Torsional and Electronic Factors Control the C?H???O Interaction

Article abstract of DOI:10.1002/chem.201602905

The precise role of non-conventional hydrogen bonds such as the C?H???O interaction in influencing the conformation of small molecules remains unresolved. Here we survey a series of β-turn mimetics using X-ray crystallography and NMR spectroscopy in conju

Full text of DOI:10.1002/chem.201602905

DOI: 10.1002/chem.201602905
Full Paper
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NMR Spectroscopy
Torsional and Electronic Factors Control the CÀH···O Interaction
Russell W. Driver,[a] Timothy D. W. Claridge,[a] Steve Scheiner,*[b] and Martin D. Smith*[a]
Abstract: The precise role of non-conventional hydrogen
bonds such as the CÀH···O interaction in influencing the con-
formation of small molecules remains unresolved. Here we
survey a series of b-turn mimetics using X-ray crystallogra-
phy and NMR spectroscopy in conjunction with quantum
calculation, and conclude that favourable torsional and elec-
tronic effects are important for the population of states with
conformationally influential CÀH···O interactions. Our results
also highlight the challenge in attempting to deconvolute
a myriad of interdependent noncovalent interactions in
order to focus on the contribution of a single one. Within
a small molecule that is designed to resemble the complexi-
ty of the environment within peptides and proteins, the in-
terplay of different steric burdens, hydrogen-acceptor/-
donor properties and rotational profiles illustrate why unam-
biguous conclusions based solely on NMR chemical shift
data are extremely challenging to rationalize.
Introduction
distinguishing between an attractive CÀH···O hydrogen bond
and a coincidental close contact proved challenging and we
subsequently began to investigate the factors that determine
whether a weak interaction is conformationally influential.[8]
A complex ensemble of noncovalent interactions, including hy-
drogen bonds, drives the folding of biopolymers into function-
al conformations. Relatively weak interactions such as the CÀ The study of noncovalent interactions is most relevant when
H···O hydrogen bond[1] make important contributions to the
folding process but their potential for directly influencing con-
formation is unclear.[2] For instance, the CÀH···O interaction
likely contributes to the stability of the A·T base pair in the
Hoogsteen geometry,[3,4] and is also a key component govern-
ing certain catalytic enantioselective processes.[5] Increasingly,
these nonconventional hydrogen bonds are considered to play
a significant role in molecular recognition involved in the bind-
ing of small molecules to large ones.[6] We have previously in-
vestigated whether an intramolecular CÀH···O interaction can
influence the conformation of small molecules in the solid-
state through a combined crystallographic and computational
study.[7] This approach demonstrated that for certain a,a-di-
fluoroamides the CÀH···O interaction could be a determinant
of conformation, with bond enthalpies of up to 3.5 kcalmolÀ1
through increased polarization of the CaÀH bond. However,
examined in a dynamic environment and hence we decided to
extend our work to encompass the solution-state. We recog-
nized that a thorough study would require: 1) a conformation-
ally well-defined platform that would allow us to study the CÀ
H···O interaction; 2) the ability to vary both acceptor and
donor groups around this scaffold; 3) suitable methods to
gauge the influence of the CÀH···O interaction on global con-
formation. Consequently, we decided to utilize an established
parallel b-turn scaffold which would allow us to systematically
probe the influence that of a CÀH···O donor on the rotation of
a single bond within the confines of a conformationally well-
defined system (Figure 1). We and others have previously ex-
tensively investigated the conformational properties of this
peptidomimetic in the solid and solution state and have
shown that b-turn like conformations stabilized by intramolec-
ular hydrogen bonding are well-populated for most deriva-
tives.[9] Our motivation in choosing a small and dynamic b-turn
mimetic was to perform our investigation in a construct resem-
bling a natural protein and peptide environment rather than
a simple chemical model. Our system has a multitude of rotat-
able bonds and many interdependent noncovalent interac-
tions, which significantly complicate analysis but which are
necessary to probe the factors that make the CÀH···O interac-
tion influential within small molecule models, synthetic foldam-
ers and ultimately biomacromolecules.
