High-Field NMR Spectroscopy Reveals Aromaticity-Modulated Hydrogen Bonding in Heterocycles

Article abstract of DOI:10.1002/anie.201705023

From DNA base pairs to drug–receptor binding, hydrogen (H-)bonding and aromaticity are common features of heterocycles. Herein, the interplay of these bonding aspects is explored. H-bond strength modulation due to enhancement or disruption of aromaticity of heterocycles is experimentally revealed by comparing homodimer H-bond energies of aromatic heterocycles with analogs that have the same H-bonding moieties but lack cyclic π-conjugation. NMR studies of dimerization in C₆D₆ find aromaticity-modulated H-bonding (AMHB) energy effects of approximately ±30 %, depending on whether they enhance or weaken aromatic delocalization. The attendant ring current perturbations expected from such modulation are confirmed by chemical shift changes in both observed ring C?H and calculated nucleus-independent sites. In silico modeling confirms that AMHB effects outweigh those of hybridization or dipole–dipole interaction.

Full text of DOI:10.1002/anie.201705023

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: High-Field NMR Spectroscopy Reveals Aromaticity-Modulated
Hydrogen Bonding (AMHB) in Heterocycles
Authors: Tayeb Kakeshpour, John P. Bailey, Madison R. Jenner, Darya
E. Howell, Richard J. Staples, Daniel Holmes, Judy I. Wu, and
James E. Jackson
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705023
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High-Field NMR Spectroscopy Reveals Aromaticity-Modulated
Hydrogen Bonding (AMHB) in Heterocycles
[
a]
[b]
[a]
[a]
[a]
Tayeb Kakeshpour, John P. Bailey, Madison R. Jenner, Darya E. Howell, Richard J. Staples,
[
a]
[c]
[a]
Daniel Holmes, Judy I. Wu,* and James E. Jackson*
Abstract: From DNA base pairs to drug-receptor binding, hydrogen
instance involving ring 1’ is biotin, which complexes with avidin by
accepting two H-bonds from residues Ser16 and Tyr33, and
donating one to Asn118 (Scheme 1c).[
(H-)bonding and aromaticity are common features of heterocycles.
6]
Herein, the interplay of these bonding aspects is explored; H-bond
strength modulation due to enhancement or disruption of heterocycles’
aromaticity is experimentally revealed by comparing homodimer H-
bond energies of aromatic heterocycles with analogues that have the
same H-bonding moieties but lack cyclic π-conjugation. NMR studies
6 6
of dimerization in C D find aromaticity-modulated H-bonding (AMHB)
energy effects of ca. ±30%, depending on whether they enhance or
weaken aromatic delocalization. The attendant ring current
perturbations expected from such modulation are confirmed by
chemical shift changes in both observed ring C-H and calculated
nucleus-independent sites. In silico modeling confirms that AMHB
effects outweigh those of hybridization or dipole-dipole interaction.
In recent quantum chemical analyses of hydrogen (H-) bonding
heterocycles,[1] using the nucleus-independent chemical shift
(
NICS) method as an index of aromatic or antiaromatic π-
delocalization,[ we found a systematic relationship between their
2]
anti)aromaticity and H-bond association energies. Specifically,[
3]
(
“
H-bonding interactions that enhance aromaticity or relieve
antiaromaticity are fortified, whereas those that intensify
antiaromaticity or disrupt aromaticity are weakened, relative to
analogues lacking full π-circuits.”[1b] As H-bonds play key roles in
the interactions of biologically important heterocycles such as
DNA bases, enzyme cofactors, and drugs, such insights into the
factors affecting H-bond strength are of broad interest and use.[4]
The interplay between aromaticity and H-bonding can be
probed by comparing heterocyclic dimers with H-bonds that
strengthen or weaken aromatic delocalization; compounds 1 and
Scheme 1. a) Structures of compounds studied here, and b,c) two examples
showing the significance of their H-bonding in ligand-protein binding.
