"bridged" n →π* interactions can stabilize peptoid helices

Article abstract of DOI:10.1021/jo4014113

Peptoids are an increasingly important class of peptidomimetic foldamers comprised of N-alkylglycine units that have been successfully developed as antimicrobial agents, lung surfactant replacements, enzyme inhibitors, and catalysts, among many other applications. Since peptoid secondary structures can be crucial to their desired functions, significant efforts have been devoted to developing means of modularly controlling peptoid backbone amide cis-trans isomerism using side chains. Strategic engineering of interactions between side chain aromatic rings and backbone cis-amides (n→π_Ar interactions) is an attractive strategy for stabilizing helical structures in N-a-chiral aromatic peptoids, which are among the most utilized classes of structured peptoids. Herein, we report the first detailed computational and experimental study of n→π_Ar interactions in models of peptoids containing backbone thioamides, which we term "thiopeptoids". Our work has revealed that these interactions significantly affect amide rotamerism in both peptoid and thiopeptoid models via a newly characterized "bridged" mode of interaction mediated by the N-α-C-H σ orbitals. Overall, this work elucidates new strategies for controlling both peptoid and thiopeptoid folding and suggests that thiopeptoids will be highly structured and therefore potentially useful as therapeutics, biological probes, and nanostructural engineering elements.

Full text of DOI:10.1021/jo4014113

Article
pubs.acs.org/joc
“Bridged” n→π* Interactions Can Stabilize Peptoid Helices
Benjamin C. Gorske,* Ryan C. Nelson, Zara S. Bowden, Turner A. Kufe, and Adam M. Childs
Department of Chemistry, Bowdoin College, 6600 College Station, Brunswick, Maine 04011-8466, United States
S
* Supporting Information
ABSTRACT: Peptoids are an increasingly important class of
peptidomimetic foldamers comprised of N-alkylglycine units
that have been successfully developed as antimicrobial agents,
lung surfactant replacements, enzyme inhibitors, and catalysts,
among many other applications. Since peptoid secondary
structures can be crucial to their desired functions, significant
efforts have been devoted to developing means of modularly
controlling peptoid backbone amide cis−trans isomerism using
side chains. Strategic engineering of interactions between side
chain aromatic rings and backbone cis-amides (n→π*Ar
interactions) is an attractive strategy for stabilizing helical
structures in N-a-chiral aromatic peptoids, which are among the most utilized classes of structured peptoids. Herein, we report
the first detailed computational and experimental study of n→π*Ar interactions in models of peptoids containing backbone
thioamides, which we term “thiopeptoids”. Our work has revealed that these interactions significantly affect amide rotamerism in
both peptoid and thiopeptoid models via a newly characterized “bridged” mode of interaction mediated by the N-α-C−H σ
orbitals. Overall, this work elucidates new strategies for controlling both peptoid and thiopeptoid folding and suggests that
thiopeptoids will be highly structured and therefore potentially useful as therapeutics, biological probes, and nanostructural
engineering elements.
biostability, facile synthesis, and structural diversity (Figure
1A).1−13 These advantages have recently spurred the expansion
INTRODUCTION
■
Nature relies upon a select few classes of biopolymers such as
proteins and nucleic acids to carry out a majority of the
biochemical processes essential to cellular function and
reproduction. The wide spectrum of chemical transformation
and informational processing mediated by these biopolymers
belies the limited number of monomeric building blocks
typically required to achieve such diverse functions. The
mechanisms by which the one-dimensional information
encoded in biopolymer sequences gives rise to biological
complexity have enthralled researchers in the fields of
biochemistry, molecular biology, and chemistry for decades.
Chemists in particular have been inspired to develop artificial
polymers that might harness the inherent advantages of
modular molecular assembly in order to mimic the functions
of biological molecules. Peptides and proteins were especially
attractive early targets for mimicry, as they can often function
independently of other cellular machinery. The development of
peptide mimics such as β-peptides1−3 and peptoids,1,3−5 along
with many classes of polypeptide isosteres,1,3−13 heralded the
emergence of the field of peptidomimetics, which has grown
rapidly since its inception. The more broadly defined term
“foldamer”1,3−5,12,14 was later introduced in recognition of the
fact that peptidomimetic design principles can also be
employed to construct abiotic folded structures, which have
potential applications in materials design, nanoengineering, and
molecular computing.
Figure 1. (A) Generic peptoid structure. (B) 3D-representations of
n→π*Am and (C) n→π*Ar interactions (indicated by yellow arrows) in
peptoid model systems that stabilize the trans- and cis-rotamers,
respectively.
of the peptoid family to include oligomers such as β-
peptoids15−19 and azapeptoids.20,21 Although peptoids were
originally designed to be rapidly accessible via combinatorial
chemistry, specific subclasses of peptoids and their congeners
have also been shown to fold predictably into discrete
structures.22−31 Recent advances in understanding this folding
have catalyzed interest in the rational design of peptoid
secondary and tertiary structures and have aided the develop-
Peptoids, which are polymers of N-substituted glycine, are an
increasingly important class of foldamers due to their
Received: June 29, 2013
Published: September 19, 2013
© 2013 American Chemical Society
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Figure 2. Structures of the peptoid (X = O; 1x−15x with x = O) and thiopeptoid (X = S; 1x−15x with x = S) model compounds examined in this
study.
ment of peptoids as therapeutic agents,5,32−38 catalysts,39 and
nanostructural elements.40−44
peptoid backbone amides can interact with each other via an
“n→π*Am interaction” similar to that observed in polyprolines
(Figure 1B).53−55 This interaction entails the delocalization of
electron density from a donor amide lone pair into the π*
orbital of a neighboring amide. Importantly, the requirement
Peptoids containing N-α-chiral aromatic side chains con-
stitute perhaps the most utilized class of structured peptoids to
date.24,31,37,45−47 Despite lacking hydrogen bond donors and
stereogenic centers in their backbones, early computational
work suggested that N-α-chiral peptoids could adopt a helical
structure analogous to a polyproline type I (PPI) helix, which is
comprised entirely of cis-amides;22 these predictions were later
borne out by circular dichroism, nuclear magnetic resonance,
and X-ray crystallography studies.24,25,45,48 A “threaded loop”
structure stabilized by hydrogen bonds and containing several
trans-amides can also predominate for certain N-α-chiral
aromatic peptoids;47,49,50 this finding highlights how a few
relatively weak noncovalent interactions can dramatically affect
the secondary structures of this peptoid class. Indeed, the small
differences in energy between the cis- and trans-rotamers of the
tertiary amides in the peptoid backbone typically lead to an
undesirable ensemble of interconverting structures in solu-
tion.48
Since the helicities of N-α-chiral aromatic peptoids have been
correlated to their functions in many applications,5,34,37,46,51
considerable effort has been devoted to developing strategies
for limiting their conformational heterogeneity by promoting
helical structure. Head-to-tail cyclization26 and “stapling”
together proximal side chains within the helix52 have proven
to be very successful approaches in this regard. Alternatively,
directing the cis−trans isomerism of specific backbone amides
using their pendant side chains holds a particular appeal due to
its complete compatibility with the powerful and facile
“submonomer” peptoid synthesis protocol.27,28,30,31,49,53,54
Moreover, the ability to modularly and rationally “program”
rotameric propensities for specific peptoid backbone amides
simply by the choice of side chain would represent a powerful
methodology for the design of new, nonhelical peptoid
structures. Previous work along these lines has revealed how
that this interaction occur along the Burgi-Dunitz trajectory
̈
dictates that it can only lower the energy of the trans-rotamer of
the donor amide. A complementary interaction between a
peptoid backbone amide and π* orbitals of an electron deficient
aromatic ring in the side chain (an “n→π*Ar interaction”) has
been shown to stabilize the cis-rotamer of the donor amide
(Figure 1C).53,54 The usefulness of this interaction in stabilizing
cis-amides was recently demonstrated in peptoids containing a
triazolium side chain that serves as a junction to additional side
chain constituents attached using click chemistry.56
We reasoned that advancing our understanding of n→π*Ar
interactions could aid the development of new strategies for
controlling peptoid amide isomerism and thereby peptoid
secondary structure. While the electrophilicity of the aromatic
ring has previously been investigated in this context, the
nucleophilicity of the amide donor has not been as extensively
examined thus far.57 Inspired by reports that related n→π*Am
interactions in prolines and β-peptoid models can be
strengthened using thioamide donors,57,58 we sought to
determine whether thioamide analogs of α-peptoids, which
we have dubbed “thiopeptoids”, could also engage in stronger
n→π*Ar interactions.
