The Most Twisted Acyclic Amides: Structures and Reactivity

Article abstract of DOI:10.1021/acs.orglett.8b03175

The synthesis, crystal structures, and reactivity of the most twisted acyclic amides described to date are reported. Substitution at the nitrogen atom in simple benzamides with Ts and acyl or carbamate groups provides a unique way to achieve almost perpendicular twist in N-acyclic amides (= 77°, N = Ac; = 87°, N = Boc). The overlap between the Nlp and CO π? orbital is disrupted due to geometrical constraints around the N-substituents. The perpendicular acyclic twisted amides represent a transition state mimic of cis-trans peptide isomerization thus far only accessible by excessively twisted bridged lactams.

Full text of DOI:10.1021/acs.orglett.8b03175

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
The Most Twisted Acyclic Amides: Structures and Reactivity
Chengwei Liu, Shicheng Shi,† Yongmei Liu, Ruzhang Liu, Roger Lalancette,
†
†,§
§
†
Roman Szostak,‡ and Michal Szostak*
,†
†
Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States
College of Chemistry and Chemical Engineering, Yangzhou University, 180 Siwangting Road, Yangzhou 225002, China
Department of Chemistry, Wroclaw University, F. Joliot-Curie 14, Wroclaw 50-383, Poland
§
‡
*
S Supporting Information
ABSTRACT: The synthesis, crystal structures, and reactivity of the most twisted acyclic amides described to date are reported.
Substitution at the nitrogen atom in simple benzamides with Ts and acyl or carbamate groups provides a unique way to achieve
almost perpendicular twist in N-acyclic amides (τ = 77°, N = Ac; τ = 87°, N = Boc). The overlap between the Nlp and CO π*
orbital is disrupted due to geometrical constraints around the N-substituents. The perpendicular acyclic twisted amides
represent a transition state mimic of cis−trans peptide isomerization thus far only accessible by excessively twisted bridged
lactams.
hemists have long strived to prepare fully perpendicular
not reach perpendicularity characteristic to 1-aza-2-adamanta-
none and 2-quinuclidonium tetrafluoroborate.
1
,2
6
7
C
amides. However, disruption of amidic resonance (nN
conjugation, Figure 1A) is not trivial, despite it
→
π*
Herein, we report the synthesis, the crystal structures and
reactivity of the most twisted acyclic amides crystallized to date
(Figure 1C). We demonstrate that substitution at the nitrogen
atom in simple benzamides with Ts and acyl or carbamate
groups provides a unique way to achieve almost perpendicular
twist in N-acyclic amides (τ = 77°, N = Ac; τ = 87°, N = Boc),
further emphasizing the utility of steric repulsion, as defined by
CO
being proposed in numerous biological processes, including
peptide hydrolysis, peptide folding, and cis−trans isomer-
3
,4
2
ization of proteins. Following the early proposal by Lukes,
̌
the first example of a substantially twisted amide was reported
by Yamada in 1993 using a conformationally constrained 1,3-
5
thiazolidine-2-thione (Figure 1B, τ = 74°). The structural
characterization of 1-aza-2-adamantanone by Kirby in 1998
10c
Yamada, as a means to achieving full distortion of the amide
6
(
Figure 1B, τ = 89.5°) and 2-quinuclidonium tetrafluor-
12,13
bond.
7
oborate by Stoltz in 2006 (Figure 1B, τ = 89.2°) represented a
major breakthrough. Another intriguing example of a doubly
twisted amide was reported by Harrison (Figure 1B, τ = 66.4°
Amides 1 and 2 were prepared by the acylation route in 46%
and 72% yields on gram scale, respectively (amine, benzoyl
chloride, 1.0 equiv, DMAP, 0.50 mol %, Et N, 2.0 equiv,
8
3
and 54.3°) using a 2,5-dithioglycoluril scaffold, wherein severe
CH Cl , RT), and were conveniently purified by chromatog-
2
2
ring strain and nonbonding interactions forced the pivaloyl
groups to heavily deviate from the amide bond planarity.
