Reversible Twisting of Primary Amides via Ground State N-C(O) Destabilization: Highly Twisted Rotationally Inverted Acyclic Amides

Article abstract of DOI:10.1021/jacs.7b11309

Since the seminal studies by Pauling in 1930s, planarity has become the defining characteristic of the amide bond. Planarity of amides has central implications for the reactivity and chemical properties of amides of relevance to a range of chemical disciplines. While the vast majority of amides are planar, nonplanarity has a profound effect on the properties of the amide bond, with the most common method to restrict the amide bond relying on the incorporation of the amide function into a rigid cyclic ring system. In a major departure from this concept, here, we report the first class of acyclic twisted amides that can be prepared, reversibly, from common primary amides in a single, operationally trivial step. Di-tert-butoxycarbonylation of the amide nitrogen atom yields twisted amides in which the amide bond exhibits nearly perpendicular twist. Full structural characterization of a range of electronically diverse compounds from this new class of twisted amides is reported. Through reactivity studies we demonstrate unusual properties of the amide bond, wherein selective cleavage of the amide bond can be achieved by a judicious choice of the reaction conditions. Through computational studies we evaluate structural and energetic details pertaining to the amide bond deformation. The ability to selectively twist common primary amides, in a reversible manner, has important implications for the design and application of the amide bond nonplanarity in structural chemistry, biochemistry and organic synthesis.

Full text of DOI:10.1021/jacs.7b11309

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Article
Reversible Twisting of Primary Amides via Ground State N–C(O)
Destabilization: Highly Twisted Rotationally-Inverted Acyclic Amides
Guangrong Meng, shicheng shi, Roger A Lalancette, Roman Szostak, and Michal Szostak
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 14 Dec 2017
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Reversible Twisting of Primary Amides via Ground State N–C(O)
Destabilization: Highly Twisted Rotationally-Inverted Acyclic Am-
ides
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Guangrong Meng,†,§ Shicheng Shi,†,§ Roger Lalancette,† Roman Szostak,‡ and Michal Szostak*,†
†Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States
‡Department of Chemistry, Wroclaw University, F. Joliot-Curie 14, Wroclaw 50-383, Poland
Supporting Information
ABSTRACT: Since the seminal studies by Pauling in 1930s, planarity has become the defining characteristic of the amide bond.
Planarity of amides has central implications for the reactivity and chemical properties of amides of relevance to a range of chem-
ical disciplines. While the vast majority of amides are planar, non-planarity has a profound effect on the properties of the amide
bond, with the most common method to restrict the amide bond relying on the incorporation of the amide function into a rigid
cyclic ring system. In a major departure from this concept, here, we report the first class of acyclic twisted amides that can be
prepared, reversibly, from common primary amides in a single, operationally-trivial step. Di-tert-butoxycarbonylation of the
amide nitrogen atom yields twisted amides in which the amide bond exhibits nearly perpendicular twist. Full structural charac-
terization of a range of electronically-diverse compounds from this new class of twisted amides is reported. Through reactivity
studies we demonstrate unusual properties of the amide bond, wherein selective cleavage of the amide bond can be achieved by
a judicious choice of the reaction conditions. Through computational studies we evaluate structural and energetic details per-
taining to the amide bond deformation. The ability to selectively twist common primary amides, in a reversible manner, has
important implications for the design and application of the amide bond non-planarity in structural chemistry, biochemistry and
organic synthesis.
Introduction
The amide bond represents one of the most vital functional
groups in chemistry and biology.1–3 As predicted by the Pau-
ling’s resonance theory,4 the vast majority of amides are pla-
nar,5 which has important implications for the reactivity (e.g.
neutral hydrolysis of unactivated amides has a half-life of ca.
500 years),6 structure (e.g. α-helix as a fundamental building
block of proteins)7 and chemical properties (e.g. vastly pre-
ferred O-protonation)8 of amides. Extensive studies have
shown that deviations of the amide bond from planarity
greatly affect the stability and reactivity of amides.9 Further-
more, amide bond twisting has been proposed as a central
design element of enzymatic processes, including cis-trans
isomerization,10 amide hydrolysis11 and protein splicing.12
Recently, amide bond twisting has been demonstrated as a
part of the mechanism in protein N-glycosylation involving
primary carboxamide groups.13 Moreover, recent work has
implicated amide bond deformations as a controlling factor
for selective amide bond activation/cross-coupling,14 thereby
Figure 1. (a) Examples of highly distorted amides in cyclic frame-
works (classic bridged lactams). (b) Amide distortion by peripheral
coordination (Shibasaki et al.). (c-d) Reversible twisting of acyclic
primary amides by ground-state N–C(O) destabilization (this study,
insets show view along N–C(O) axis).