Herein we report our experimental and computational
studies of peptoid and thiopeptoid model systems in which
both the n→π*Ar interaction donor and acceptor are system-
atically probed. Our analyses of these systems have elucidated a
new “bridged” mode of n→π*Ar interaction that is facilitated by
a N-α-C−H σ* orbital, and that operates concurrently with the
previously reported “direct” mode of n→π*Ar interaction. Our
data suggest that this bridged mode of n→π*Ar interaction can
play a considerable role in determining Kcis/trans for amides and
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Table 1. Peptoid (1o−15o) and Thiopeptoid (1s−15s) Model Systems (Figure 2), Amide and Thioamide Cis/Trans Ratios in
a
b,c
CDCl3 (Kcis/trans) and Corresponding Free Energy Differences (ΔGcis/trans
)
oxoamide
thioamide
a
b
d
b
d
side chain designation
σ
entry
Kcis/trans
ΔG (kcal/mol)
entry
Kcis/trans
ΔG (kcal/mol)
p-OMe
p-Me
−0.27
−0.17
0
1o
1.95 0.03
1.72 0.01
−0.39
−0.32
−0.34
−0.56
−0.59
−0.67
−0.70
−0.86
−0.85
−0.74
−1.4
1s
2s
3s
4s
5s
6s
7s
8s
9s
1.99 0.05
1.77 0.01
1.9
−0.41
−0.34
−0.39
−0.59
−0.61
−0.73
−0.69
−0.93
−0.96
2o
e
p-H
3o
1.8
p-F
0.06
0.23
0.43
0.54
0.71
0.78
4o
2.57 0.06
2.73 0.07
3.13 0.06
3.24 0.07
4.31 0.05
2.72 0.04
2.80 0.05
3.4 0.1
3.2 0.1
4.8 0.1
5.1
p-Cl
5o
m-CF3
p-CF3
m-NO2
p-NO2
4py
6o
7o
8o
e
9o
4.2
f
10o
11o
12o
13o
14o
3.5
NA
NA
4pyH+
m-NO2 pm
p-NO2 pm
o-Me
10.1 0.7
2.65 0.06
2.73 0.08
3.71 0.07
10.4 0.3
NA
12s
13s
14s
15s
NA
0.71
0.78
NA
−0.58
−0.58
−0.78
−1.4
3.1 0.1
2.95 0.09
3.84 0.03
14.6 0.5
−0.67
−0.64
−0.79
−1.6
1ne
NA
15o
b
a
1
Hammett substituent constant; see ref 65. Determined by integrating H NMR spectra of 15 mM solutions in CDCl3 at 24 °C. Data ranges
indicate standard error, when applicable. Single stereocenters do not influence Kcis/trans in these systems; enantiomeric excesses were therefore not
determined. The cis-rotamer was defined as that which orients the side chain and the oxygen/sulfur atom on the same side of the amide/thioamide
c
d
e
f
bond (see Figure 3A). ΔG = −RT ln(Kcis/trans). Previously reported in ref 53. Data not available.
thioamides in the backbones of peptoids and thiopeptoids,
respectively. The backbone side-chain interactions observed in
thiopeptoids suggest that thiopeptoid oligomers will be capable
of adopting robust PPI helix structures with at least comparable
conformational stability and homogeneity relative to typical α-
peptoids. We also explore the tactical disruption of bridged n→
π*Ar interactions that could potentially lead to the formation of
new peptoid secondary structures containing trans-amides.
Overall, these interactions constitute a new architectural
element for constructing highly structured peptoids and
thiopeptoids that could serve as potent antimicrobial agents,37
enzyme inhibitors, and ligands of proteins and nucleic
acids,59,60 as well as components of higher order foldameric
structures such as helix bundles.42,43
RESULTS AND DISCUSSION
■
Density Functional Theory (DFT) Calculations of
Figure 3. (A) Structures of the cis- and trans-rotamers of a previously
Conformational Energies for 3o, 9o, and 16o. Computa-
tional modeling is a powerful tool for investigating weak
interactions, so we initiated our investigations of n→π*Ar
interactions in peptoids and thiopeptoid models by calculating
the conformational energies of previously reported peptoid
models 3o (containing an unsubstituted aromatic ring) and 16o
(containing an N-methylpyridinium ring) using DFT methods
(Figure 2, Table 1, Figure 3A).53 Compound 16o was
previously shown to exhibit a very high cis−trans amide ratio,
such that the trans-rotamer is nearly undetectable by 1H NMR.
1H nuclear Overhauser effect (NOE) spectroscopy indicated
that the cis-rotamer (cis-16o) favors a conformation in which
the amide oxygen and the ipso carbon are in close proximity
(Camide−Namide−Cbenzyl−Cipso dihedral angle between −75° and
+75°; Figure 3B), suggesting the influence of a strong, direct
n→π*Ar interaction. In contrast, NOE data suggested that this
conformation was not extensively populated in compound 3o.
Constrained geometry potential energy surface (PES) scans of
the Camide−Namide−C benzyl−Cipso dihedral angle (Figure 3) for
both amide rotamers of 16o corroborate these previous
experimental results (Figure 4). Plots of the computed energies
reported peptoid model containing an N-methylpyridinium group in
its side chain and the corresponding phenyl analogue with relevant
atomic labels. (B) Newman projections of conformations of 3o with
Camide−Namide−Cbenzyl−Cipso dihedral angles of 0°, 120°, and 180°.
(relative to those of the global minima) and Cipso−Oamide
interatomic distances as functions of the dihedral angle suggest
that a strong direct n→π*Ar interaction indeed stabilizes the cis-
amide rotamer of 16o. Specifically, the calculated global
minimum for compound 16o corresponds to a conformation
in which the Camide−Namide−C benzyl−Cipso dihedral angle is near
−50°, giving a Cipso−Oamide interatomic distance that is shorter
than the sum of the carbon and oxygen van der Walls radii
(3.22 Å). In contrast, a similar conformation in which this
direct n→π*Ar interaction can occur represents only a local
minimum for 3o (Figure 4B), with the calculated global
minimum corresponding to the conformation in which the
amide carbonyl and N-α-C−H bonds are roughly eclipsed
(Camide−Namide−C benzyl−Cipso dihedral angle near 120°; Figure
3B). This conformation is reminiscent of those adopted by
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isomerism in N-α-chiral aromatic peptoids as functions of the
electrophilicity of the side chain aromatic ring. We began by
performing a dihedral scan for both amide rotamers of
compound 9o, which contains a para-nitroaromatic ring that
we surmised to be of intermediate electrophilicity compared to
those of 3o and 16o (Figure 5A). As expected, a local minimum
Figure 4. Computed energies (left axis, circles) and Cipso−Oamide
interatomic distances (right axis, triangles) for cis- (blue) and trans-
(green) rotamers of 16o (A) and 3o (B) as functions of the Camide
−
Namide−Cbenzyl−Cipso dihedral angle. Energies are reported relative to
the global minima of the dihedral scans. Dihedral angles are defined as
shown in Figure 3. The horizontal arrow shows the distance at which
the carbon and oxygen atoms make contact as defined by the sum of
their van der Waals radii (3.22 Å).
Figure 5. Computed energies (left axis, circles) and Cipso−O/Samide
interatomic distances (right axis, triangles) for cis (blue) and trans
(green) isomers of 9o (A) and 9s (B) as a function of Camide−Namide
−
proline residues within the α-helices of proteins and is
consistent with the operation of 1,3-allylic strain. However,
Cbenzyl−Cipso dihedral angle. Energies are reported relative to the global
minimum of the dihedral scan. The dihedral angles are defined as
shown in Figure 3. The horizontal arrow shows the distance at which
the Cipso and O/Samide atoms make contact, as defined by the sum of
their van der Waals radii (3.22 Å for oxygen, 3.50 Å for sulfur).