[a] Dr. R. W. Driver, Prof. T. D. W. Claridge, Prof. M. D. Smith
Chemistry Research Laboratory, University of Oxford
12 Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: martin.smith@chem.ox.ac.uk
Homepage: http://msmith.chem.ox.ac.uk
[b] Prof. S. Scheiner
Department of Chemistry and Biochemistry
Utah State University, Logan, Utah 84322-0300 (USA)
E-mail: steve.scheiner@usu.edu
Supporting information and ORCID from the author for this article are
available on the WWW under http://dx.doi.org/10.1002/chem.201602905.
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of the Creative Commons At-
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medium, provided the original work is properly cited.
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jacent molecules can be observed within the crystal lattice of
these and all other compounds.[10] Close examination of the X-
ray crystal structure of acyl derivative 1 reveals a b-turn-like
motif featuring an NÀH···O=C distance of 2.2 ꢁ, consistent with
this hydrogen bond being a stabilizing element. The CÀH···O=
C distance (2.5 ꢁ) and angle q (1478, CÀH···O=C) in 1 is also
consistent with the presence of a CÀH···O interaction, but we
have previously commented that the shallow rotational energy
profile for related materials bearing simple acyl groups is in-
consequential to the observed conformation.[7] Therefore we
also compared the CÀH···O=C distances in 2–6 to determine
whether disubstitution and cyclization could be influencing
the putative CÀH···O interaction. These internuclear distances
are between 2.4 and 2.6 ꢁ and all are consistent with the pres-
ence of a CÀH···O hydrogen bond. Similarly, examination of the
angle q(CÀH···O=C) across structures 1–6 reveals a relatively
narrow range of values between 1478 and 1558, all of which lie
within the conventionally accepted angle ranges for identifica-
tion of a CÀH···O interaction.[13] For compounds 2–6 the mea-
sured angles and distances are largely similar to those ob-
served for 1.
Figure 1. Strategy to probe torsional and electronic control of the CÀH···O
interaction.
Results and Discussion
We next decided to examine compounds 7–14, which bear
substituents designed to probe the effect of changing the CaÀ
H acidity relative to acyl control compound 1. All appear to
populate turn-like conformations in the solid-state, but a closer
examination of BocGly derivative 14 shows an intramolecular
distance (3.2 ꢁ) much larger than normal; this is consistent
with the global conformation in this case being dominated by
intermolecular hydrogen bonding interactions in the crystal
lattice.[14] In contrast, compounds 7–13 show no additional im-
portant intermolecular interactions and have relatively short
NÀH···O=C distances (between 2.0 and 2.5 ꢁ) consistent with
hydrogen bonding. CÀH···O=C distances vary between 2.2 ꢁ
(for bistrifluoromethylamide derivative 8) and 2.7 ꢁ (for penta-
fluorophenylbenzyl derivative 12). Bistrifluoroamide 8 has a sig-
nificantly shorter CÀH···O=C distance than any other member
in this series, which appears to be consistent with its powerful
electron withdrawing ability. Compound 7, which has a benzylic
CÀH proton, and would consequently be expected to be more
acidic, does not have a significantly shorter CÀH···O=C distance
than 1. A similar observation can be made for cyclopropane 9,
which is somewhat more acidic than an acyclic alkane by
virtue of its greater s-orbital character.[15] Substituted benzyl
derivatives 10, 11 and 12 have relatively long CÀH···O=C dis-
tances (2.8, 2.6 and 2.7 ꢁ, respectively) when compared to 1,
which appears to result from a balance between the proximity
of the sterically demanding arene and Boc groups and stabili-
zation by the CÀH···O interaction. There is no indication that
pentafluorophenyl derivative 12 participates in significant CÀ
H···p interactions. BocPro derivative 13 possesses a relatively
short CÀH···O=C distance of 2.3 ꢁ; this is shorter than geomet-
rically similar cyclopentane 5 and electronically similar BocGly
derivative 14 and likely results from unique torsional preferen-
ces within the turn scaffold.