emphasizing the role of amide bond twist as an enabling
avenue in modern organic synthesis.15
The most common method to achieve amide bond twist-
ing relies on the incorporation of the amide function into a
rigid cyclic ring system (Figure 1A).9a-c These bicyclic bridge-
head lactams feature extreme geometric properties of struc-
turally-characterized amide bonds16 (Winkler-Dunitz distor-
tion parameters,17 up to τ = 90°, χN = 60°). However, the syn-
thesis of these lactams is notoriously challenging1–3 due to
severe diminution of amidic resonance (e.g. the landmark
syntheses of the parent 2-quinuclidonium tetrafluoroborate2
and 1-aza-2-adamantanone16e featured unique amide forming
transforms), and typically this distortion method cannot be
adapted to readily-available common acyclic amides.
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Recently, Kumagai, Shibaski et al. devised a new type of
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non-planar amides bearing predominantly pyramidalized
amide bonds in which reversible deformation has been
achieved by peripheral coordination of Pd(II) to Lewis basic
nitrogen moieties (Figure 1B).18 The method resulted in am-
ides with remarkable deformations from planarity of up to χN
= 56° and τ = 19°. However, the identification of peripheral
coordination in these structurally intriguing amides renders
the direct distortion of common acyclic amides more chal-
lenging. In addition, the emergence of specifically-tailored
N-tetramethylpiperidine (TMP),19 N-glutarimide20 and N-1,3-
thiazolidine-2-thione amides21 has provided controlled access
to non-planar amide bond geometries; however, these com-
pounds are synthesized from the corresponding carboxylic
acids and derivatives and often suffer from high susceptibil-
ity to hydrolysis as exemplified by TMP amides.19
Figure 2. One-step synthesis of twisted amides.
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Table 1. Summary of Structural Parameters for the X-
ray Structures of 2a–e and Reference Benzamidea
N–C(O)
C=O
τ
χΝ
τ+χΝ
Entry
2
(Å)
(Å)
(deg)
81.9
(deg)
1.1
(deg)
83.0
2a
2b
2c
1.483
1.201
1
2
With these considerations in mind, here, we report the
first class of acyclic twisted amides that can be prepared,
reversibly, from common primary amides22 in a single, opera-
tionally-trivial step (Figure 1C-D). Amide bond distortion is
triggered by selective di-tert-butoxycarbonylation of the am-
ide nitrogen atom furnishing twisted amides in which the
amide bond exhibits nearly perpendicular twist (up to τ =
82°). We report full structural characterization of a range of
electronically-varied amides, and demonstrate through reac-
tivity studies unusual properties of the amide bond in this
new class of twisted amides, wherein selective cleavage of the
N–C(O) or N–Boc bond can be achieved by a judicious choice
of the reaction conditions. Through computational studies23
we evaluate structural and energetic details pertaining to the
amide bond distortion. We demonstrate that the amide bond
deformation can be attributed to ground-state destabiliza-
tion,3 which results in the most twisted acyclic amide bonds
reported to date.1–3,9 Overall, our results demonstrate the
ability to selectively induce twist of common primary amides,
in a reversible manner, which may have broad implications
for the design and application of non-planar amides in bio-
chemistry, organic synthesis and molecular switching.24
1.458
1.467
1.433
1.418
1.414
1.205
1.200
1.206
1.205
1.209
1.265
59.2
72.5
38.3
28.9
20.0
0.0
0.2
3.6
59.4
76.1
43.0
48.4
46.8
0.1
3
2d
2e
2e’
4.7
4
5b
6b
7c
19.5
26.8
0.1
benzamide 1.342
Crystallographic data have been deposited with the Cambridge Crys-
tallographic Data Center. See SI for details and expanded tables.
bTwo independent molecules in the unit cell. cBenzamide, ref. 30.
ters of the corresponding parent benzamide.30 The structures
of amides 2a-e together with Newman projections along the
N–C(O) axis are presented in Figure 3. The structure of the
corresponding parent benzamide is shown in Figure 1D (see
the SI, Supporting Information, for expanded ORTEP struc-
tures). Notably, the well-studied availability of the crystal
structure of benzamide (1c, PhCONH2) allows comparison of
the parent amide and its N,N-Boc2 twisted amide product.