61
the stabilization of this conformation has also been attributed in
part to a Cα−H···OC interaction.62,63 Although such
interactions are typically referred to as conventional, purely
electrostatic hydrogen bonds, contributions from weak covalent
interactions between the amide π system and the Cα−H bond
have also been suggested. 62 This same interaction has recently
been shown to significantly affect proline cis−trans isomerism in
a model peptide.64 Most importantly, the geometric arrange-
ments of atoms required for this interaction pervade the
previously reported solution-phase and solid-state structures of
peptoid PPI-like helices and are consistent with NOE
spectroscopy data for compound 3o (vide infra).25,31,48 In
addition, a thiopeptoid model compound with an N-α-naphthyl
side chain has been shown to adopt a similar conformation in
the solid state that would facilitate a CαH···SC
interaction.57 Notably, natural bond orbital (NBO) calculations
suggested that the cis-amide rotamers of peptoids and
thiopeptoids with N-α-naphthyl side chains are also stabilized
by a C−H···OC interaction between the carbonyl oxygen
and an aromatic hydrogen.
occurs near the point where the Cipso−Oamide interatomic
distance dips below the sum of the van der Waals radii,
suggesting that a direct n→π*Ar interaction contributes to
lowering the energy of cis-9o. However, we were intrigued to
find that the global minimum again corresponds to the
conformation in which the amide carbonyl and the N-α-C−H
bonds are roughly eclipsed. Furthermore, the difference in
energy between the global minima of the cis and trans rotamers
of 9o is larger compared to that for 3o, commensurate with the
larger ΔGcis/trans for 9o as compared to 3o that was previously
observed experimentally.53 These energy differences are not
readily attributable to 1,3-allylic strain, since both 9o and 3o are
calculated to adopt essentially identical global minimum
conformations while exhibiting notably different cis/trans ratios.
Determination and Analysis of Kcis/trans for Peptoid
and Thiopeptoid Models. In order to investigate the relative
contributions of electrostatic vs weak covalent interactions to
We sought to assess the relative contributions of direct n→
π*Ar and C−H···OC interactions to amide cis−trans
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the calculated global minimum conformations of 3o and 9o, we
synthesized a series of peptoid models in which the
electrophilicity of the N-α-chiral aromatic ring was systemati-
cally altered (Table 1). We then synthesized thiopeptoid
analogs of these models in order to probe how the
nucleophilicity of the n→π*Ar donor affects Kcis/trans. Thio-
amides are useful probes of electrostatic and weak covalent
attractions, as the thioamide sulfur is less negatively polarized as
compared to the oxygen of an amide, while concomitantly
exhibiting heightened nucleophilicity that enhances covalent
interactions.58 Therefore, significantly lower Kcis/trans values
would be expected if the global minimum conformation were
stabilized primarily by electrostatic interactions involving the
thioamide sulfur, while higher Kcis/trans values would indicate
such interactions are significantly covalent in nature. Notably,
these model systems do not contain additional amides, and thus
preclude the interference of amide−amide “n→π*Am” inter-
actions previously observed in peptoids and polyprolines.
Regardless, such backbone−backbone interactions are weaker
than the competing backbone-side chain interactions in
homologous dimeric peptoid models.53−55,57 While neither
the electron density in the aromatic ring nor the nucleophilicity
of the donor chalcogen (oxygen or sulfur) correlate with the
observed cis-trans ratios (Kcis/trans) for neutral or electron-rich
aromatic rings (1−3), Kcis/trans increases markedly as the
electrophilicity of the ring is increased (4−9). Furthermore,
the differences between the ΔGcis/trans values for the oxoamides
and the corresponding thioamides (Table 1) increase as the
electrophilicity of the aromatic ring increases, consistent with a
primarily covalent, as opposed to electrostatic, interaction
dictating ΔGcis/trans A paired t test of the complete Kcis/trans data
set confirmed that the thioamide model systems exhibited
statistically significant increases in Kcis/trans compared to the
analogous peptoid models. In addition, previous studies have
shown that ΔGcis/trans values for most α-chiral aliphatic peptoid
model systems are typically near or even greater than zero;54,66
thus, interactions involving the α-chiral aromatic side chains of
our model systems are likely the primary source of stabilization
of the cis-rotamer over the trans-rotamer. In light of these
observations, we hypothesized that an orbital-controlled
covalent stabilization of the global minimum conformation
identified above for cis-3o and cis-9o (Figures 4 and 5) becomes
more significant as the electron density in the ring is decreased.
Identification and Analysis of a “Bridged” n→π*Ar
Interaction. In order to corroborate this hypothesis and
identify the most important weak covalent interaction affecting
ΔGcis/trans in these systems, we opted to perform NBO
calculations, as these can offer an intuitive, localized orbital
perspective of such interactions.67 In particular, NBO second-
order perturbation (SOP) energies are indicative of the
importance of filled-to-empty NBO interactions in structural
stabilization, and thus provide a means of identifying weak
covalent interactions. We first calculated NBO SOP energies
for the global minima of the cis- and trans-rotamers of 9s
identified in a dihedral scan (Figure 5B). Since a large number
of SOP interactions for each rotamer were identified, we first
focused on interactions that were significantly perturbed upon
contributors to ΔGcis/trans. Of these, the interaction calculated to
be affected most significantly by cis-trans isomerization of 9s is
that between a sulfur lone pair and the σ* orbital of the N-α-
C−H bond (Figure 8.) The significance of this interaction is
remarkable in light of the poorer spatial overlap of these
orbitals in thioamides as compared to amides due to the longer
CS vs CO bond. (The offsetting of this poorer orbital
overlap with enhanced donor nucleophilicity in the thioamide
vs amide model systems may play a role in producing the
similarity in Kcis/trans values for 1o−3o vs 1s−3s.) We inferred
that the loss of this interaction upon cis-trans isomerization
would most significantly affect Kcis/trans in N-α-chiral thio-
peptoids. Notably, the N-α-C−H bonding NBO is in turn
calculated to interact with the π-system of the aromatic ring
(see the Supporting Information). We thus conjectured that the
overall trend of increasing Kcis/trans with increasing ring
electrophilicity for 1−9 might be best be explained by an
increasingly favorable “bridged” n→π*Ar interaction, in which
the n→π*Ar electron density shift is mediated by the N-α-C−H
σ* orbital (Figure 6). According to this central hypothesis, the
Figure 6. 2D and 3D representations of the interaction between a lone
pair NBO on the thioamide sulfur atom of 9s (red and blue) and the
N-α-C−H σ* NBO (yellow and green), which could serve as a
“bridge” for electron density transfer from the thioamide sulfur atom
to the electron-deficient aromatic ring.
N-α-C−H σ* orbital effectively serves as a conduit for electron
density transfer from the chalcogen lone pair to the
electrophilic aromatic π system. To further validate this
hypothesis, we examined the changes in the NBO SOP
interactions between the (thio)amide chalcogen donor and the
N-α-C−H σ* acceptor for peptoid models 1o−9o and
thiopeptoid models 1s−9s. The calculated strengths of the
putative bridged n→π*Ar interactions in these models
correlated exceedingly well with both the calculated ΔEcis/trans
(see the Supporting Information) and the experimentally
determined ΔGcis/trans (Figure 7) values. Subsequent analysis of
the SOP interactions in these models likewise implicated this
same interaction as the primary contributor to ΔGcis/trans (see
the Supporting Information). Although weaker than the Cα−
H···OC interactions in polyprolines, which have estimated
energies of 1.23.6 kcal/mol,63 the energies of these bridged
n→π*Ar interactions (greater than 0.65 kcal/mol for electron
deficient systems 6−9) are considerable in light of the inherent
flexibility of the peptoid backbone and are comparable to
hydrogen bonds. Moreover, since peptoid helix formation has
been shown to be cooperative,23 bridged n→π*Ar interactions
may contribute more significantly to peptoid structural stability
than suggested by the single interaction energies.
cis-trans isomerization (i.e., exhibited large “ΔE(SOP)cis/trans
”
values). We then discounted groups of interactions that
changed in a self-compensatory manner upon isomerization
such that their net contribution to the calculated ΔEcis/trans was
negligible (see the Supporting Information). We reasoned that
the remaining interactions would be the most important
In order to obtain further experimental evidence for bridged
n→π*Ar interactions in our model compounds, we measured
the 1JCH coupling constants for the N-α-C−H bonds of the cis-
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phase NMR data that implicate the direct mode of n→π*Ar
interaction as the primary determinant of Kcis/trans in peptoids
containing pyridinium rings in their side chains.53 Overall, these
data suggest that the bridged n→π*Ar interaction is the primary
mode of chalcogen-to-aromatic electron density transfer in cis-
N-α-chiral aromatic peptoids containing electron-rich, neutral,
and moderately electron-poor aromatic rings, while the direct
mode of n→π*Ar interaction dominates for cis-N-α-chiral
aromatic peptoids containing highly electron-deficient aromatic
rings.