Measurements of association energetics in classic H-bonded
systems such as alcohols or water are complicated by formation
of a range of aggregates. To avoid this complexity, 1, 1’, 2, and 2’
were designed for simple pairwise homodimerization by blocking
any “extra” potential H-bond donor moieties with methyl (in 1 and
1’) or ethanato (in 2 and 2’) groups. Another possible complication
is tautomerization, as in 2-pyridone vs. 2-hydroxypyridine; such
tautomeric equilibria are strongly affected by H-bonding media.[7]
However, G3(MP2) calculations find compounds 1, 1’, and 2 to
be well below their tautomers in energy, both in the gas-phase
(8.7, 16.8, and 8.8 kcal/mol, respectively), and in implicit benzene
solvent (9.9, 18.1, and 8.8 kcal/mol) (Table S1).[8]
2
(Scheme 1a) were chosen for these two cases, respectively. To
quantify the effect, their H-bond energies are compared with those
of compounds 1’ and 2’, which have the same H-bonding motifs
but lack π-conjugated circuits. Apart from their simplicity for this
fundamental study, these heterocyclic frameworks can be found
in many biologically active compounds. As an example for 1,
compound A (Scheme 1b) accepts two H-bonds from Arg74 and
Thr101, while donating one to Gln105 in the binding pocket of
pseudomonas aeruginosa thymidylate kinase.[5] A well-known
For the dimerization energy differences between 1 and 2 and
their reference compounds to be meaningful, accurate equilibrium
1
data was needed. Though H NMR spectroscopy was a natural
[
a]
T. Kakeshpour, M. R. Jenner, D. Howell, R. J. Staples, D. Holmes,
and J. E. Jackson
Department of Chemistry, Michigan State University, East Lansing,
Michigan 48824, United States
E-mail: Jackson@chemistry.msu.edu
J. P. Bailey
tool to use, MSU’s 500 and 600 MHz spectrometers did not allow
measurements of sufficiently low concentrations to yield reliable
association energies for compound 1. The high sensitivity of the
900 MHz NMR instrument (Bruker AVANCE) was the key to this
[
b]
c]
Chemistry Department, Kalamazoo College, Kalamazoo, Michigan,
problem, enabling useful spectra to be collected at concentrations
as low as 10 µM. There, even compound 1, the strongest H-
bonded dimer studied, was substantially dissociated. Measured
enthalpies of dimerization are presented in Figure 1 (see the
experimental section for details and other extracted values).
49006, United States
[
J. I. Wu
Department of Chemistry, University of Houston, Houston, Texas,
77204, United States
E-mail: jiwu@central.uh.edu
Supporting information for this article is given via a link at the end of
the document.
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As an aromaticity index, changes in the π-ring currents of
change (∆NICS(1)zz = –1.57 ppm, increased aromaticity) in the
compounds 1 and 2 upon dimerization were probed via NICS(1)zz
,
five-membered ring upon dimerization of 1 to 1dimer.
the dissected nucleus-independent chemical shift. This analysis
uses only the zz components of the isotropic shift tensors,
computed at points 1 Å above the ring centers (to minimize σ-
orbital effects).[2a] Upon dimerization, a negative change in
NICS(1)zz value indicates increased aromatic character, while a
positive change signifies the opposite. The observed methine CH
chemical shift changes upon dimerization serve as additional
probes for the enhanced resonance forms shown in Figure 1.
Figure 2. H-bonded heteroatom distances from X-ray structures of 1, 1t-butyl and
(left) vs. their reference compounds 1’, 1’t-butyl and 2’ (right). Oxygen, nitrogen,
2
carbon and hydrogen atoms are red, blue, gray and white respectively.
Dimerization of 2 to 2dimer decreases cyclic six π-electron
aromaticity in the lower ring of 2dimer (see Figure 1b, top), resulting
in a 2.39(16) kcal/mol weaker dimerization enthalpy for 2 vs. 2’
(∆dimH = –6.57 vs. –8.96 kcal/mol, respectively), a 0.108(2) Å
longer intermolecular N···N distance in 2dimer than in 2’dimer (see
Figure 2), and upfield shifts (by 0.011(1) and 0.128(1) ppm) in the
1
E F
H NMR signals for H and H in 2dimer relative to those in 2 (blue
Figure 1. The two cases of aromaticity-modulated H-bonding. Enthalpies were
values, Figure 1b).[10] H-bond-induced disruption of aromaticity in
upon dimerization to 2dimer is also supported by the +1.75 ppm
1
measured in C
6
D
6
via H NMR spectroscopy. Aromatic rings are shown in red.