Remarkably, the structure of 2a (R = NMe2) shows that this
compound belongs to the most twisted amides isolated to
date (τ = 81.9°).1–3,9 Moreover, the N–CO amide bond length
of 1.483 Å in 2a is the longest recorded so far for an acyclic
amide derivative. The observed length for the C=O bond is
1.201 Å. Interestingly, nitrogen in 2a is basically sp2 hybrid-
ized (χN = 1.1°), indicating that 2a belongs to classic twisted
amides as defined by Yamada et. al. The X-ray structures of
2b-e (R = OMe, H, F, CN) reveal substantial twisting of the
amide bond. The N–C(O) twisting is approximately aligned
in the direction of the electron-density of the aromatic ring
(vide infra), while the nitrogen becomes pyramidalized for
more electron-withdrawing substituents. The amide 2e (R =
CN) was crystallized as two independent molecules in the
unit cell. Analysis of the pyramidalization at nitrogen angle
reveals significant pyramidalization in 2e (up to χN = 26.8° in
2e’). Pyramidalization at nitrogen has historically been one
of the most valuable parameters to describe structural distor-
tion of the amide bond.1–9 More recent studies demonstrated
that the additive amide bond distortion parameter, Σ(τ+χN),
provides a more accurate description of non-planarity of the
amide linkage.29 In the present case, it is likely that planarity
around the nitrogen atom plays a role in the O-protonation
of the amide oxygen despite high twist (vide infra).
Results and Discussion
Synthesis and Proof of Structure. Based on the experience
in the chemistry of amides, we began our study by isolating
N,N-di-Boc amides and growing single crystals of 2 (Figure
2). All amides 2 were prepared directly in one-step from the
corresponding benzamides25,26 by site-selective N,N-di-tert-
butoxycarbonylation of the amide bond under mild condi-
tions. It is worthwhile to point out that this widely-
applicable process enables to directly engage common pri-
mary amides in amide bond twisting.27 Since primary amides
are among the most ubiquitous amide derivatives in organic
synthesis and constitute widespread structural motifs in
pharmaceutical industry,22 the present study puts emphasis
on the use of common acyclic amides28 as models for amide
bond distortion and establishes a distinguishing feature of
this approach.
Amides 2a-e (R = NMe2, OMe, H, F, CN) were crystalline
and their structures could be confirmed by X-ray crystallog-
raphy (Tables 1-2, Figure 3). Table 1 summarizes the Winkler-
Dunitz distortion parameters (τ, χN), the additive distortion
parameter Σ(τ+χN),29 and selected bond lengths of the N,N-
Boc2-amides. The table also includes geometric parame-
It is instructive to compare structural parameters of the
parent benzamide30 (1c, R = H; τ = 0.0°; χN = 0.1°; N–C(O) =
1.342 Å; C=O = 1.265 Å, X-ray data) with the corresponding
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Figure 3. Crystal structures of amides 2a-e
.
2e: two molecules in the unit cell. Insets show Newman projections along N–C(O) bonds.
philicity of the amide bond and lengthening the N–
C(O) bond.
Table 2. Summary of Additional Bond Lengths (Å) and
Angles (deg) for the X-ray Structures of 2a–ea
(2) Moreover, a closer analysis reveals an excellent in-
verse linear correlation between the N–C(O) amide
bond length and the N–Boc bond length (R2 = 0.99)
(Chart 1B), and a good inverse linear correlation be-
tween the N–C(O) bond twist angle and the Ar–C(O)
twist angle (R2 = 0.86) (see the SI).
C1–C2
ω1
(deg)
-98.4
ω2
(deg)
-97.9
ω3
(deg)
81.0
ω4
(deg)
82.7
Entry
2
(Å)
2a
2b
2c
1.452
1
1.470
1.479
1.479
1.493
1.495
-58.8
71.6
-59.6
73.4
-34.9
18.1
120.5
-110.2
140.4
-142.4
146.8
121.0
-104.8
143.0
-159.9
173.2
2
3
4
5
6
2d
2e
2e’
-41.7
39.7
-33.6
(3) Finally, an excellent linear correlation between the
Ar–C(O) bond length and σ Hammett parameter is
observed (R2 = 0.99 (Chart 1C, see the SI for addition-
al plots and discussion).
-6.4
aω1 = C2–C1–N1–C3; ω2 = O1–C1–N1–C4; ω3 = O1–C1–N1–C3; ω4 = C2–
C1–N1–C4. See SI for details and expanded tables.