Solid state studies
We rationalized that to probe the influence of the CÀH···O in-
teraction would require the synthesis of a series of a,a-disub-
stituted derivatives possessing donor and acceptor moieties of
different sizes (and hence different torsional profiles) and vary-
ing electronic properties. The conformation of these materials
was initially examined in the solid-state using single crystal X-
ray crystallography (Figure 2).[10] The substrates we examined
are sterically and electronically diverse, but the vast majority
were found to populate b-turn like structures with intranuclear
distances consistent with a NÀH···O=C hydrogen bond be-
tween the aromatic amide proton donor and the carbonyl
oxygen acceptor, as expected. These distances varied signifi-
cantly between 2.0 ꢁ for powerful a-electron withdrawing
groups such as the bistrifluoromethyl substrate 8, and 2.5 ꢁ for
other groups such as pentafluorophenylbenzyl derivative 12.
Less polarized substituents such as alkyl groups (typified by 2–
6) generally possess longer NÀH···O=C bond lengths.[11] We rec-
ognized that many substrates contain aromatic rings and were
therefore capable of engaging in additional inter- and intramo-
lecular interactions that could potentially affect the global con-
formation. In our search for these additional interactions (par-
ticularly CÀH···p contacts) we were guided by distance criteria
established during surveys of protein X-ray structures and the-
oretical studies.[12]
We were initially interested in whether changing the size of
a-carbonyl substituents through disubstitution and cyclization
without explicitly increasing CaÀH acidity, would affect rota-
tion around the HCCO torsion. Compounds 1–6 explore this
question through a series of simple alkyl derivatives. Although
there are no obvious additional interactions in the crystals of
these materials (1–6) that appear to be responsible for influ-
encing the rotational states of the a,a-disubstituted amide
moiety, incidental intermolecular hydrogen bonds between ad-
Bistrifluoromethyl derivative 8 has the shortest CÀH···O=C
distance and was therefore used as a baseline to evaluate
other compounds with various hydrogen-bond acceptor
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Figure 2. Solid-state conformations of b-turn mimic bearing different CÀH···O donors with relevant intramolecular distances and angles (some atoms omitted
for clarity; distances [ꢁ] are indicated between atoms in bold).[10] Positions of hydrogen atoms are calculated. *: Asymmetric unit contains two conformational-
ly similar but crystallographically unique molecules; distances and hydrogen-bond angles are given for only one molecule. Xanth=9-xanthene.
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groups (16–18). As ureas are somewhat better hydrogen-bond
acceptors than carbamates,[16] we first synthesized urea deriva-
tive 16. This compound has a short (2.2 ꢁ) CÀH···O=C distance,
which again (see 10–12 above) likely results from a balance
between the steric demand of the bistrifluoromethylaryl group
and the increased hydrogen-bond acceptor ability of the urea.
We also synthesized amides 17 and 18 with the expectation
that the trifluoromethyl amide 18 would be a poorer hydro-
gen-bond acceptor than 17. This is borne out by the observa-
tion that the H···O=C distances are 2.3 and 2.6 ꢁ (for 17 and
18, respectively), although the steric demands of these two
amides are obviously different. We also examined the X-ray
structures of 15, 16 and 17 for evidence of interactions involv-
ing the aromatic group (particularly H···p contacts) but as in
10–12 no interactions relevant to the global conformation
were found.
potential strength of these interactions through quantum cal-
culation (Figure 4).[17] We chose a structurally diverse series of
derivatives to investigate the effects of both torsional and elec-
tronic factors on the CÀH···O interaction, and also prepared
a corresponding series of control compounds that do not pos-
sess the carbamate intramolecular hydrogen-bond acceptor.
These are imperfect control compounds as their conformation-
al preferences are necessarily different from compounds bear-
ing an intramolecular hydrogen-bond acceptor group, but
they nonetheless provide a valuable benchmark for compari-
son. Dilution experiments ruled out intermolecular aggregation
at concentrations below 50 mm, and a suite of 2D experiments
permitted assignment of all spin systems and confirmed that
all compounds examined populate a turn-like conformation in
solution, similar to that observed in the solid-state (Figure 4).