A similar transition from the bridged to direct mode of n→
π*Ar interaction also appears to occur in the thiopeptoid
models. Hammett plots for these compounds deviate from
linearity at high σ values, suggesting that the mechanism of cis-
rotamer stabilization changes as the side chain aromatic rings
become highly electron deficient (see the Supporting
Information). In order to better understand this phenomenon,
we performed constrained geometry PES scans of the Camide
Namide−Cbenzyl−Cipso dihedral angle (Figure 3) for both
thioamide rotamers of 9s (Figure 5B) and compared them to
−
those of the oxo-analogue 9o (Figure 5A). As the Cipso
−
chalcogen interatomic distances dip below the sum of the van
der Waals radii near the −75° dihedral angle, the conforma-
tional energies of cis-9o increase while those of cis-9s decrease
in a manner similar to that calculated for cis-16o, which exhibits
a favorable direct n→π*Ar interaction. These calculations thus
imply that a direct n→π*Ar interaction, though not occurring in
the global minimum conformation, plays a more important role
in dictating Kcis/trans for 9s vs 9o; this hypothesis is supported by
the lower JCH and smaller Δ1JCH observed for cis-9s as
1
Figure 7. Calculated ΔE(SOP)cis/trans values for the interaction
between the (thio)amide chalcogen lone pair and the N-α-C−H σ*
orbital in oxoamide (A) and thioamide (B) model compounds, plotted
against the experimentally determined ΔGcis/trans values for each
compound (Table 1).
compared to cis-9o. Given that both modes of n→π*Ar
interactions are as strong or stronger in thiopeptoid vs peptoid
models containing electron-deficient aromatic rings, the former
foldamer class could exhibit a strong propensity to form cis-
thioamides and PPI-type helices.
Disruption of n→π*Ar Interactions Using Peptoid and
Thiopeptoid Side Chains. We also tested our hypothesis that
bridged n→π*Ar interactions play an important role in
determining Kcis/trans in peptoid and thiopeptoid models by
synthesizing model compounds in which both the thermody-
namic and kinetic stabilities of the conformations engendering
the interactions were altered. Compounds 12 and 13 lack an N-
α-methyl group but are otherwise identical to 8 (m-NO2) and 9
(p-NO2), respectively. We expected that this change would
reduce steric interactions and thereby lower the energies of
alternate conformations (in which the bridged n→π*Ar
interaction could not occur) and the rotational barriers leading
to them, resulting in a weakening of the bridged n→π*Ar
interaction as evidenced by a lower Kcis/trans. This supposition
was borne out by the experimental data for 12 and 13 (Table
1), which show an overall lowering of Kcis/trans for the
compounds lacking an N-α-methyl group. Moreover, the
1
Table 2. Experimentally Measured JCH Coupling Constants
for the N-α-C−H Bonds of the Cis- and Trans-Rotamers of
Selected Model Compounds
1
N-α-C−H JCH
a
compd side chain designation
σ
cis
trans
Δ1JCH
1o
p-OMe
p-NO2
p-NO2
4py
−0.27
0.78
137.9
141.1
139.4
140.6
139.5
138.4
134.7
137.5
136.6
136.4
3.2
3.6
2.8
4.2
9o
9s
0.78
10o
11o
13o
b
4pyH+
p-NO2 pm
ND
138.4
0
a
b
See ref 61. Rotamer not detected.
and trans-rotamers of selected molecules (Table 2). Increases in
this coupling constant have been cited previously as evidence of
C−H···O interactions.68−70 A larger 1JCH coupling constant was
detected for the cis- vs the trans-rotamer of each compound
except 13o, while cis−trans isomerization did not affect any
other measurable JCH coupling constants. Furthermore, the
magnitudes of JCH for the cis-rotamers roughly correlate with
the observed Kcis/trans values. Intriguingly, JCH for cis-11o
1
magnitude of JCH for N-α-C−H bond in the cis-rotamer of
13o is indistinguishable from that of the trans-rotamer (Table
2). These data suggest that the lower Kcis/trans values for 12 and
13 are due in part to a weaker bridged n→π*Ar interaction in
these systems, and are not entirely dictated by the reduced sizes
of the side chains.
1
1
1
We also synthesized derivatives of 3 containing either an o-
methyl group (14o and 14s) or a naphthyl ring (15o and 15s)
designed to increase steric interactions and rotational barriers.
Interestingly, while the o-methyl group significantly increased
containing a protonated, pyridinium side chain was lower than
that for the neutral pyridine-containing cis-10o, suggesting that
the bridged n→π*Ar interaction plays a lesser role in
determining Kcis/trans for cis-11o. This finding supports both
our calculations (vide supra) and previously reported solution
K
cis/trans in 14o compared to 3o, thionation did not result in any
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Figure 8. Structures of polypeptoids reported to form helices in the solid state (17) and in solution (18) and the geometry-optimized subunits used
for calculating the energies of the bridged n→π*Ar interactions in each compound (19 and 20; gray = carbon, blue = nitrogen, red = oxygen, white =
hydrogen; most hydrogen atoms removed for clarity).
further increase. In contrast, 15o, in which a naphthyl ring
carbon is attached at the ortho-position, exhibited a larger
Kcis/trans value vs 3o; this difference was also amplified in the
thionated analog 15s. We therefore speculate that o-alkyl
substitution of N-α-chiral side chains simply increases their
effective steric bulk, leading to larger Kcis/trans values. While the
large ΔΔGcis/trans observed for the compounds containing the
naphthyl (1ne) side chain (15o and 15s) could be due in part
to strong n→π*Ar interactions in cis-15o and cis-15s that are
enhanced by conformational restriction, a recently elucidated
naphthyl C−H···OC interaction could also play a significant
role in these systems.57
monomeric models highlights the potentially cooperative
nature of these types of interactions in stabilizing the secondary
structures of peptoid oligomers. Thus, given that the reported
Kcis/trans equilibria for most α-chiral aliphatic peptoid model
systems are typically near unity,54,66 the bridged n→π*Ar
interactions facilitated by α-chiral aromatic side chains in
these helices could play a significant role in dictating both
amide isomerism and, thereby, overall folding. Indeed, early
peptoid structural studies demonstrated that incorporation of
electron-deficient α-chiral aromatic side chains, which have
been shown above to enhance bridged n→π*Ar interactions,
amplified circular dichroism signatures associated with peptoid
helices.23
Evidence of Bridged n→π*Ar Interactions Contribu-
ting to Polypeptoid Structure. Examination of previously
reported solution- and solid-phase structures of peptoid helices
strongly suggests that the bridged n→π*Ar interactions affecting
Kcis/trans in our monomeric models play an important role in the
folding of polypeptoids as well. Inspection of the helical solid-
state structure of 1731 and the solution-phase structure of 1848
(which notably contains a preponderance of electron-deficient
α-chiral aromatic side chains) reveals that the conformation of
each interior monomer unit closely corresponds to the
calculated global minimum conformations of 1−9 in which
the bridged n→π*Ar interaction can occur (Figure 8). To
determine if bridged n→π*Ar interactions might similarly
operate within these polypeptoid helices as in our model
systems, NBO calculations were performed on geometry
optimized subunits (19 and 20) of the helices. (The geometry
optimizations had little effect on the overall structures but were
necessary to ensure that experimental structural metrics were
not significantly affected by model simplification.) The bridged
n→π*Ar SOP interaction energies were calculated to be −1.73
kcal/mol and −1.92 kcal/mol for 19 and 2.18 kcal/mol for 20;
these energies are in line with those determined for our model
systems. Furthermore, the fact that the n→π*Ar SOP
interaction energies in 20 are larger than those in the analogous
SUMMARY AND CONCLUSIONS
■
Our computational and experimental studies of chalcogen−
aromatic interactions in models of N-α-chiral aromatic peptoids
and thiopeptoids suggest that n→π* Ar interactions can operate
in two distinct modes: either via a direct n→π*Ar interaction
between the amide or thioamide and the aromatic ring, or via a
newly characterized “bridged n→π*Ar” mode of interaction in
which electron density transfer from the amide/thioamide to
the aromatic ring is facilitated by an intermediary N-α-C−H σ*
orbital. Although both interaction modes are calculated to
operate to some extent within the compounds examined in this
study, the latter mode appears to be most significant for
electron-rich, neutral, and moderately electron-poor aromatic
side chains, while the former mode increasingly affects cis−trans
isomerism in compounds containing more strongly electron-
deficient aromatic side chains. Both interaction modes are
calculated to be enhanced by electron-deficient aromatic side
chain acceptors and thioamide donors, and stabilize the cis-
rotamer of the proximal backbone amide or thioamide. Thus,
these interactions could potentially be exploited to construct
robust PPI-type helices useful in a wide range of applications.