Collectively, the observed changes indicate that electron-
donating groups promote an increase of rotation around the
N–C(O) axis, which is accompanied by flattening of the Ar–
C(O) twist angle to reinforce Ar to π*C=O conjugation. Simul-
taneously, elongation of the N–C(O) bond is accompanied by
a reinforced nN to π*C=O(Boc) conjugation as evidenced by a
shortening of the N–Boc bond. Thus, on the basis of struc-
tural parameters, these amides can be regarded as electroni-
cally-tunable twisted amides, wherein electron-donor groups
switch-off amidic resonance.24e
N,N-Boc2 twisted amide 2c (R = H; τ = 72.5°; χN = 3.6°; N–
C(O) = 1.467 Å; C=O = 1.200 Å). As shown in Table 1, N,N-di-
tert-butoxycarbonylation dramatically enhances the twist
angle (from 0° to 72.5°). This is accompanied by a significant
increase of the N–C(O) bond length (by 0.125 Å) and a con-
siderable shortening of the C=O bond (by 0.065 Å). Moreo-
ver, the observed N–C(O) bond length in 2e’ (1.414 Å) is
shorter by 0.069 Å than the N–C(O) bond length in 2a (1.483
Å), while the C=O bond lengths in 2a (1.201 Å) and 2e’ (1.209
Å) differ by only 0.008 Å. Overall, these structural features in
2a-e structures indicate substantial amide bond deviation
from planarity upon N,N-di-tert-butoxycarbonylation. Fur-
thermore, the observed changes in the N–C(O) and C=O
bond lengths are consistent with classical amide resonance
model.1–3,23
Bending Angle. We have also calculated ξ (ξ, C=O bend-
ing angle) in 2a-e. This geometric parameter was recently
introduced by Stoltz et al. to provide an additional measure
of the stability of non-planar amides.16b We found positive ξ
values of 4.4° and 2.6° for 2a (R = NMe2) and 2b (R = OMe),
respectively, indicating bending toward nitrogen, while 2c (R
= H), 2d (R = F) and 2e/2e’ (R = CN) showed negative ξ val-
ues of–2.7°, –1.6° and –0.8°/–0.9°, respectively, indicating
bending toward the aromatic ring. The observed values of ξ
further support increased Ar to π*C=O conjugation for elec-
tron-donating groups as a consequence of destabilizing nO to
σC–C /stabilizing nO to σ*C–N interactions. Note that the ob-
served ξ value of 4.4° for 2a is in the range of the ξ value of
5.8° determined for the most twisted bridged lactam isolated
to date, namely 7-hypoquinuclidone BF3 complex,16b indicat-
ing an early stage of N–C(O) cleavage via oxocarbenium.
Detailed insight into the properties of 2a-e can be gained
from correlating structural and electronic parameters of the
amide bond. The availability of five fully characterized com-
pounds in one series allowed us for the first time to readily
compare the effect of distortion on properties of the amide
bond in twisted acyclic amides. The observed correlations are
summarized as follows:
(1) Remarkably, a plot of N–C(O) bond length vs. τ gives
an excellent linear correlation in the series (R2 = 0.99)
(Chart 1A). Thus, rotation around the N–C(O) bond
disrupts nN→π*
delocalization, increasing electro-
C=O
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Plot of N
−
C(O) Bond Length vs. Twist Angle
Plot of N
−
C(O) vs. N
−
Boc Bond Length
Plot of C
−
C Bond Length vs.
σ
Parameter
1.49
1.48
1.47
1.46
1.45
1.44
1.43
1.42
1.41
1.49
1.48
1.47
1.46
1.45
1.44
1.43
1.42
1.41
1.50
1.49
1.48
1.47
1.46
1.45
y = -1.7503x + 3.930, R2 = 0.991
y = 0.0012x + 1.349, R2 = 0.990
y = 0.0277x + 1.4767, R2 = 0.999
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1.39
1.40
1.41
1.42
1.43
1.44
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
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τ [°]
σ
N−Boc [Å]
) for amides 2a-e. (b) Correlation of N–C(O) bond length [Å] to
Chart 1. (a) Correlation of N–C(O) bond length [Å] to twist angle (
N–Boc bond length [Å] for amides 2a-e. (c) Correlation of C–C bond length [Å] to Hammett parameter for amides 2a-e (X-ray data).
τ
σ
amides do not benefit from the thermodynamic stability af-
forded by a scaffolding effect of the medium-sized ring,16f,g
which rules out reversibility of the amide bond hydrolysis.
