm), respectively. Mass spectra were recorded by
electrospray ionization (TOF).
4.2. Synthesis of 2,4,6-tri-tert-butylanilides
Anilides 1aed and 1feh were prepared in accordance with
previously reported procedure.5 NMR spectra of 1aed and 1feh
coincided with those of literature.5 Anilide 1e was prepared in ac-
cordance with following procedure.
Fig. 3. Chemical shifts of the NH-hydrogen in Z-1aeh in CDCl3.

1016
N. Ototake et al. / Tetrahedron 69 (2013) 1013e1016
4.2.1. N-(2,4,6-Tri-tert-butylphenyl)thiophene-2-carboxamide
(1e). To a solution of NaH (60% assay, 40 mg, 1.0 mmol) in 1,4-
dioxane (8 mL) was added 2,4,6-tri-tert-butylaniline (261 mg,
1.0 mmol) at rt. After being stirred for 10 min at rt, 2-thiophene
carbonyl chloride (0.11 mL, 1.0 mmol) was added to the mixture
and then the reaction mixture was stirred for 18 h at 130 ꢀC. The
mixture was poured into 2% HCl and extracted with AcOEt. The
AcOEt extracts were washed with saturated NaCl aq, dried over
MgSO4, and evaporated to dryness. Washing of the solid residue
using solvent (hexane and AcOEt¼40 mL and 5 mL) gave 1e
(225 mg, 60%). Z-1e: white solid (mp>299 ꢀC in sealed capillary); IR
s), 6.04 (1H, qd, J¼1.6, 15.1 Hz), 1.94 (3H, dd, J¼1.6, 6.9 Hz), 1.39
(18H, s), 1.31 (9H, s); 13C NMR (CDCl3)
: 166.2, 149.4, 148.3, 141.3,
130.5, 125.8, 123.1, 36.3, 35.0, 32.0, 31.4, 17.9. E-1d: 1H NMR (CDCl3)
: 7.41 (2H, s), 6.94 (1H, qd, J¼6.9, 15.6 Hz), 6.75 (1H, br s), 5.30 (1H,
d, J¼15.6 Hz), 1.71 (3H, dd, J¼2.0, 6.9 Hz), 1.37 (18H, s), 1.35 (9H, s);
13C NMR (CDCl3)
: 168.1, 150.2, 148.6, 142.0, 131.0, 123.1, 122.7, 36.5,
d
d
d
35.1, 32.1, 31.4, 17.9.
4.3.4. N-(2,4,6-Tri-tert-butylphenyl)thiophene-2-carboxamide
(1e). Z-1e: see Section 4.2.1. E-1e: 1H NMR (CDCl3)
d: 7.45 (2H, s),
7.31 (1H, dd, J¼0.8, 5.2 Hz), 7.06 (1H, br s), 6.76 (1H, dd, J¼4.0,
(CH2Cl2) 3297, 1633 cmꢁ1
;
1H NMR (CDCl3)
d
: 7.66 (1H, dd, J¼0.8,
5.2 Hz), 6.45 (1H, dd, J¼0.8, 4.0 Hz), 1.38 (18H, s), 1.33 (9H, s); 13C
3.6 Hz), 7.54 (1H, dd, J¼0.8, 5.2 Hz), 7.44 (2H, s), 7.19 (1H, br s), 7.17
NMR (CDCl3) d: 164.2, 151.5, 149.2, 137.3, 132.4, 131.8, 131.1, 126.8,
(1H, dd, J¼3.6, 5.2 Hz), 1.41 (18H, s), 1.34 (9H, s); 13C NMR (CDCl3)
d:
123.7, 36.6, 32.0, 31.5, 29.7.
162.0, 149.7, 148.4, 140.0, 130.2, 130.1, 128.8, 128.0, 123.2, 36.3, 35.0,
32.0, 31.4; MS (m/z) 394 (MNaþ); HRMS. Calcd for C23H33NOSNa
(MNaþ) 394.2181. Found: 394.2180.
Supplementary data
Copies of 1H and 13C NMR of compounds Z-1aeh and E, Z-
mixture of 1a,b,d,e. Supplementary data related to this article can
be found online at http://dx.doi.org/10.1016/j.tet.2012.11.096.
4.3. Isomerization experiment between anilide rotamers
Anilide 1 (0.03 mmol) was dissolved in CDCl3 (1 mL), and the
solution was stood for one week at rt. Subsequently, 1H NMR of the
solution was measured and the Z/E ratio between rotamers was
determined. In anilides 1c and 1feh, no isomerization to E-rotamer
was observed. Anilides 1a,b,d,e gave equilibrium mixtures of Z- and
E-rotamers. NMR spectra of rotamers of 1a,b,d,e were as follows.
References and notes
1. (a) LaPlanche, L. A.; Rogers, M. T. J. Am. Chem. Soc. 1964, 86, 337; (b) Rae, J. D.