2
change in NICS(1)zz value (i.e. decreased aromaticity).
Charge polarization vs. AMHB: Chemical shifts. The
respective downfield and upfield shifts of the methine protons of
compounds 1 and 2 upon dimerization qualitatively agree with
expected AMHB trends. But these changes reflect not only π-
delocalization effects; H-bond-induced polarization (expected to
work in the same direction as aromaticity enhancement) must also
be considered. For example, the two methylene groups of
compound 1’ shift by +0.502(4) and +0.126(19) ppm upon H-
bonding. Thus, the methine peak shifts in 1 and 2 reflect both π-
aromaticity perturbations and overall polarization effects (Figure
To complement the NMR data, single crystals of compounds
and 2 (grown and characterized via X-ray crystallography) and
1
known crystal structures of compounds 1t-butyl, 1’, 1’t-butyl, and 2’
were examined to assess the geometric effects of AMHB.[9]
Energetic, geometric, and magnetic evidence document the
effects of aromaticity gain. Upon dimerization of 1, cyclic six π-
electron delocalization is enhanced in the five-membered rings of
dimer (Figure 1a, top, red highlights). The measured dimerization
enthalpy is 2.35(15) kcal/mol more negative for 1 than it is for 1’
dimH = –8.92 vs. –6.57 kcal/mol), the analogue with no π-
conjugated circuit and thus no AMHB. The N···O distance
shortening (by 0.061(4) and 0.092(2) Å) in the structures of 1 vs.
’ and 1t-butyl vs. 1’t-butyl (Figure 2, top and middle) also support
the stronger H-bonding in 1 and 1t-butyl. (Unlike 1’, compound 1
1
(
∆
1, resonance structures) for 1dimer, 1’dimer, and 2dimer; in 2’dimer, fast
degenerate tautomerization averages resonances, complicating
this analysis. Nonetheless, all the proton peaks of these
compounds shift downfield upon dimerization, except those of the
methine groups of compound 2 (see Table S2 for a listing of shift
values); it is this exception that highlights the role of AMHB.
Hybridization vs. AMHB: Energetics. Comparisons of the
computed association energies of 1 and 2 to a series of reference
compounds without a cyclic π-conjugated circuit, 1’ and 1’a-c and
1
and the tert-butyl derivatives, 1t-butyl and 1’t-butyl, form simple
1
dimers in their crystals.) Downfield shifted H NMR signals for H
A
B
and H in 1dimer (by 0.062(1) ppm and 0.597(1), relative to those
[
10]
of 1; see blue values, Figure 1a) document the magnetic effects
of AMHB. Computed NICS(1)zz agrees, showing a negative
2’ and 2’a-c (see Figure 3), show that ring carbon hybridizations
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of the reference compounds have little effect on AMHB. As shown
data for H-bonding interactions in solution may also serve as
reference standards for the evaluation and improvement of
theoretical solvation models, enabling more realistic descriptions
of molecules and their reactions in solution.
2
in Figure 3, the computed ∆dimE for 1 (two sp carbons) is
2
consistently more negative than for 1’ (zero sp carbons), 1’a and
2
2
1
’b (one sp carbon each), and 1’c (two sp carbons), indicating
2
aromaticity gain in 1dimer, while that of 2 (two sp carbons) is less
negative compared to 2’ (zero sp carbons), 2’a and 2’b (one sp
carbon each), and 2’c (two sp2 carbons). These comparisons
2
2
Table 1. Dipole-dipole interaction energies (Ed-d) obtained from monomer
dipole moments (µ) calculated at the MP2/aug-cc-pVTZ level in the gas-
phase. ϴ and d are respectively the angles and distances between the two
µ vectors of monomers in their dimer geometries, respectively.
support the notion that aromaticity modulates H-bond strengths in
a manner distinct from simple rehybridization effects.