Furthermore, 2c is remarkably stable to acidic conditions
(Scheme 1A, see SI, page 14, for additional examples). For
example, incubation of 2c with HBF4 (2 equiv) in CH3CN at
23 °C for 15 h had no impact of the recovery of starting mate-
rial (vide infra). In addition, amide 2c is recovered un-
changed from common nucleophilic solvents (e.g., DMSO,
MeOH, 23 °C, 7 days, see SI). Amide 2c is also very stable in
aqueous solutions (e.g., D2O:CH3CN, 1:1, v/vol, 75% recovery,
23 °C, 7 days, vide infra). Collectively, these studies unam-
biguously demonstrate that acyclic twisted amides 2 show
substantially higher stability to nucleophilic N–C(O) cleav-
age than classical bridged lactams. We note that the high
stability of amides 2 bodes well for the development of syn-
thetically-valuable reactivity governed by amide bond twist
in easily accessible from 1° amides twisted acyclic amides.27
Scheme 1. N–C(O) Cleavage Reactivity of Amides 2
Scheme 2. Thermal and Acid-Mediated Deconstruc-
tion of Amides 2: N–Boc Cleavage
Despite high stability to nucleophilic cleavage relative to
other classes of twisted amides, amides 2 react with nucleo-
philes under neutral conditions, i.e. in the absence of addi-
tional Lewis bases (Scheme 1B). For instance, the reaction of
2c with MeOH (neat, 100 °C) or aniline (2.0 equiv, CH3CN,
100 °C) cleanly affords the corresponding ester or amide by
N–C(O) nucleophilic opening. Moreover, amides 2 react in-
stantaneously with organometallic reagents, such as PhLi, at
-78 °C resulting in exhaustive nucleophilic addition (Scheme
1C). The formation of acetophenone is not observed, even
when limiting organometallic reagent is used. This is in
sharp contrast to bridged lactams, which react by stable tet-
rahedral intermediates due to the lack of nO to σ*C–N over-
lap,31 but also differs from N,N-dialkylbenzamides (e.g. dime-
thylbenzamide), which give approx. 2:1 mixture of ke-
tone:alcohol using the organometallic reagent in excess.32
Collectively, these reactions demonstrate that while amides 2
show high stability, a property important from the practical
standpoint, in the reactions with organometallic reagents
these amides behave as acylating reagents with reactivity
reminiscent of acyl halides.
Chemical Reactivity. It is well-established that deviations
of the amide bond from planarity engender unusual reactivi-
ty of amides as a result of diminished resonance, including
(1) hypersensitivity to hydrolysis, (2) N-protonation, and (3)
high susceptibility to nucleophilic addition.1–3,9 An interest-
ing feature from the reactivity perspective, N–C(O) cleavage
reactions substantially impact the overall applicability of
non-planar amides.2,9c Having established a survey of struc-
tural properties of acyclic twisted amides 2, next, we exam-
ined their chemical reactivity. The parent amide 2c (R = H)
was used as a model substrate.
The most remarkable feature of the reactivity of amides 2
is their capacity to revert to benzamides upon a judicious
choice of the reaction conditions (Scheme 2).33 We found
that a simple exposure of amides 2 to thermal (120 °C,
CH3CN, 24 h) or acidic (HCl, 2 equiv, CH3CN, 80 °C, 24 h)
conditions results in fully chemo- and regioselective (vs. am-
ide acyl N–C(O) bond) cleavage of the carbamate N–Boc
As expected, the chemical reactivity of amides 2 is remark-
able. Most notably, although twisted amides with a similar
amide bond distortion are hypersensitive to hydrolysis,9 we
found that incubation of amide 2c in aqueous CH3CN (10
equiv of H2O) at 80 °C for 15 h afforded only recovered start-
ing material (Scheme 1A). Importantly, these acyclic twisted
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bonds likely via thermal/acid-mediated deprotection of the
to furnish primary amides, which appears to be more chal-
lenging with N,N-(CO2Et)2-benzamides.
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carbamate group (see SI, page 19, for additional discussion).
Note that the reaction was completely regioselective with
respect to the C–N bond that is less distorted from the C=O π
system, in contrast to the previous examples of N–C cleavage
of twisted amides.16g,34
Energetic Parameters. Computational studies were con-
ducted to gain further insight into the structures of N,N-
Boc2-twisted amides.23,29 Specifically, energetic parameters
were analyzed to address the origin of amide bond defor-
mation in these twisted amides.37
Overall, these results unambiguously demonstrate novel
reactivity of non-planar acyclic amides 2. Importantly, in
combination with the rapid access to N,N-Boc2 twisted am-
ides from common primary amides (Figure 2),25 these studies
illustrate the capacity to readily change molecular confor-
mation around the amide bond in a highly efficient manner.
To the best of our knowledge, this is the first example of a
rapid formation/deconstruction of a twisted amide bond
from the corresponding primary amide.1–3,9 The abundance of
primary amides22 renders this process particularly attractive
for a plethora of synthetic applications.
Scheme 5. Conformational Equillibria of Amides and
Twisted Amides
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Scheme 3. Stability of Amides 2 in Aqueous Solutions
Scheme 4. Reactivity of N,N-(CO2Et)2-Benzamide (cf.