Our studies have focused on a family of nonplanar N-
raphy on silica gel. Crystals suitable for X-ray crystallography
were obtained by slow evaporation from CH Cl (1, mp = 76−
2
2
9
78 °C; 2, mp = 80−81 °C). ORTEP drawings showing two
orthogonal representations of 1 and 2 along with Newman
projections along N−C(O) bonds are shown in Figure 2.
Almost perfect perpendicular arrangement around the amide
bond in 2 should be noted. Table 1 summarizes the key
geometric parameters of amides 1 and 2, including relevant
bond lengths (entries 1−5), dihedral angles (entries 6−9), the
acylglutarimides, which although severely twisted, have been
limited to an N-cyclic substituent that cannot be rationally
modulated and clearly represents a unique case in comparison
10
with other related structures. Furthermore, we recently
demonstrated a reversible twisting of N,N-Boc2 amides
characterized by a twist angle of 72.5° in the parent
1
1
compound. Although the high lability of the N-Boc
substituents enabled reversible deprotection of twisted amides,
this instability limited the scope of valuable processes of the
nonplanar amide bond, and furthermore, these amides could
Received: October 5, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03175
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Selected Geometric Parameters of Amides 1 and 2
entry
parameter
N1−C1
C1−O1
C1−C3
N1−C2
value for 1
value for 2
1
2
3
4
5
6
7
8
9
1.481(2)
1.201(2)
1.470(2)
1.406(2)
1.681(1)
110.4(2)
95.8(2)
−68.3(2)
−85.5(1)
76.9,15.9,1.3
92.8
1.486(2)
1.193(2)
1.483(2)
1.404(2)
1.679(1)
91.4(1)
94.2(1)
−87.2(2)
−87.2(1)
87.2,1.4,1.4
88.6
N1−S1
C3−C1−N1−C2
O1−C1−N1−S1
O1−C1−N1−C2
C3−C1−N1−S1
τ, χ , χ
10
11
12
N
C
τ + χN
θ
358.1
360.0
a
This study. X-ray structures. Bond lengths and angles are given in
angstroms/degrees. For structural parameters of representative
twisted amides, see ref 13a,b and ref 14.
It is further interesting to note that the N−CO amide bond
lengths of 1.481 Å in 1 and 1.486 Å in 2 are the longest
5
−11
reported for acyclic amides.
These values can be compared
5
with Yamada’s amide (N−CO = 1.448 Å) and Kirby’s most
Figure 1. (a) Amide resonance model. (b) Examples of excessively
twisted amides. (c) Most twisted acyclic amides (this study).
6
twisted amide (N−CO = 1.475 Å) in the neutral form.
Furthermore, the CO bond lengths of 1.201 Å in 1 and
1
=
.193 Å in 2 are in the same range as in Kirby’s amide (CO
1.196 Å). Notably, the nitrogen atom in 1 and 2 is practically
Winkler−Dunitz distortion parameters (entries 10 and 11),
and the sum of angles around the nitrogen atom (entry 12).
Notably, the structures of 1 (τ = 76.9°) and 2 (τ = 87.2°)
show that the benzoyl amides are extremely twisted, while their
twist angles represent the highest τ values reported to date for
planar (1, χ = 15.9°, θ = 358.1°; 2, χ = 1.4°, θ = 360.0°). As
N
N
a consequence, amides 1 and 2 are best defined as classic
twisted amides with the N−C(O) plane perpendicular to the
2
5,10c
N-substituents in an sp arrangement.
As expected,
pyramidalization at the carbon atom (1, χ = 1.3°; 2, χ =
C
C
5
−11
simple N-acyclic amides.
It is particularly noteworthy that
1.4°) is not affected by the geometrical changes of the amide
13
the twist angle in 2 matches the perpendicularity thus far
characteristic only to bridged and hypersensitive to hydrolysis
of 1-aza-2-adamantanone and 2-quinuclidonium tetrafluorobo-
bond.