Hydrogen bonding is manifested in 1H NMR spectroscopy
through a reduction in diamagnetic shielding and hence we
examined the chemical shifts of amide NÀH (shown in green
in all Figures) and CaÀH (shown in red in all Figures) pro-
tons.[18] 1H NMR chemical shift data appear consistent with the
involvement of amide NÀH and CaÀH protons in hydrogen
bonds for all compounds (with the possible exception of 15),
as both are deshielded relative to their controls. Fluorenyl de-
rivative 15 has only small chemical shift differences relative to
its control 32, potentially consistent with relatively weak and
conformationally inconsequential solution-state interactions.
This is a significant departure from the solid-state structure of
15, in which close CÀH···O and NÀH···O contacts were ob-
served. This discrepancy may derive from differences in the so-
lution and solid-state conformations of 15, but is more likely
a demonstration of the limitations intrinsic to our control com-
pounds. In general the amide NÀH and CaÀH proton chemical
shift differences vary significantly within the series, particularly
for the CaÀH protons.[19] For our nominal control compound 1,
the change in chemical shift (DdCH) versus control compound
31 is 0.78 ppm.[20] The CaÀH donor in 1 is only very moderate-
ly polarized by the adjacent carbonyl; we have previously
demonstrated that similar compounds have an almost flat ro-
tational profile, consistent with a very weak CÀH···O interac-
tion.[7] This suggests that a significant contributor to the de-
shielding observed in 1 is an effect other than hydrogen bond-
ing. It is known that proton chemical shifts are sensitive to
magnetic anisotropic effects from carbonyl groups proximal to
the CaÀH, and also to steric and electric field effects; these are
These bistrifluoromethylamides can also be compared with
monotrifluoromethylamides 20 and 21, which possess different
hydrogen-bond acceptor groups. It was expected that a mono-
trifluoromethylamide group would be a poorer H···O donor
than a bistrifluoromethylamide group, and this is in fact re-
flected in the longer CÀH···O=C distance in 21 (2.6 ꢁ) versus 8
(2.2 ꢁ). It is relevant to note that several of the compounds we
examined (specifically 22 and 23) did not populate turn-like
conformations in the solid-state (Figure 3).The global confor-
mation of these materials is dominated by intermolecular hy-
drogen bonds and crystal packing forces that preclude obser-
vation of the intramolecular interactions of interest; these
compounds are thus included here for completeness but their
solid-state structures are a departure from our usual observa-
tions.
Figure 3. Solid-state conformations of constructs that do not populate b-
turn like conformations. Positions of hydrogen atoms are calculated.
Solution state study: hydrogen-bond donors
likely responsible for the observed DdCH in 1 versus 31.[21]
A
In general, our solid-state survey of CÀH···O donors and accept-
ors shows that many compounds possess internuclear distan-
ces and angles consistent with the presence of multiple non-
covalent interactions. However, in isolation these observations
do not constitute a demonstration that a specific potential in-
teraction is necessarily important or influential in the overall
folding process, as solid-state studies of crystals provide
a wealth of information about small-molecule geometry but
betray little about the energetic or dynamic aspects. Conse-
quently we decided to expand our study and examine the
1H NMR spectra of a cross-section of these compounds and
related study estimated that the deshielding of a proton in-
volved in CÀH···O hydrogen bonding in bindone analogues
was mostly due to these other effects, with only 0.6 ppm (of
a 1.8 ppm shift) ascribed to the influence of hydrogen bond-
ing.[22] Examination of 24[23] versus 29, and 2 versus 28 demon-
strated that the chemical shift differences are significantly
higher (DdCH=1.03 and 1.07 ppm, respectively) than the dif-
ference between 1 and 31; this is counterintuitive as com-
pounds bearing a,a-dialkyl groups such as 24 or 2 are not sig-
nificantly better hydrogen-bond donors than 1.[24] This shift dif-
ference is instead consistent with a larger population of con-
formers that place the CaÀH in proximity to the carbonyl
1
relate observable parameters such as H chemical shift to the
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group, possibly because non-hydrogen bonded conformers are