Importantly, although the C−H···OC interaction component
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of the bridged n→π*Ar interaction has previously been observed
to affect proline cis-trans isomerism,64 peptoids and thiopep-
toids present a unique opportunity to modulate the strength of
this interaction via readily incorporated N-α-chiral aromatic
side chains. Although beyond the scope of this study, the
intentional disruption of these n→π*Ar interactions might allow
other weaker interactions to play a more dominant role in
controlling amide/thioamide isomerism, potentially leading to
the formation of new structures containing trans-rotamers.
In addition, we have conducted the first detailed study on the
conformational preferences of thiopeptoid monomers. This
work provides an important foundation for predicting and
understanding the folding of N-α-chiral aromatic thiopeptoids.
Although the synthesis and structural characterization of
polythiopeptoids is ongoing in our laboratory, it is as yet
unclear how the subtle balance of weak interactions that
operate to direct peptoid amide isomerism will differ from that
in thiopeptoids. Given that thioamides have already been
shown to engage in enhanced n→π*Am interactions as
compared to their oxo-counterparts,58,71 we postulate that
stabilization of both cis- and trans-rotamers by rational design
might be readily orchestrated in thiopeptoids. Our findings, in
conjunction with this previous report, suggest that thiopeptoids
and mixed peptoid/thiopeptoid oligomers would constitute a
fundamentally new and manipulable class of peptidomimetics,
and that they could find numerous applications in medicine,
materials design, and chemical biology. Current efforts in our
laboratory are dedicated to realizing the potential of
polythiopeptoids in these areas, focusing on the construction
of biomimetic structures such as PPII-type helices that could be
used to interrogate protein−protein interactions.
Scheme 1. One-Pot Synthesis of Peptoid Model Compounds
to this study and therefore were not determined. Peptoid model
systems 3o, 9o, 10o, and 13o were synthesized as previously
reported.53,54 Full characterization data for model systems 1o−8o,
12o, 14o, 15o, 1s−9s, and 12s−15s are provided below. After
purification, a 15 mM solution of each compound in CDCl3 was
1
prepared and a H NMR spectrum was obtained using a relaxation
delay of 35 s. Kcis/trans values were determined by comparing the
integrations of the cis- and trans-rotamer peaks in the 1H NMR
spectra. Reported data ranges for Kcis/trans correspond to standard
errors for these sets of measurements, when applicable. Proton-
coupled 13C NMR spectra were obtained using gated decoupling
experiments.
Representative Model Peptoid Synthesis (3o; Scheme 1). To
a dry 25-mL flask were added 4 Å molecular sieves, a magnetic stirring
bar, 2 M methylamine in methanol (16.7 mL, 33.3 mmol),
acetophenone (388 μL, 3.33 mmol), and sodium cyanoborohydride
(146 mg, 2.33 mmol). The reaction mixture was stirred under nitrogen
for 48 h. The solution was then cooled to 0 °C, and acetic anhydride
(2.3 mL, 33.3 mmol) was added dropwise to the stirred solution. After
5 min, the solution was placed in a separatory funnel, ethyl acetate (25
mL) was added, and the organic layer was washed with aqueous 10%
citric acid (25 mL), saturated aqueous sodium bicarbonate (25 mL),
and saturated aqueous sodium chloride (25 mL). The organic layer
was dried over magnesium sulfate and filtered. Removal of the solvent
in vacuo yielded pure N-methyl-N-(1-phenylethyl)acetamide (384 mg,
67% yield) as a colorless oil.
Representative Model Thiopeptoid Synthesis (9s).58 To a dry
50-mL round-bottom flask were added N-methyl-N-(1-(4-
nitrophenyl)ethyl)acetamide (574 mg, 2.58 mmol), 15 mL of dry
tetrahydrofuran, a magnetic stirring bar, and Lawesson’s reagent (522
mg, 1.29 mmol). The reaction mixture was refluxed for 15 h, after
which the reaction was allowed to cool to room temperature and then
quenched with 1 N HCl (1 mL). The resulting mixture was extracted
with ethyl acetate (3 × 15 mL), and the combined organic layers were
washed with saturated aqueous sodium bicarbonate (50 mL) and
saturated aqueous sodium chloride (50 mL). The organic layer was
dried over magnesium sulfate, filtered, and concentrated in vacuo to
yield a brown oil. The oil was purified by silica gel chromatography
(100% n-hexanes to 100% ethyl acetate gradient) to give 9s (428 mg,
50% yield) as a yellow solid. Model peptoid 9s was fully characterized;
see below.
N-(1-(4-Methoxyphenyl)ethyl)-N-methylacetamide (1o).
Aqueous workup yielded 212 mg (54% yield) of N-(1-(4-
methoxyphenyl)ethyl)-N-methylacetamide as a clear oil with sufficient
purity such that column chromatography was not required: TLC Rf =
0.1 (2:1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3; major
rotamer) δ 7.16 (AA′BB′, J = 8.9 Hz, 2H), 6.86 (AA′BB′, J = 8.8 Hz,
2H), 6.02 (q, J = 7.0 Hz, 1H), 3.80 (s, 3H), 2.63 (s, 3H), 2.12 (s, 3H),
1.45 (d, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3; major
rotamer) δ 170.2, 158.5, 132.4, 128.2, 113.5, 55.0, 49.3, 29.7, 22.0,
13.9; HRMS m/z [M + H]+ calcd for C12H18NO2 208.1332, found
208.1329.
EXPERIMENTAL SECTION
■
General Methods. Unless otherwise noted, all reagents were 99%
purity, ACS-grade or HPLC-grade. Thin-layer chromatography (TLC)
was performed on glass silica gel plates, 250 μm, with UV254. TLC
plates were visualized using an ultraviolet lamp and heat-activated
staining with potassium permanganate, ceric ammonium molybdate,
and p-anisaldehyde.
Instrumentation. All 1H nuclear magnetic resonance (NMR)
spectra were collected on a 400 MHz NMR spectrometer. All samples
were prepared in CDCl3, unless otherwise noted. Chemical shifts were
recorded in parts per million (ppm), using tetramethylsilane (TMS) as
the 0.0 ppm reference, unless otherwise noted. 13C NMR spectra were
1
obtained using H-broadband decoupling.
High-resolution mass spectrometric analysis was performed using a
quadrupole time-of-flight (Q-TOF) mass analyzer, equipped with a
nanoelectrospray ionization (nanoESI) source. Chromatographic
separation and nanoESI was performed using a 40 nL enrichment
column and a 43 mm × 75 μm analytical column, both packed with
300 Å, 5 μm particles with C18 stationary phase. The mobile phases
were 0.1% formic acid/H2O (A) and 0.1% formic acid/acetonitrile
(B). Samples were loaded using 98:2 (A/B) and eluted using a linear
gradient with 30:70 (A/B) at 12 min. Mass spectra were collected in
positive ion mode; spectra were internally calibrated using methyl
stearate (C17H35CO2CH3) and hexakis(1H,1H,4H-hexafluorobutyl-
oxy)phosphazine (HP-1221; C24H18O6N3P3F36), continuously intro-
duced and detected as [M + H]+.