Cpd.
1
d (Å)
ϴ (°)
µ (D)
E
d-d (kcal/mol)
5.313
5.424
5.171
5.299
54.52
55.27
58.83
56.63
4.3458
4.7805
4.6188
3.8340
0.02
–0.05
–0.44
–0.13
1’
2
2’
Experimental and Computational Section
For compounds 1, 1’, 2, and 2’ in benzene, the homodimerization equilibria
were established faster than the NMR time scale, so observed chemical
shifts appeared as weighted averages of monomer and dimer forms.
These averaged shifts were measured over a range of concentrations at
four temperatures, namely ca. 280, 290, 300 and 310 K. Fitting to the
equation for monomer-dimer equilibrium (equation S1 in the SI)[11] enabled
the extraction of equilibrium constants, which in turn yielded dimerization
enthalpy ΔdimH and entropy ΔdimS values via the Van’t Hoff equation.
These quantities, along with Gibbs free energy ΔdimG and equilibrium
constant K values at 298.15 K, are summarized in Table 2 for compounds
Figure 3. Counterpoise-corrected gas-phase dimerization energies (kcal/mol)
and their differences relative to 1 and 2 at the ωB97X-D/aug-cc-pVDZ level.
1, 1’, 2, and 2’. The near perfect fit of experimental data to equation S1
Dipole-dipole Interaction vs. AMHB: Energetics. Besides
supports the absence of aggregates larger than dimers in the temperature
and concentration ranges chosen for this study (see SI for plots). All
measurements were performed in triplicate; standard deviations are
shown in parentheses. While 91% and 84% data completeness was
obtained (and needed) for species 1 and 2’ respectively, for 1’ and 2, data
covering 77% and 65% (solubility limited) of the monomer-dimer chemical
shift range was enough to obtain the uncertainties seen in Table 2.
Because the N–H resonances show by far the largest changes in chemical
shift between dimer and monomer forms, they were the primary data used
in computing association constants. Between the monomer and dimer
aromaticity, another property that changes upon hydrogenation of
1
and 2 to their corresponding reference compounds is dipole
moment (µ). To investigate the magnitude of the dipole effect on
interaction energies, the µ vectors of monomers of 1, 1’, 2, and 2’
were calculated using the geometries found in the optimized C
i
or
C2h symmetry dimers. Dipole-dipole distances, angles, and
interaction energies (r, ϴ and Ed-d) for the dimers were then
computed and are listed in Table 1. Notably, for all four species,
the µ values are similar and the angles (ϴ) relating the (parallel)
dipoles to the interdipole axes in the dimers are close to the magic
angle (54.74°), making all the Ed-d values small. For 1 and 1’,
these Ed-d values are essentially negligible, whereas those of 2
and 2’ are slightly attractive. In both cases, the dipole effects are
opposite to and substantially smaller than those of AMHB. Thus,
dipole-dipole interactions do not account for the dimerization
energy differences seen upon hydrogenation.
chemical shift values δ
M
and δ
D
of the studied compounds’ N–H sites, δ
D
is uniformly several ppm downfield from δ
M
, due to H-bond induced
deshielding. These chemical shifts were computed as variables in the
fitting of the model equation at the studied temperatures. Their values at
298.15 K, along with the corresponding temperature coefficients, denoted
as dδ /dT and dδ /dT, are listed in Table 2. Though their chemical shift
M D
ranges were smaller (see Table S2), fitting the C–H data of 1 and 2 gave
essentially identical equilibrium constants and thermodynamic data.
C D was the solvent selected for the present study. While it has weak
6 6
In sum, experimental and theoretical evidence clearly point to
significant geometric, energetic, and magnetic effects of AMHB.
As illustrated herein, perturbations of aromaticity can modulate
the H-bonding energies of heterocycles in solution by as much as
interactions with solute due to its low polarity, it dissolves all compounds
studied. Notably, compared to the gas-phase calculated association
energies (Figure 3), the experimental energy differences are smaller.