disfavoured through steric or torsional effects, thereby increas-
ing the significance of the CÀH···O interaction across the time-
averaged ensemble. Although this mechanism is well known in
peptides containing a,a-dialkyl amino acids,[25] it is difficult to
prove here conclusively. Azetidine 3-carboxylic acid derivative
3 and its control 27 demonstrate a larger shift difference than
we examined the temperature dependence of four key com-
pounds (Table 1).[30] The amide temperature coefficients are
almost identical across this series, consistent with the thermally
mediated change in environment being similar. We interpret
this as being a reflection of conserved NÀH···O hydrogen bond
strength, as the length (2.0–2.2 ꢁ) is almost invariant across 1,
2, 8 and 24. In contrast, examination of the temperature coeffi-
cients for the CaÀH protons shows that: 1) 8 has the largest
negative coefficient; 2) 2 and 24 have very similar and relative-
ly large negative coefficients; and 3) the temperature coeffi-
cient for 1 has a significantly smaller value than 2, 8, or 24
(Table 1). We interpret these larger CaÀH temperature coeffi-
cients as reflecting more drastic environmental changes upon
thermal perturbation that ultimately lead to an increase in the
average internuclear CaÀH to O=C distance. With increasing
temperature in an aprotic solvent, the population-weighted
average will reflect: 1) a greater contribution from non-hydro-
gen-bonded conformations leading to reduced deshielding of
protons involved in hydrogen bonds, and hence larger nega-
tive temperature coefficients, 2) a smaller contribution of the
magnetic anisotropic effect as proximity to the carbonyl group
is reduced. The larger temperature coefficient of CaÀH in 24
and 2 versus 1 could thus be a consequence of a “stronger”
CÀH···O interaction. However, although torsional restriction
could certainly potentiate the CÀH···O interaction in 24 by dis-
favouring conformations with f(OCCH) significantly different
from 1808, we feel that the contribution of this effect to the
temperature coefficient is likely small compared to that of
magnetic anisotropy. Compound 8 has a significantly larger
CaÀH temperature coefficient than 2, 24 or 1 and we attribute
this to a combination of significant torsional restriction (plac-
ing the CÀH group closer to the carbonyl oxygen) and consid-
erable CaÀH polarization (increasing the hydrogen-bond
donor ability). In the case of 8 we are confident that the large
cyclobutanes
2 and 28 (DdCH=1.34 ppm vs. DdCH=
1.07 ppm, respectively); this appears to be at odds with solid-
state data, where CÀH···O=C distances for 2 and 3 are 2.4 and
2.5 ꢁ, respectively. This is likely a consequence of the azetidine
Boc group functioning as a hydrogen-bond donor in the solid-
state, which obscures the increased hydrogen bond acidity of
the azetidine 3 CaÀH versus cyclobutane 2. An even larger
chemical shift difference is apparent in the cyclopropanes 9
and 26 (DdCH=1.51 ppm),[26] which is consistent with favoura-
ble electronic and torsional effects working in concert to en-
hance cyclopropane CaÀH hydrogen-bond donor ability
through increased s-orbital character and restriction around
the f(OCCH) torsion by virtue of a,a-disubstitution. Bistrifluor-
omethyl substituted example 8 exhibits the largest chemical
shift difference versus 25 (DdCH=2.51 ppm).[27] We attribute
this predominantly to the electron-withdrawing effect of the
trifluoromethyl groups, enhancing the hydrogen-bond donor
ability of the CaÀH, but also to their increased size versus the
alkyl groups (compounds 2–6) described earlier.[28,29] Thus, if 8
is compared to 24, there is a clear effect due to the increased
size of CF3 relative to CH3, which leads to torsional restriction
about the OCCH bond and favours conformations that place
CaÀH in close proximity to the carbonyl oxygen (as in 9). How-
ever, the largest contributor to chemical shift is likely the elec-
tron-withdrawing effect of substitution with electronegative
fluorine atoms, which polarize the CaÀH bond and result in
a more significant CÀH···O interaction. The combination of
these favourable torsional and electronic factors leads to the
large DdCH observed for 8.
1
positive chemical H shift difference versus control (2.51 ppm)
and large negative temperature coefficient (4.1 ppbKÀ1) indi-
cate the presence of a CÀH···O interaction that influences
global conformation in the solution-state.