Can. J. Chem. 1967, 44, 1334; (c) Stewart, W. E.; Sidwell, T. H., III. Chem. Rev. 1970,
70, 517; (d) Kashio, S.; Ito, K.; Haisa, M. Bull. Chem. Soc. Jpn. 1979, 52, 365.
2. Kessler, H.; Rieker, A. Liebigs Ann. Chem. 1967, 708, 57.
3. Examples of secondary amides having relatively high E-rotamer proportion. (a)
Gardner, R. R.; McKay, S. L.; Gellman, S. H. Org. Lett. 2000, 2, 304; (b) Forbes, C.
C.; Beatty, A. M.; Smith, B. D. Org. Lett. 2001, 3, 3595.
4. Zyryanov, G. V.; Hampe, E. M.; Rudkevich, D. M. Angew. Chem., Int. Ed. 2002, 41,
3854 In this paper, only isomerization of N-octanoyl-2,4,6-tri-tert-butylaniline
has been described.
5. Ototake, N.; Nakamura, M.; Dobashi, Y.; Fukaya, H.; Kitagawa, O. Chem.dEur. J.
2009, 15, 5090.
6. (a) Nakamura, M.; Takahashi, I.; Yamada, S.; Dobashi, Y.; Kitagawa, O. Tetrahe-
dron Lett. 2011, 52, 53; (b) Ohnishi, Y.; Sakai, M. ,; Nakao, S.; Kitagawa, O. Org.
Lett. 2011, 13, 2840.
4.3.1. N-(2,4,6-Tri-tert-butylphenyl)acetamide (1a). Z-1a5: 1H NMR
(CDCl3)
d
: 7.41 (2H, s), 6.70 (1H, br s), 2.18 (3H, s), 1.40 (18H, s), 1.31
(9H, s); 13C NMR (CDCl3)
d: 170.3, 149.5, 148.1, 130.6, 123.2, 36.3,
35.0, 32.0, 31.4, 24.6. E-1a: 1H NMR (CDCl3)
d: 7.40 (2H, s), 6.80 (1H,
br s),1.59 (3H, s),1.40 (18H, s),1.33 (9H, s); 13C NMR (CDCl3)
150.2, 148.2, 132.2, 123.1, 36.5, 35.0, 31.9, 31.4, 21.4;
d: 173.8,
4.3.2. N-(2,4,6-Tri-tert-butylphenyl)propinamide (1b). Z-1b5: 1H
7. (a) Chupp, J. P.; Olin, J. F. J. Org. Chem. 1967, 32, 2297; (b) Molin, W. T.; Porter, C.
A.; Chupp, J. P.; Naylor, K. Pestic. Biochem. Physiol. 1990, 36, 277.
8. When Z-1a in CHCl3 was heated for 16 h at 60 ꢀC, the equilibrium mixtures was
obtained in a ratio of Z/E¼1.4. Meanwhile, heating at 80 ꢀC in toluene gave the
equilibrium mixtures (Z-1a/E-1a¼1.4) in 3 h.
NMR (CDCl3)
d
: 7.40 (2H, s), 6.70 (1H, br s), 2.43 (2H, q, J¼7.6 Hz),
1.39 (18H, s), 1.31 (9H, s), 1.28 (3H, t, J¼7.6 Hz); 13C NMR (CDCl3)
d:
173.2, 149.3, 148.1, 130.8, 123.2, 36.3, 35.0, 32.0, 31.4, 30.9, 9.3. E-1b:
1H NMR (CDCl3)
d: 7.39 (2H, s), 7.08 (1H, br s), 1.80 (2H, q, J¼7.6 Hz),
9. Similar solvent effect was also observed in other secondary amides Radzicka,
A.; Pederson, L.; Wolfenden, R. Biochemistry 1988, 27, 4538 See also Ref. 3b.
10. The E-rotamer preference of N-substituted anilides has been rationalized on
1.39 (18H, s), 1.33 (9H, s), 1.01 (3H, t, J¼7.6 Hz); 13C NMR (CDCl3)
d:
176.7, 150.0, 148.1, 131.4, 123.2, 36.6, 35.0, 32.0, 31.4, 26.1, 8.0.
the basis of nep interaction. (a) Itai, A.; Toriumi, Y.; Tomioka, N.; Kagechika, H.;
Azumaya, I.; Shudo, K. Tetrahedron Lett. 1989, 30, 6177; (b) Saito, S.; Toriumi, Y.;
Tomioka, N.; Itai, A. J. Org. Chem. 1995, 60, 4715; (c) Yamasaki, R.; Tanatani, A.;
Azumaya, I.; Saito, S.; Yamaguchi, K.; Kagechika, H. Org. Lett. 2003, 5, 1265.
4.3.3. N-(2,4,6-Tri-tert-butylphenyl)but-2-eneamide (1d). Z-1d5: 1H
NMR (CDCl3)
: 7.41 (2H, s), 6.94 (1H, qd, J¼6.9,15.1 Hz), 6.66 (1H, br
d