N,N-Boc2-Benzamide as in Scheme 2)
Acyclic amides typically adopt a trans conformation
around the amide bond; however, conformational prefer-
ences can be influenced by sterics and non-covalent interac-
tions38 (Scheme 5A-B). Principally, symmetrical acyclic imides
may exist in three conformations: cis-cis, cis-trans, and trans-
trans, while the presence of an additional N-acyl rotor yields
further cis-trans’ conformation (Scheme 5C).39 Interestingly,
we observed all four possible conformations in the solid state
(Figure 3, cis-cis: R = CN-1, 2e; cis-trans: R = H, 2c; F, 2d;
trans-trans: R = NMe2, 2a; OMe, 2b; cis-trans’: R = CN-2, 2e’).
Geometry optimizations were performed using amides 2a-e.
Amides R = CF3 (2f), Cl (2g), NO2 (2h) were also included for
comparison due to potential synthetic utility of these sub-
strates. Calculations predict the following order of conformer
stability: cis-trans’ > trans-trans > cis-trans > cis-cis, in
agreement with the repulsive 1,5-syn-pentane type interac-
tions between imide oxygens (cis- cis) and electronic repul-
sion of the imide carbonyls (trans-trans).40 The cis-trans’
conformer is more stable than cis-trans due to avoidance of
1,5-nonbonding interactions between the carbonyl groups.
However, the energy difference between the conformers is
negligible and ranges between 0.0-1.5 kcal/mol (R = CN) to
0.0-2.1 kcal/mol (R = NMe2).
As noted earlier, amides 2 are very stable to aqueous con-
ditions. We showed that the reaction of 2c with D2O:CH3N
(1:1, v/vol) at room temperature led to the recovery of 2c and
production of the parent benzamide 1c in a 3:1 ratio after 7
days (Scheme 3). Thus, deconstruction of these twisted am-
ides under mild, aqueous, thermodynamic conditions also
appears to be synthetically accessible.
To gain insight into the factors that contribute to the rapid
formation and deconstruction of acyclic twisted N,N-Boc2-
amides, synthesis of the corresponding N,N-(CO2Et)2-
benzamide was studied (6, see SI). Under various conditions,
only trace quantities of the product were formed with the
majority of the mass balance corresponding to mono-
acylation. Nevertheless, we were able to isolate the di- acyla-
tion product (6) and subject this amide to stability studies
(Scheme 4). We found that (6) shows even higher stability
than the corresponding N,N-Boc2-benzamide.26
From the synthetic and stability studies of amides 2 and 6,
we conclude that (1) the observed reactivity in the synthesis
of N,N-Boc2-amides is consistent with sterically-induced O-
to N-acyl transfer;35 (2) the observed reactivity in the stability
studies is consistent with N,N-Boc2 cleavage reactivity path-
way induced by thermal/acid-mediated deprotection of the
carbamate.36 (3) Computational studies (vide infra) demon-
strate that t-Bu group is not critical to amide bond distortion
(t-Bu vs. Et). High yields and stability of N,N-Boc2 amides
make the lack of success to rapidly prepare N,N-(CO2Et)2-
benzamide inconsequential to the overall picture. Moreover,
N,N-Boc2 amides undergo reagent-controlled deconstruction
Resonance energies of the amide bond in the parent amide
(R = H) were calculated using the COSNAR method.23a Reso-
nance energy in 2c (RE = 6.3 kcal/mol) is much lower than in
planar amides5a,f (approx. 65% decrease in amidicity com-
pared with the planar N,N-dimethylacetamide, RE = 18.3
kcal/mol). Moreover, calculations predict the amide bond
resonance energy in the corresponding N,N-Boc2-acetamide
(2i) as 7.6 kcal/mol, also dramatically lower than in N,N-
dimethylacetamide (60% decrease in amidicity), and this is
in line with the activating effect of N,N-Boc2 substitution in
both aromatic and aliphatic amides (eq. 1).
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Plot of N
−
C(O) Bond Length vs. Twist Angle (cis-trans')
Plot of N
−
C(O) vs. C
−
C Bond Length (cis-trans')
Plot of N
−
C(O) Bond Length vs.