In order to probe further whether these chemical-shift
changes are consistent with the presence of hydrogen bonds,
Figure 4. 1H NMR chemical shift data for selected compounds bearing different CÀH···O bond donors versus controls (C6D6, 298 K, 50 mm). Compounds are in
decreasing CaÀH DdH.
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this series; the DdCH value may reflect only electronic factors,
as the steric profile of the ethyl substituent is small. Although
it is possible that the unexpectedly low DdCH value for 16 re-
sults from shielding of the CaÀH by the bistrifluoromethyl-
phenyl substituent, there is no indication of this in the X-ray
structure, and it may that the solution and solid-state confor-
mational preferences differ substantially (as in fluorenyl deriva-
tive 15). In contrast, amides 17 and 33 show relatively large
DdCH values, which is consistent with their steric relatively
bulk, favouring hydrogen-bonded conformations. Trifluoro-
methyl substituted amide 18, which would be expected to be
a poorer hydrogen-bond acceptor, does present a smaller
DdCH than the other amides. There are only relatively small
differences between carbamates 34 and 8, consistent with an
increase in bulk (for 8) having relatively little effect when dis-
tant from hydrogen bonding sites. This series demonstrates
the challenges in attempting to deconvolute a myriad of inter-
dependent noncovalent interactions within a construct that re-
sembles the complex environment of peptides and proteins. In
particular, the interconnectedness of the NÀH···O and CÀH···O
hydrogen bonds coupled with the interplay of different steric
burdens, hydrogen-acceptor/-donor properties and rotational
Table 1. Temperature coefficients for protons potentially involved in H-
bonding interactions.[a]
Cmpd.
R1/R2
CaÀH
NÀH
(red)
(green)
8
2
24
1
CF3/CF3
cyclobutyl
Me/Me
H/H
À4.1
À3.0
À3.0
À1.7
À5.1
À5.5
À5.2
À5.2
[a] Spectra recorded at 500 MHz, [D8]toluene, 50.0 mm, Dd in ppbKÀ1
.
Solution state study: hydrogen-bond acceptors
We next surveyed the effects of changing the hydrogen-bond
1
acceptor group in 8 by comparing the H NMR chemical shifts
of amide NÀH and CaÀH protons to those of control molecule
25 (Figure 5). We chose to examine compounds possessing
a bistrifluoromethyl group as the putative CÀH···O donor be-
cause both solid-state and solution-state data for 8 were con-
sistent with the presence of a conformationally influential CÀ profiles make clear and unambiguous trends based solely on
H···O interaction in this molecule. As discussed earlier, it is chal-
lenging to deconvolute the factors contributing to a chemical
shift and observe directly the effect of hydrogen bonding
NMR chemical shift data difficult to rationalize.[32]
Quantum chemical calculations
1
within an individual compound, but using H NMR spectrosco-
py data from a short series of amides, carbamates and ureas,
all of which are proficient hydrogen-bond acceptors, we
sought to delineate general trends. When analysing com-
pounds such as carbamate 8, where the hydrogen-bond ac-
ceptor oxygen has two lone pairs, we must also consider how
one hydrogen bond could affect the strength of the other, as
it has been shown that participation in an intramolecular hy-
drogen bond reduces the propensity of an atom to accept ad-
ditional intermolecular hydrogen bonds.[31] The largest DdCH
shifts are observed for amides 17 and 33 (DdCH 3.18 and
3.01 ppm, respectively), followed by carbamates 34 and 8,
whilst ureas 35 and 16 demonstrate smaller shifts. By some
measures, ureas may be considered to be more powerful hy-
drogen-bond acceptors than amides which makes this obser-
vation difficult to directly explain.[16] While ethyl urea 35 has
a DdCH value similar to that observed in 34 and 8 it does
have a significantly higher DdNH value and therefore poten-
tially a stronger NÀH···O bond than the other compounds in
Our solution-state and solid-state analyses suggest a correlation
between the steric and electronic properties of different CaÀH
substituents and the propensity of those substituents to func-
tion as donors in CÀH···O interactions. To further evaluate
whether these observations—the close contacts observed in
1
crystal structures and chemical shift changes seen by H NMR
spectroscopy—are a consequence of an attractive CÀH···O in-
teraction we applied quantum calculation using the Gaussi-
an09 package at the M06-2X/6-31+G** level of theory.[33] The
geometry of compounds 8, 9, 2 and 1 and their respective
controls 25, 26, 28 and 31 were probed by rotating the amide
group about torsion angle f(OCCH); fully optimized geome-
tries of minima are presented above (Figure 6).[28] These calcu-
lated geometries are in excellent agreement to those observed
by X-ray crystallography and exhibit only minor differences.