N-Methyl-N-(1-(p-tolyl)ethyl)acetamide (2o). Silica gel chro-
matography (3:1 diethyl ether/chloroform) yielded 246 mg (29%
yield) of N-methyl-N-(1-(p-tolyl)ethyl)acetamide as a clear oil: TLC
Rf = 0.45 (3:1 ether/chloroform); 1H NMR (400 MHz, CDCl3; major
rotamer) δ 7.21−7.11 (m, 4H), 6.03 (q, J = 7.1 Hz, 1H), 2.64 (s, 3H),
2.33 (s, 3H), 2.12 (s, 3H), 1.45 (d, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3; major rotamer) δ 170.6, 170.5, 137.7, 137.3, 136.9,
129.5, 129.2, 127.3, 126.4, 55.2, 53.6, 49.8, 30.2, 27.7, 22.4, 21.5, 21.1,
Synthesis and Characterization of Model Peptoids and
Thiopeptoids. Model peptoids 1o−15o (Figure 2, Table 1) were
synthesized using previously reported procedures53,54 or using a one-
pot reductive amination protocol (Scheme 1). Thiopeptoid model
compounds 1s−15s (Figure 2, Table 1) were prepared from the
corresponding peptoid models using Lawesson’s reagent. All
compounds were purified to homogeneity by silica gel chromatog-
raphy. Absolute configurations and enantiopurities were not germane
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21.0, 17.7, 15.7; HRMS m/z [M + H]+ calcd for C12H18NO 192.1383,
found 192.1195.
1H), 4.68 (s, 2H), 3.00 (s, 3H), 3.00 (s, 3H), 2.20 (s, 3H); 13C NMR
(100 MHz, CDCl3; major rotamer) δ 170.8, 148.2, 139.6, 133.9, 129.5,
122.3, 122.2, 50.0, 35.8, 21.5; HRMS m/z [M + H]+ calcd for
C10H13N2O3 209.0921, found 209.0922.
N-(1-(4-Fluorophenyl)ethyl)-N-methylacetamide (4o). Silica
gel chromatography (3:1 diethyl ether/chloroform) yielded 463 mg
(59% yield) of N-(1-(4-fluorophenyl)ethyl)-N-methylacetamide as a
white crystalline solid: mp 87−88 °C; TLC Rf = 0.5 (3:1 ether/
N-Methyl-N-(1-(o-tolyl)ethyl)acetamide (14o). Silica gel chro-
matography (2:1 EtOAc/hexanes) yielded 275 mg (54% yield) of N-
methyl-N-(1-(o-tolyl)ethyl)acetamide as an amorphous white solid:
1
chloroform); H NMR (400 MHz, CDCl3; major rotamer) δ 7.27−
1
TLC Rf = 0.40 (2:1 hexanes/EtOAc); H NMR (400 MHz, CDCl3;
7.19 (m), 7.10−6.99 (m), 6.05 (q, J = 7.1 Hz, 1H), 2.65 (s, 3H), 2.13
(s, 3H), 1.46 (d, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3; major
rotamer) δ 170.2, 170.0, 162.8, 160.2, 136.2 (d, J = 3.3 Hz), 135.8 (d, J
= 3.3 Hz), 128.5 (d, J = 8.2 Hz), 127.9 (d, J = 8.2 Hz), 115.1 (d, J =
21.4 Hz), 114.8 (d, J = 21.4 Hz), 54.8, 49.0, 29.6, 27.1, 21.8, 21.3, 17.3,
15.4; HRMS m/z [M + H]+ calcd for C11H15FNO 196.1132, found
196.1131.
major rotamer) δ 7.29−7.33 (m, 1H), 7.13−7.21 (m, 3H), 5.97 (q, J =
6.9 Hz, 1H), 2.51 (s, 3H), 2.20 (s, 3H), 2.07 (s, 3H), 1.44 (d, J = 6.9
Hz); 13C NMR (100 MHz, CDCl3; major rotamer) δ 169.2, 137.5,
137.2, 130.1, 127.1, 126.4, 125.2, 48.0, 29.6, 21.6, 18.5, 15.2; HRMS
m/z [M + H]+ calcd for C12H18NO 192.1383, found 192.1393.
N-Methyl-N-(1-(naphthalen-1-yl)ethyl)acetamide (15o).
Aqueous workup yielded 366 mg (17% yield) of N-methyl-N-(1-
(naphthalen-1-yl)ethyl)acetamide as an amorphous white solid with
sufficient purity such that column chromatography was not required:
N-(1-(4-Chlorophenyl)ethyl)-N-methylacetamide (5o). Silica
gel chromatography (3:1 diethyl ether/chloroform) yielded 263 mg
(79% yield) of N-(1-(4-chlorophenyl)ethyl)-N-methylacetamide as a
1
1
TLC Rf = 0.35 (2:1 hexanes/EtOAc); H NMR (400 MHz, CDCl3;
yellow oil: TLC Rf = 0.35 (3:1 ether/chloroform); H NMR (400
major rotamer) δ 8.03 (d, J = 8.2 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H),
7.80 (d, J = 8.1 Hz, 1H), 7.43−7.53 (m, 4H), 6.61 (q, J = 6.8 Hz, 1H),
2.47 (s, 3H), 2.09 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3; major rotamer) δ 169.9, 136.0, 133.7, 131.3, 128.6,
128.5, 126.7, 125.9, 124.8, 124.8, 123.8, 47.6, 29.9, 22.3, 15.7; HRMS
m/z [M + H]+ calcd for C15H18NO 228.1383, found 228.1387.
N-(1-(4-Methoxyphenyl)ethyl)-N-methylethanethioamide
(1s). Silica gel chromatography (3:1 hexanes/EtOAc) yielded 106 mg
(41% yield) of N-(1-(4-methoxyphenyl)ethyl)-N-methylethanethioa-
mide as a white crystalline solid: mp 75 °C; TLC Rf = 0.5 (2:1
hexanes/EtOAc); 1H NMR (400 MHz, CDCl3; major rotamer) δ 7.25
(AA′BB′, J = 9.0 Hz, 2H), 7.18 (q, J = 7.2, 1H), 6.88 (AA′BB′ J = 8.8,
2H), 3.81 (s, 3H), 2.84 (s, 3H), 2.67 (s, 3H), 1.54 (d, J = 7.0, 3H); 13C
NMR (100 MHz, CDCl3; major rotamer) δ 199.5, 159.0, 131.0, 128.2,
113.8, 57.8, 55.1, 33.5, 33.1, 14.4; HRMS m/z [M + H]+ calcd for
C12H18NOS 224.1104, found 224.1104.
MHz, CDCl3; major rotamer) δ 7.35−7.16 (m, 4H), 6.04 (q, J = 7.1
Hz, 1H), 2.65 (s, 3H), 2.13 (s, 3H), 1.46 (d J = 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3; major rotamer) δ 170.5, 170.2, 139.0, 138.6,
133.1, 132.8, 128.6, 128.4, 120.3, 127.6, 55.0, 49.2, 29.9, 27.4, 21.5,
17.4, 15.4; HRMS m/z [M + H]+ calcd for C11H15ClNO 212.0837,
found 212.0841.
N-Methyl-N-(1-(3-(trifluoromethyl)phenyl)ethyl)acetamide
(6o). Silica gel chromatography (2:1 EtOAc/hexanes) yielded 304 mg
(47% yield) of N-methyl-N-(1-(3-(trifluoromethyl)phenyl)ethyl)-
acetamide as a clear oil: TLC Rf = 0.4 (2:1 hexanes/EtOAc); 1H
NMR (400 MHz, CDCl3; major rotamer) 1H NMR δ 7.50−7.41 (m),
7.41 (s), 6.12 (q, J = 7.1 Hz, 1H), 2.68 (s, 3H), 2.16 (s, 3H), 1.52 (q, J
= 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3; major rotamer) δ 170.2,
141.6, 130.3, 130.2 (q, JC−F = 32.1 Hz), 128.5, 125.0, 123.5 (q, JC−F
=
3.7 Hz), 123.2 (q, JC−F = 3.7 Hz), 49.2, 29.6, 21.6, 15.0; HRMS m/z
[M + H]+ calcd for C12H15F3NO 246.1100, found 246.1112.