σ Parameter (cis-trans')
1.47
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1.42
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1.46
1.45
1.44
1.43
1.42
1.47
1.46
1.45
1.44
1.43
1.42
y = -1.4179x + 3.549, R2 = 0.988
y = 0.0023x + 1.350, R2 = 0.998
y = -0.0243x + 1.445, R2 = 0.990
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1.500
-1.0 -0.8 -0.6 -0.4 -0.2 0.0
0.2
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σ
C−C [Å]
τ [°]
Chart 2. (a) Correlation of N–C(O) bond length [Å] to twist angle (τ) for amides 2a-h. (b) Correlation of N–C(O) bond length [Å] to C–C bond
length [Å] for amides 2a-h. (c) Correlation of N–C(O) bond length [Å] to Hammett σ parameter for amides 2a-h (cis-trans’, B3LYP/6-311++G(d,p)
data).
energy minimum at ca. 50° O–C–N–C angle) with significant-
ly reduced barrier to rotation (cf. planar amides). Generally
speaking, the amide N–C(O) bond rotates from planarity to
avoid steric interaction with the carbamate substituents.9b In
contrast to typical cyclic twisted amides, the N–C(O) rotation
occurs primarily as a consequence of N,N-Boc2 substitution,
which enables alternative nN to π*C=O delocalization. This is
further supported by a rotational profile of N,N-Boc2-
acetamide (2i), which shows energy minimum at ca. 0°, while
the energy reaches maximum at ca. 90°, in a close analogy to
dimethylacetamide, but at a dramatically lowered rotational
barrier. During the O–C–N–C amide rotation, the N,N-Boc2
linkage rotates along the N–C carbamate axes as measured
by C–N–C=O and C–N–C–O carbamate dihedral angles. The
rotational barrier was determined to be 3.33 kcal/mol (R =
Ph, 0° O–C–N–C angle), and 5.63 kcal/mol (R = Me, 90° O–
C–N–C angle).
In contrast, resonance energies of the N-Boc carbamate
groups in both the parent N,N-Boc2-benzamide (2c) and
N,N-Boc2-acetamide (2i) are significantly lower: 2c, 1.3 and 1.5
kcal/mol; 2i, 2.4 and 0.0 kcal/mol, and indicate that RE of the
N–Boc bonds are almost completely switched off as a result
of electronic activation. The low energy difference between
the conformers and the ability to freely-rotate the carbamate
substituents accounts for the difference in conformers ob-
served in the solid state. It is well-established that crystal
packing can influence molecular conformation.41
As a further support of this notion, an excellent correlation
between the N–C(O) bond length and twist angle for amides
2a-e for the X-ray conformations has been found (R2 = 0.99,
see the SI). Furthermore, our analysis of the calculated struc-
tures for the most stable cis-trans’ conformation reveals an
excellent N–C(O) vs. τ correlation for amides 2a-h (R2 = 0.99,
Chart 2A). Similarly, N–C(O) bond length correlates well
with the Ar–C(O) bond length (R2 = 0.99, Chart 2B) and with
the Hammett σ parameter (R2 = 0.99, Chart 2C) for the most
stable cis-trans’ conformation for the expanded set of N,N-
Boc2 activated amides 2a-h. Moreover, separate analyses on
the less stable but accessible cis-cis, cis-trans, and trans-trans
conformations reveal similar relationship between structure
and geometric properties in the series (see the SI for addi-
tional discussion).
Finally, the unique properties of twisted N,N-di-Boc am-
ides are demonstrated by the protonation aptitude. As a con-
sequence of nN→π*C=O conjugation, there is a strong intrinsic
bias for protonation of planar amides at the oxygen atom
(e.g., 1-Me-pyrrolidinone, ꢀPA = 14.8 kcal/mol).23b Twisted
amides often undergo selective N-protonation with the N-
/O-protonation switch proposed to occur around the amide
bond geometry corresponding to Σ(τ+χN) = 50-60°.29a In this
context, Greenberg and co-workers reported an interesting
O-to-N crossover in the protonation of bicyclic lactam 1-
azabicyclo[3.3.1]nonan-2-one (τ = 20.8°; χN = 48.8°; Σ(τ+χN) =
69.6°), wherein the presence of both protonated tautomers
was observed by 1H and 13C NMR spectroscopy.16h
The computational data closely parallel the experimental
properties of the amide bond in 2. As expected, computed
data provide improved correlations vs. solid state struc-
tures.23,29
Remarkably, proton affinities (PA) in the parent amide 2c
(R = H) indicate that these N,N-Boc2 twisted amides vastly
favor protonation at the amide oxygen atom despite signifi-
cant amide bond twist (ꢀPA = 17.4 kcal/mol, vs. nitrogen).
The viability of the proposed ground-state destabilization
of amides 2 as the major contributor to amide deformation
was further studied by obtaining a detailed rotational profile
of the parent amide 2c by systematic rotation along the O–C–
N–C dihedral angle. The rotation was performed in both di-
rections. We employed the X-ray structure of N,N-Boc2 ben-
zamide as the starting geometry and performed full optimi-
zation. Figure 4 shows rotational profile of 2c (R = Ph) in
comparison with 2i (R = Me) and N,N-dimethylacetamide
(DMAC). Rotational profile in 2c confirms inverted rotation
in 2c (the energy maximum at ca. 0° O–C–N–C angle; the
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In conclusion, we have reported the first class of acyclic
Plot of Energy vs. O−C−N−C Dihedral Angle
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twisted amides that can be prepared directly, in a reversible
manner, from ubiquitous primary amides in a single opera-
tionally-trivial step. More importantly, our data demonstrate
the propensity of common acyclic amides to participate in
amide bond deformation pathways that can be attributed to
ground-state destabilization of the amide bond, resulting in
the most twisted acyclic amide bonds reported to date.