For example: in a,a-bistrifluoromethylamide 8, the optimized
conformation is remarkably similar to that seen in the crystal
structure, with
a
short CÀH···O distance of 2.18 ꢁ and
Figure 5. 1H NMR chemical shift data for selected compounds bearing different hydrogen-bond acceptors versus control 25 (C6D6, 298 K, 50 mm). Compounds
are ordered in decreasing CaÀH DdH. Ar=3,5-(CF3)2C6H3.
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a f(OCCH) torsion angle of 1618 (Figure 2). This conformation
is significantly different from that of its control 25, which pos-
sesses a f(OCCH) torsion angle of 48.[34] The minima illustrated
for 9 and 2, and their controls 26 and 28 have f(OCCH) tor-
sion angles close to 1808; only 28 has an additional minimum
with f(OCCH) close to 08 within 3 kcalmolÀ1. For 1 and 31, ro-
tation about the OCCH torsion from the illustrated minimum is
effectively free, with other minima within 0.1 kcalmolÀ1. This
(in ca. 308 increments) around the f(OCCH) torsion, generating
a series of structures that were fully optimized, tracing out
a potential energy curve as a function of dihedral angle
(Figure 7). The profile shows a clear minimum at f(OCCH)=
1618 and two maxima at f(OCCH)=428 and f(OCCH)=2828.
In both of the maxima, the amide C=O is effectively trans-
planar to one of the CF3 groups, with the NÀH···O hydrogen
bond intact. In contrast, the minimum at f(OCCH)=1618 cor-
appears to be consistent with a weak and inconsequential CÀ responds to the optimum geometry of the CÀH···O hydrogen
H···O interaction. In order to estimate the strength of these in-
tramolecular interactions, we examined the second-order per-
turbation energy E(2) for 8, 9, 2, and 1 through natural bond
orbital (NBO) analysis.[35] This provides an estimation of the
donor–acceptor interaction energy between the oxygen lone-
pair acceptor and the s* orbital of the CaÀH donor. E(2) is
equal to 5.08, 1.66, 2.00, and 1.61 kcalmolÀ1 for molecules 8, 9,
2, and 1, respectively, consistent with values normally observed
for CÀH···O hydrogen bonds.[36] A second metric to estimate
bond.
We subsequently quantified the strength of this interaction
using an approach that has previously been applied to protein
b-sheets.[38] Taking 8 and removing all atoms except those di-
rectly related to the CÀH···O hydrogen bond left two frag-
ments, which were frozen in their precise relative orientations.
The energy of this complex was then compared with the sum
of the energies of each isolated monomer, leading to a value
of 3.6 kcalmolÀ1. This is a relatively strong interaction, consis-
tent with the acidifying trifluoromethyl group, which, in combi-
nation with the torsional effects of geminal Ca-substitution,
led to the observed rotational minimum.
1
the strength of a CÀH···O interaction is the H NMR deshielding
of the bridging CaÀH.[17] The calculated deshielding (DdCHcalcd
)
in 8, 9, 2, and 1 (relative to controls 25, 26, 28 and 31, respec-
tively) was 1.88, 1.26, 0.75, and 0.45 ppm. These values are
smaller than, but consistent with the order observed experi-
mentally in 8, 9, 2, and 1 but refer to a single, static conforma-
tion without thermal averaging. To give an indication of how
much of this deshielding can be attributed to the CÀH···O hy-
drogen bond, we compared the CaÀH chemical shift when in
the optimized geometry (Figure 6) to that after rotating about
the OCNH torsion by 1808. The deshielding of the CaÀH calcu-
lated in this manner is: 1.42, 0.67, 0.50, and 0.38 ppm, for 8, 9,
2, and 1, respectively. It is notable that all of the metrics out-
lined above suggest that the CÀH···O interaction is strongest
for 8 and least significant for 1.[37]
Compound 8 appears to provide the clearest evidence for
a conformationally influential solution and solid-state CÀH···O
interaction. To further explore the relationship between energy
and f(OCCH) torsion, the terminal CH(CF3)2 group was rotated
Figure 7. Computed rotational profiles of 8 as a function of dihedral angle
f(OCCH). Optimized structures are illustrated for important geometries.