The additive Winkler−Dunitz distortion parameter (τ + χ )
N
provides a useful description of the properties of nonplanar
6
,7
14
rate.
amides. The (τ + χ ) values of 92.8° and 88.6° in 1 and 2,
N
Figure 2. Two different views of the graphical representation of 1 and 2. Inset shows Newman projection along N−C(O) bonds. Note the almost
perfect perpendicular arrangement around the amide bond in 2. Hydrogen atoms have been omitted for clarity, 50% ellipsoids. (1, C H NO S,
1
6
15
4
monoclinic, space group P21/n, a = 7.6777(4) Å, b = 15.0221(8) Å, c = 13.1271(8) Å, β = 95.618(4)°, T = 100 K, Z = 4, R1 = 0.044; 2,
C H NO S, monoclinic, space group C2/c, a = 26.595(5) Å, b = 9.089 (2) Å, c = 16.938 (3) Å, β = 119.43 (3)°, T = 100 K, Z = 8, R1 = 0.036.)
19
21
5
See the SI for details and expanded tables.
B
DOI: 10.1021/acs.orglett.8b03175
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Organic Letters
Letter
of 1698 cm−
1
respectively, further highlight that the overlap between the Nlp
and CO π* orbital is disrupted due to steric interactions
around the N-substituents. Furthermore, it should be noted
IR data is less straightforward. The benzoyl ν
C=O
−
1
(1) and νC=O of 1697 cm (2) indicate highly electrophilic
amide carbonyls in these amides and are close to the range
expected for saturated ketones. Ongoing studies are focused on
determining the effect of twist on IR data in a broader range of
acyclic amides. Likewise, it should be noted that in these
amides twisting occurs as a consequence of both steric and
electronic activation of the amide bond. Accordingly, these
amides could also be referred to as N-sulfonylimides.
According to the IUPAC definition, amides are compounds
in which the “acidic hydroxy group has been replaced by an
amino or substituted amino group.” As such, it is critical that
when referring to twisted amide bonds a correct N−C(O)
bond is assigned as the twisted bond. In a broader sense, it is
important to note that it is possible that even more twisted
amides than 1 and 2 have already been synthesized, but their
twist remains unknown. In general, there are very few examples
of extremely twisted amides with twist values approaching 90°.
Future work will focus on expanding the current understanding
of amide bond twist in cyclic and acyclic amides.
that the N-acetyl group in 1 is practically planar (τ = 4.6°, χ =
N
1
6.4°, N−C(O) = 1.406 Å, CO = 1.208 Å), indicating that
the twist around the N−Ac group is relieved by rotation
around the N−Bz bond.
Significantly, the unique structures of 1 and 2 in conjunction
15,16
9
−11
with the literature data
permit us to arrange the effect of
N-substitution on the twist of acyclic amides in the following
order: Boc/Ts > Ac/Ts > Boc/Boc > R/Ac > R/Boc > R/Ts.
The stability, ease of synthesis, and flexibility in the preparation
of analogues are additional positive factors that should be
taken into account when considering using the steric repulsion
10c
method to attain amide bond distortion.
Given the unique structures of 1 and 2, we performed
preliminary reactivity studies to gain insight into the properties
of the perpendicular amide bond (Scheme 1). While it is well-
Scheme 1. N−C(O) Cleavage Reactivity of Amides 1 and 2
In summary, we have reported the synthesis and full
structural characterization of the most twisted acyclic amides
described to date. Upon judicious N-substitution, the overlap
between the lone pair at nitrogen and the carbonyl π system is
disrupted, which results in full rotation around the N−C(O)
axis. The twist angle of 87° for the first time matches
perpendicular twist inherent thus far only to 1-aza-2-
adamantanones and 2-quinuclidones. The method of amide
bond twisting by geometric distortion in acyclic amides
represents a powerful approach to unveil properties of the
10a−c
nonplanar amide bond.