Mechanistic and synthetic studies have provided insight into
the structural and energetic properties of the amide bond
and showed evidence for controlled generation/ deconstruc-
tion of acyclic twisted amides, wherein selective cleavage of
the N–C(O) or N–Boc bond can be achieved by controlling
the reaction conditions. On a fundamental level, our studies
show that these structures are best represented as classic
twisted amides as defined by Yamada et al., providing an
alternative to generating substantial non-planarity of the
amide bond without resorting to complex frameworks. Fu-
ture work will focus on evaluating the generality of amide
deformation modes that activate the amide linkage toward
unusual reactivity. We fully expect that the results presented
herein will contribute to a better understanding of the prop-
erties of the amide bond, including in structural chemistry
and metal catalyzed reactions of amides. Further studies as
well as the development of catalytic processes enabled by
amide bond distortion of common primary amides are in
progress.
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DMAc
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-2
-150
-100
-50
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100
150
O−C−N−C [°]
Figure 4. Correlation of ꢀE [kcal/mol] to O–C–N–C [°] in 2c, 2i and
DMAc (N,N-Dimethylacetamide).
Protonation of the carbamate carbonyls is energetically ac-
cessible in 2c (ꢀPA = 15.0 and 19.9 kcal/mol, vs. nitrogen),
while N,N-Boc2-acetamide (2i) favors protonation at the am-
ide oxygen atom (ꢀPA = 20.3 kcal/mol, vs. nitrogen; carba-
mates: ꢀPA = 18.7 and 19.7 kcal/mol, vs. nitrogen). Note that
while O-protonation at the amide oxygen leads to flattening
of the amide bond (2c: τ = 40.1°; N–C(O) = 1.442 Å; 2c-OH+: τ
= 8.0°; N–C(O) = 1.355 Å), the switchable O-/O-protonation
of the carbamate oxygen leads to a very significant increase
of twist (2c: τ = 40.1°; N–C(O) = 1.442 Å; 2c-OH+: τ = 87.3°; N–
C(O) = 1.542 Å), activating the amide bond towards nucleo-
philic addition. Thus, these twisted amides present an excit-
ing potential for switchable N–C(O) to N–Boc protonation at
the oxygen atom to trigger the electrophilic reactivity of the
amide bond.42 As expected, protonation of the carbamate
oxygen twists the acyl-amide bond, activating the N–C(O)
bond towards nucleophilic addition.
ASSOCIATED CONTENT
Supporting Information
Experimental details, characterization data, Cartesian coor-
dinates, energies with zero-point energy and thermal correc-
tions, CIF files for amides 2a-e. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
michal.szostak@rutgers.edu
Finally, it is worthwhile to point out that in the case of
N,N-Boc2 amides, the twisting occurs as a consequence of
both steric and electronic activation of the acyclic amide
bond. As such, these amides could also be referred to as N-
acyl-imides rather than N,N-diacyl-amides. According to the
IUPAC Gold Book, amides are denoted as compounds in
which “acidic hydroxy group has been replaced by an amino
or substituted amino group”, while imides are denoted as
“diacyl derivatives of ammonia or primary amides”.43 In the
present case, N,N-Boc2 amides may indeed be described as
N-acylimides rather than N,N-diacylamides. However, the
major difference originates from the synthetic disconnection
by which the twisted amide bond is formed. In this regard,
N,N-Boc2 amides are unique from all other acyl- or acyl-type
amide derivatives because these non-planar amides can be
routinely prepared from the corresponding primary ben-
zamides. This is distinct from N-acyl-glutarimides,20 Yamada
amides,21 or related compounds1–4,19 which are prepared by
acylation of the imide component. The presented results
demonstrate the first examples of reversible twisting of the
amide bond, thereby providing novel handles on structure
and reactivity of readily accessible acyclic benzamides.
§
These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Rutgers University and the NSF (CAREER CHE-1650766) are
gratefully acknowledged for support. The Bruker 500 MHz
spectrometer used in this study was supported by the NSF-
MRI grant (CHE-1229030). We thank the Wroclaw Center for
Networking and Supercomputing (grant number WCSS159).
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