Figure 6. Optimized geometries of minima in the surfaces of 8, 9, 2 and 1 (and their respective controls 25, 26, 28 and 31) with close contacts indicated (dis-
tances in ꢁ). Chemical shift changes (DdHcalcd, ppm) were estimated by first calculating the chemical shifts for 8, 9, 2 and 1 in their energy minimized confor-
mations and subtracting the chemical shifts calculated for optimized conformations of 25, 26, 28 and 31, respectively. *: For 31 only one of two energetically
equivalent minima are pictured, and DdHcalcd is the mean of these two conformers (for 31: f(OCCH)=1138; DdHcalcd =0.45 ppm. f(OCCH)=1788;
DdHcalcd =1.06 ppm).
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Chem. 2011, 76, 4432; d) A. M. Vibhute, R. G. Gonnade, R. S. Swathi,
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Conclusions
Through a combined crystallographic, spectroscopic and quan-
tum computational study we have probed the presence and
influence of the CÀH···O interaction in a series of b-turn mimet-
ics and demonstrated that electronic and torsional effects act
in concert to modulate the potential influence of the CÀH···O
hydrogen bond. Considerably polarized CaÀH donor atoms
and conformational restriction appear to be necessary for the
CÀH···O interaction to play a significant role in conformation.
Our results also highlight the challenges in attempting to de-
convolute a myriad of interdependent noncovalent interac-
tions in order to focus on the contribution of a single one.
Within a biomimetic construct designed to resemble the com-
plexity of the environment within peptides and proteins, the
interconnectedness of different hydrogen bonds coupled with
the subtle interplay of steric burdens, hydrogen acceptor/
donor properties and rotational profiles illustrate why unam-
biguous conclusions based solely on NMR chemical shift data
are extremely challenging to rationalize, even for carefully cali-
brated model systems. These conclusions are directly relevant
to foldamer and protein conformational preferences, especially
b-sheets,[13] where a-electronegative atoms can enhance CaÀH
acidity and work in concert with conformational and torsional
restriction provided by an extensive network of strong hydro-
gen bonds to potentiate weaker CÀH···O interactions. In the
context of designing and developing new folded systems and
hydrogen-bonding organocatalysts that exploit the CÀH···O hy-
drogen bond as a structural element, it is clear that a combina-
tion of favourable electronic and torsional effects is a prerequi-
site for such interactions to be conformationally influential.[39]
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Acknowledgements
The European Research Council has provided financial support
(FP7/2007-2013)/ERC grant agreement no. 259056. This work
was supported by EPSRC (EP/I003398/1) and NSF (CHE-
1026826). We are extremely grateful to Dr. Amber Thompson
for expertise and training in X-ray crystallography, and Barbara
Odell for assistance with NMR spectroscopy. We gratefully ac-
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Keywords: crystallography · density functional calculations ·
foldamers · hydrogen bonds · NMR spectroscopy
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Published online on && &&, 0000
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FULL PAPER
A social network: A survey of the con-
formation of derivatives of a b-turn-like
scaffold with the use of X-ray crystallog-
raphy and NMR spectroscopy in con-
junction with quantum calculation,
demonstrate that a combination of tor-
sional and electronic effects is likely im-
portant for the population of states
with conformationally influential CÀ
H···O interactions.
&
NMR Spectroscopy
R. W. Driver, T. D. W. Claridge,
S. Scheiner,* M. D. Smith*
&& – &&
Torsional and Electronic Factors
Control the CÀH···O Interaction
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10
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!