Further work on mechanistic
investigations of amide bond twisting and the preparation of
new analogues of twisted acyclic amides is ongoing and will be
reported in due course.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03175.
established that excessively twisted bridged lactams, such as 1-
aza-2-adamantanones and 2-quinuclidones, suffer from hyper-
6
,7
reactivity of the amide bond toward hydrolysis,
we
Experimental details, characterization data, and crystallo-
graphic details for amides 1 and 2 (PDF)
hypothesized that the special characteristics of twisted acyclic
amides might enable convenient handling, thus making this
class of compounds particularly attractive as models of a fully
perpendicular amide bond. Indeed, although twisted lactams
with similar amide distortion undergo rapid hydrolysis, we
Accession Codes
CCDC 1870944−1870945 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
found that incubation of amides 1 and 2 in aqueous CH CN
3
(
(
1:1 v/vol) for 15 h afforded only recovered starting material
Scheme 1A). Furthermore, amides 1 and 2 serve as highly
reactive acylating reagents, as expected from high twist and
exemplified in the reactions with amines (Scheme 1B). Note
that full selectivity in nucleophilic scission was observed in that
AUTHOR INFORMATION
11
■
only the twisted amide bond underwent the cleavage. Finally,
we demonstrated that both amides 1 and 2 behave as highly
reactive acylating reagents in the transition-metal-catalyzed N−
Corresponding Author
*E-mail: michal.szostak@rutgers.edu.
ORCID
17
C(O) Suzuki cross-coupling (Scheme 1C). These prelimi-
nary studies provide a solid foundation for the development of
an array of reactions of twisted acyclic amides and bring about
the key advantage of high stability over conventional bridged
lactams.
Chengwei Liu: 0000-0003-1297-7188
Shicheng Shi: 0000-0001-8124-9235
Ruzhang Liu: 0000-0002-9569-2622
Roger Lalancette: 0000-0002-3470-532X
Roman Szostak: 0000-0002-5436-7284
Michal Szostak: 0000-0002-9650-9690
The carbonyl stretching frequency in the IR data can reveal
14b
the presence of twisting in nonplanar amides. However, in
our experience, the correlation between amide distortion and
C
DOI: 10.1021/acs.orglett.8b03175
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Notes
(c) Kemnitz, C. R.; Loewen, M. J. J. Am. Chem. Soc. 2007, 129, 2521.
(d) Glover, S. A.; Rosser, A. A. J. Org. Chem. 2012, 77, 5492.
e) Morgan, J.; Greenberg, A. J. Chem. Thermodyn. 2014, 73, 206.
The authors declare no competing financial interest.
(
(
14) (a) Szostak, R.; Aube,
6395. (b) Szostak, R.; Aube,
905.
15) Winkler, F. K.; Dunitz, J. D. J. Mol. Biol. 1971, 59, 169.
́
J.; Szostak, M. Chem. Commun. 2015, 51,
J.; Szostak, M. J. Org. Chem. 2015, 80,
ACKNOWLEDGMENTS
■
́
7
(
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). Y.L. acknowledges a scholarship
from the Priority Academic Program Development of Jiangsu
Higher Education-Yangzhou University (BK2013016) and the
National Natural Science Foundation of China (21472161).
Support of our research program from Wroclaw Center for
Networking and Supercomputing (Grant WCSS159) is
acknowledged.
Winkler−Dunitz distortion parameters: τ (twist angle), χ (pyramid-
alization at N), and χ (pyramidalization at C) describe the
magnitude of rotation around the N−C(O) bond, pyramidalization
at nitrogen, and pyramidalization at carbon; τ is 0° for planar amide
bonds and 90° for fully orthogonal bonds; χ and χ are 0° for planar
bonds and 60° for fully pyramidalized bonds.
(16) (a) Wiberg, K. B. Acc. Chem. Res. 1999, 32, 922. (b) Hoffmann,
R.; Hopf, H. Angew. Chem., Int. Ed. 2008, 47, 4474.
N
C
N
C
(17) Meng, G.; Szostak, M. Eur. J. Org. Chem. 2018, 2018, 2352.
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