N-Methyl-N-(1-(p-tolyl)ethyl)ethanethioamide (2s). Silica gel
chromatography (4:1 hexanes/EtOAc) yielded 70 mg (30% yield) of
N-methyl-N-(1-(p-tolyl)ethyl)ethanethioamide as an amorphous white
solid: TLC Rf = 0.5 (4:1 hexanes/EtOAc); 1H NMR (400 MHz,
N-Methyl-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide
(7o). Silica gel chromatography (2:1 EtOAc/hexanes) yielded 345 mg
(53% yield) of N-methyl-N-(1-(4-(trifluoromethyl)phenyl)ethyl)-
1
acetamide as a yellow oil: TLC Rf = 0.4 (2:1 hexanes/EtOAc); H
1
NMR (400 MHz, CDCl3; major rotamer) 1H NMR δ 7.63−7.58 (m),
7.41−7.35 (m), 7.26, 6.11 (q, J = 7.1 Hz, 1H), 2.68 (s, 3H), 2.15 (s,
3H), 1.51 (d, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3; major
rotamer) δ 170.5, 170.2, 144.9, 144.4, 129.5, 129.2, 128.9, 128.6 (q, J =
31.12), 127.3, 126.6, 125.4, 125.0, 122.6, 122.4, 119.9, 117.7, 55.2,
49.5, 29.9, 27.4, 21.8, 21.3, 17.2, 15.2; HRMS m/z [M + H]+ calcd for
C12H15F3NO 246.1100, found 246.1114.
CDCl3; major rotamer) δ H NMR 7.24−7.15 (m), 7.10−7.08 (m),
2.68 (s, 3H), 2.85 (s, 3H), 2.34 (s, 3H), 1.55 (d, J = 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3; major rotamer) δ 200.1, 199.2, 138.1, 137.7,
136.2, 135.7, 129.9, 129.6, 127.2, 126.5, 59.7, 58.5, 37.0, 34.1, 33.5,
32.7, 21.3, 21.2, 17.2, 14.7; HRMS m/z [M + H]+ calcd for C12H18NS
208.1154, found 208.1165.
N-Methyl-N-(1-phenylethyl)ethanethioamide (3s). Silica gel
chromatography (3:1 hexanes/EtOAc) yielded 83 mg (22% yield) of
N-methyl-N-(1-phenylethyl)ethanethioamide as a green oil: TLC Rf =
0.2 (9:1 Hexanes/EtOAc); 1H NMR (400 MHz, CDCl3; major
rotamer) δ 7.43−7.19 (m, 5H; contains q, 1H), 2.86 (s, 3H), 2.69 (s,
3H), 1.57 (d, J = 6.9, 3H); 13C NMR (100 MHz, CDCl3; major
rotamer) δ 200.1, 139.0, 128.6, 127.7, 127.0, 58.3, 33.8, 33.1, 14.3;
HRMS m/z [M + H]+ calcd for C11H16NS 194.0998, found 194.0941.
N-(1-(4-Fluorophenyl)ethyl)-N-methylethanethioamide (4s).
Silica gel chromatography (3:1 hexanes/EtOAc) yielded 326 mg (67%
yield) of N-(1-(4-fluorophenyl)ethyl)-N-methylethanethioamide as a
yellow amorphous solid: TLC Rf = 0.3 (3:1 hexanes/EtOAc); 1H
NMR (400 MHz, CDCl3; major rotamer) 1H NMR δ 7.34−7.30 (m),
7.24 (q, J = 7.1 Hz, 1H), 7.21−7.17 (m), 7.10−7.02 (m), 2.69 (s, 3H0,
2.86 (s, 3H), 1.56 (d, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3;
major rotamer) δ 200.0, 199.0, 163.2, 160.8, 134.7 (d, J = 3.3 Hz),
134.1 (d, J = 3.3 Hz), 128.6 (d, J = 8.2 Hz), 130.0 (d, J = 8.2 Hz),
115.7 (d, J = 21.4 Hz), 115.3 (d, J = 21.4 Hz), 58.9, 57.5, 36.4, 33.6,
33.0, 32.2, 16.9, 14.5; HRMS m/z [M + H]+ calcd for C11H15FNS
212.0904, found 212.0904.
N-Methyl-N-(1-(3-nitrophenyl)ethyl)acetamide (8o). Silica gel
chromatography (2:1 EtOAc/hexanes) yielded 334 mg (31% yield) of
N-methyl-N-(1-(3-nitrophenyl)ethyl)acetamide as a yellow oil: TLC
1
Rf = 0.15 (2:1 hexanes/EtOAc); H NMR (400 MHz, CDCl3; major
rotamer) δ 8.12−8.13 (m, 2H), 7.64 (m, 1H), 7.53 (m, 1H), 6.13 (q, J
= 7 Hz, 1H), 2.74 (s, 3H), 2.18 (s, 3H), 1.57 (d, J = 7 Hz, 3H); 13C
NMR (100 MHz, CDCl3; major rotamer) δ 170.9, 170.5, 148.4, 143.3,
142.8, 133.7, 132.6, 129.9, 128.5, 122.7, 122.3, 121.7, 121.4, 55.3, 49.7,
30.3, 27.7, 22.2, 21.7, 17.6, 15.7; HRMS m/z [M + H]+ calcd for
C11H15N2O3 233.1077, found 223.1077.
4-(1-(N-Methylacetamido)ethyl)pyridin-1-ium 4-Methylben-
zenesulfonate (11o). This compound was generated in situ by
addition of TsOH monohydrate (2.8 mg, 1.1 equivalents) to 1 mL of a
15 mM solution of 10o in CDCl3: 1H NMR (400 MHz, CDCl3; major
rotamer) δ 8.85 (d, J = 6.3 Hz, 2H), 7.78 (d, J = 6.3 Hz, 2H), 7.72 (d, J
= 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 7.00 (broad, 1H), 5.84 (q, J =
7.4 Hz, 1H), 2.80 (s, 3H), 2.31 (s, 3H), 2.12 (s, 3H), 1.51 (q, J = 7.3
Hz, 3H); 13C NMR (100 MHz, CDCl3; major rotamer) δ 171.6, 162.3,
142.2, 141.8, 140.1, 128.9, 125.8, 124.1, 51.3, 31.6, 21.9, 21.2, 15.6.
N-Methyl-N-(3-nitrobenzyl)acetamide (12o). Aqueous workup
yielded 283 mg (54% yield) of N-methyl-N-(3-nitrobenzyl)acetamide
as a yellow oil with sufficient purity such that column chromatography
N-(1-(4-Chlorophenyl)ethyl)-N-methylethanethioamide (5s).
Silica gel chromatography (4:1 hexanes/EtOAc) yielded 90 mg (40%
yield) of N-(1-(4-chlorophenyl)ethyl)-N-methylethanethioamide as a
1
1
was not required: TLC Rf = 0.45 (95:5 chloroform/2-propanol); H
yellow oil: TLC Rf = 0.3 (4:1 hexanes/EtOAc); H NMR (400 MHz,
1
NMR (400 MHz, CDCl3; major rotamer) δ 8.14 (d, J=8.1, 1H), 8.08
(s, 1H), 7.41 (d, J = 8.9, 2H), 7.61 (d, J = 7.7, 1H), 7.51 (t, J = 7.9,
CDCl3; major rotamer) H NMR δ 7.38−7.13 (m, 4H), 7.23 (q, J =
7.1 Hz, 1H), 2.85 (s, 3H), 2.69 (s, 3H), 1.55 (d, J = 7.1 Hz, 3H); 13C
11180
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Article
NMR (100 MHz, CDCl3; major rotamer) δ 200.7, 199.7, 137.9, 137.3,
134.3, 133.9, 129.4, 129.1, 128.7, 128.0, 59.3, 58.0, 37.0, 34.1, 33.5,
32.7, 17.3, 15.8; HRMS m/z [M + H]+ calcd for C11H15ClNS
226.0608, found 228.0607.
N-Methyl-N-(1-(3-(trifluoromethyl)phenyl)ethyl)ethane-
thioamide (6s). Silica gel chromatography (4:1 hexanes/EtOAc)
yielded 35 mg (35% yield) of N-methyl-N-(1-(3-(trifluoromethyl)-
phenyl)ethyl)ethanethioamide as a white amorphous solid: TLC Rf =
0.3 (3:1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3; major
rotamer) δ 7.47−7.62 (m, 4H), 7.32 (q, J = 7.0 Hz, 1H), 2.89 (s, 3H),
2.71 (s, 3H), 1.61 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3;
major rotamer) δ 200.9, 140.2, 131.2 (q, JC−F = 32.3 Hz), 130.6 (q,
130.8, 128.0, 127.0, 126.0, 57.5, 34.0, 33.1, 19.4, 13.9; HRMS m/z [M
+ H]+ calcd for C12H18NS 208.1154, found 208.1153.
N-Methyl-N-(1-(naphthalen-1-yl)ethyl)ethanethioamide
(15s). Silica gel chromatography (4:1 hexanes/EtOAc) yielded 30 mg
(28% yield) of N-methyl-N-(1-(naphthalen-1-yl)ethyl)-
ethanethioamide as an off-white amorphous solid: TLC Rf = 0.3
(4:1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3; major rotamer) δ
8.00 (d, J = 8.3 Hz, 1H), 7.86 (m, 2H), 7.48−7.60 (m, 4H), 7.41 (q, J
= 6.8 Hz, 1H), 2.67 (s, 3H), 2.64 (s, 3H), 1.71 (d, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3; major rotamer) δ 198.7, 135.4, 133.7, 132.1,
129.1, 128.6, 127.2, 126.1, 125.2, 125.0, 124.2, 56.8, 33.9, 33.3, 14.0;
HRMS m/z [M + H]+ calcd for C15H18NS 244.1154, found 244.1155.
Computational Methods. All electronic structure calculations
were performed using Gaussian09 (revision C.01).72 Geometry
optimizations, including relaxed potential energy scans, were
conducted at the B3LYP/6-31+G(d) level of theory. Potential energy
scans were conducted by iteratively fixing the dihedral angle of interest
in 5° increments, followed by minimization of the resulting structure.
For fully optimized cis and trans models, frequency calculations were
performed at the same level of theory to ensure that no imaginary
frequencies were found. The reported energy values are uncorrected
SCF energies. NBO analyses of optimized structures were conducted
using NBO version 5.9.73
JC−F = 1.4 Hz), 129.6, 129.2, 124.6 (q, JC−F = 3.7 Hz), 123.4 (q, JC−F
=
3.7 Hz), 57.8, 33.9, 33.1, 14.5; HRMS m/z [M + H]+ calcd for
C12H15F3NS 262.0872, Found 262.0899.
N-Methyl-N-(1-(4-(trifluoromethyl)phenyl)ethyl)ethane-
thioamide (7s). Silica gel chromatography (4:1 hexanes/EtOAc)
yielded 52 mg (14% yield) of N-methyl-N-(1-(4-(trifluoromethyl)-
phenyl)ethyl)ethanethioamide as a yellow oil: TLC Rf = 0.6 (2:3
hexanes/EtOAc); 1H NMR (400 MHz, CDCl3; major rotamer) δ
7.47−7.62 (m, 4H), 7.32 (q, J = 7.0 Hz, 1H), 2.89 (s, 3H), 2.71 (s,
3H), 1.61 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3; major
rotamer) δ 200.9, 143.1, 129.9 (q, JC−F = 32.2 Hz), 127.3, 125.6 (q,
JC−F = 3.7 Hz), 125.3, 57.8, 33.9, 33.1, 14.5; HRMS m/z [M + H]+
calcd for C12H15F3NS 262.0872, found 262.0877.
ASSOCIATED CONTENT
* Supporting Information
■
N-Methyl-N-(1-(3-nitrophenyl)ethyl)ethanethioamide (8s).
Silica gel chromatography (2:1 hexanes/EtOAc) yielded 37 mg
(35% yield) of N-methyl-N-(1-(3-nitrophenyl)ethyl)ethanethioamide
as a white crystalline solid: mp 94 °C; TLC Rf = 0.2 (2:1 hexanes/
S
Characterization data for model peptoids and thiopeptoids and
computational data. This material is available free of charge via
the Internet at http://pubs.acs.org.
1
EtOAc); H NMR (400 MHz, CDCl3; major rotamer) δ 8.13−8.23
(m, 2H), 7.70 (m, 1H), 7.55 (m, 1H), 7.38 (q, J = 7 Hz, 1H), 2.92 (s,
3H), 2.73 (s, 3H), 1.65 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3; major rotamer) δ 201.4, 141.5, 133.6, 130.2, 129.8, 122.9,
121.5, 57.5, 33.9, 33.2, 14.8; HRMS m/z [M + H]+ calcd for
C11H15N2O2S 239.0849, found 239.0858.
AUTHOR INFORMATION
Corresponding Author
*E-mail: bgorske@bowdoin.edu.
Notes
■
N-Methyl-N-(1-(4-nitrophenyl)ethyl)ethanethioamide (9s).
Silica gel chromatography (2:1 hexanes/EtOAc) yielded 112 mg
(69% yield) of N-methyl-N-(1-(4-nitrophenyl)ethyl)ethanethioamide
as a yellow crystalline solid: mp 71 °C; TLC Rf = 0.45 (2:1 Hexanes/
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
1
EtOAc); H NMR (400 MHz, CDCl3; major rotamer) δ 8.23 (d, J =
This research was supported by an award from Research
Corporation for Science Advancement. Support for the LCMS
instrumentation at Bowdoin College by the NSF (CHE-
1126657) is gratefully acknowledged. Portions of this research
were conducted using the Phoenix Cluster at the University of
WisconsinMadison, which is supported in part by National
Science Foundation Grant No. CHE-0840494. Z.S.B. and
A.M.C. acknowledge the Howard Hughes Medical Institute
Undergraduate Science Program for funding. We thank
Professor Clark Landis for contributive discussions and access
to computational resources at the University of Wisconsin
Madison.
8.9, 2H), 7.51 (d, J = 8.6, 2H), 2.91 (s, 3H), 2.73 (s, 3H), 1.64 (d, J =
3.4, 3H); 13C NMR (100 MHz, CDCl3; major rotamer) δ 201.3, 147.3,
146.5, 127.7, 123.8, 57.7, 33.9, 32.9, 14.7; HRMS m/z [M + H]+ calcd
for C11H15N2O2S 239.0849, found 239.0845.
N-Methyl-N-(3-nitrobenzyl)ethanethioamide (12s). Aqueous
workup yielded 48 mg (45% yield) of N-methyl-N-(3-nitrobenzyl)-
ethanethioamide as a yellow crystalline solid with sufficient purity such
that column chromatography was not required: mp 109−110 °C; TLC
1
Rf = 0.3 (2:1 hexanes/EtOAc); H NMR (400 MHz, CDCl3; major
rotamer) δ 8.17 (d, J = 8.5, 1H), 8.14 (s, 1H), 7.12 (d, J = 7.8, 1H),
7.54 (t, J = 7.6, 1H), 5.43 (s, 2H), 3.25 (s, 3H), 2.74 (s, 3H); 13C
NMR (100 MHz, CDCl3; major rotamer) δ 211.3, 137.6, 133.8, 131.9,
129.8, 122.8, 122.5, 57.6, 39.7, 32.9; HRMS m/z [M + H]+ calcd for
C10H13N2O2S 225.0692, found 225.0692.
N-Methyl-N-(4-nitrobenzyl)ethanethioamide (13s). Silica gel
chromatography (3:1 hexanes/EtOAc) yielded 16 mg (10% yield) of
N-methyl-N-(4-nitrobenzyl)ethanethioamide as a yellow crystalline
solid: mp 140−141 °C; TLC Rf = 0.3 (2:1 hexanes/EtOAc); 1H NMR
(400 MHz, CDCl3; major rotamer) δ 8.22 (d, J = 8.9, 2H), 7.48 (d, J =
8.9, 2H), 5.43 (s, 2H), 3.24 (s, 3H), 2.76 (s, 3H); 13C NMR (100
MHz, CDCl3; major rotamer) δ 202.1, 142.9, 128.4, 127.0, 124.0, 57.8,
39.7, 32.9; HRMS m/z [M + H]+ calcd for C10H13N2O2S 225.0692,
found 225.0691.
N-Methyl-N-(1-(o-tolyl)ethyl)ethanethioamide (14s). Silica gel
chromatography (3:1 hexanes/EtOAc) yielded 30 mg (28% yield) of
N-methyl-N-(1-(o-tolyl)ethyl)ethanethioamide as a clear oil: TLC Rf =
0.3 (3:1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3; major
rotamer) δ 7.39 (m, 1H), 7.24−7.27 (m, 3H), 6.83 (q, J = 6.9 Hz,
1H), 2.75 (s, 3H), 2.64 (s, 3H), 2.22 (s, 3H), 1.57 (d, J = 6.9 Hz, 3H);
13C NMR (100 MHz, CDCl3; major rotamer) δ 198.6, 138.3, 137.1,
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