Though the exact molecular interactions are beyond the reach of our
current experimental tools, such a general flattening effect would be
expected if the more strongly H-bonding monomer species were also more
strongly solvated via H-bonding. It also has the minimum number of
overlapping peaks in the chemical shift range where the studied N–H
peaks appear. Furthermore, its freezing and boiling temperatures allowed
measurement in the temperature range available on MSU’s 900 MHz NMR
instrument, i.e. ca. 5 to 40 °C. Deuterated methanol was used for
30%. Quantum chemical calculations find that although
hybridization and dipole effects are present, changes in aromatic
character are dominant. The AMHB relationship may help to
rationalize H-bonding interactions in nature and guide
experimental design of ligands, self-assembling supramolecular
structures, and organocatalysts. The reported high-field NMR
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Angewandte Chemie International Edition
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COMMUNICATION
temperature calibration of the cryogenic probe.[12] To rigorously exclude
water (which could hinder analyses by forming H-bonded complexes with
Schleyer, H. Jiao, N. J. R. van E. Hommes, V. G. Malkin, O. L.
Malkina, J. Am. Chem. Soc. 1997, 119, 12669–12670. c) C.
Corminboeuf, T. Heine, G. Seifert, P. von R. Schleyer, J. Weber,
Phys. Chem. Chem. Phys. 2004, 6, 273–276.
the substrates)[13]
6 6
C D was dried over molecular sieves, the substrates
were sublimed before measurement, and samples were prepared in a dry
box. In all experiments, no or negligible peaks were observed at 0.4 ppm,
the chemical shift associated with residual water impurity in C D
6 6
.[14]
[
3] As noted by a referee, elegant spectroscopic studies in porphyrinoids
by Limbach et al. have explored the relationships of intramolecular H-
bond dynamics/exchange barriers and aromatic delocalization, as well
as the cooperativity of isotopic perturbations in the two NHN H-bonds
in porphyrin and porphycene derivatives. Such unimolecular systems,
however, do not specifically relate aromatic stabilization or
destabilization with H-bond association energies. See: a) M.
Schlabach, H. Rumpel, H.-H. Limbach, Angew. Chemie Int. Ed.
English 1989, 28, 76–79. b) M. Pietrzak, M. F. Shibl, M. Bröring, O.
Kühn, H.-H. Limbach, J. Am. Chem. Soc. 2007, 129, 296–304.
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Stern, A. A. Sarjeant, J. T. Hupp, O. K. Farha, C. A. Mirkin, J. Am.
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[7] a) Ł. Szyc, J. Guo, M. Yang, J. Dreyer, P. M. Tolstoy, E. T. J.
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Chem. 2002, 67, 1515–1519. c) For the tautomer of compound 1, no
energy minimum was found for the corresponding reference species’
H-bonded dimer; all attempted geometry searches relaxed to the
dimer of the corresponding N-H···O tautomer. See reference [1b] for
a discussion of AMHB in the tautomer of compound 2.
Table 2. Thermodynamic and chemical shift values (at 298.15 K) obtained
from NMR spectroscopy in Standard deviations obtained from
triplicate measurements are shown in parentheses.
6 6
C D .
Cpd.
1
1’
2
2’
[
∆
dimH (kcal/mol)
–8.92(15)
–14.76(52)
–4.52(1)
–6.57(7)
–15.40(22)
–1.98(0)
–6.57(4)
–15.03(16)
–2.09(1)
–8.96(16)
–18.30(40)
–3.50(4)
∆dimS (cal/molK)
∆dimG (kcal/mol)
[
-
1
K (M )
(ppm)
/dT (ppb/K)
(ppm)
/dT (ppb/K)
2042(40)
5.685(10)
+0.5(7)
28.1(2)
3.221(3)
+0.8(1)
34.1(4)
2.899(3)
+0.7(1)
370(26)
3.108(21)
+2.7(2.7)
9.564(41)
δ
M
[
dδ
M
δ
D
12.532(7)
8.070(5)
8.169(15)
dδ
D
–7.0(3)
–9.4(1)
–10.2(8)
–8.5(6)
[
8] a) M. J. Frisch, et al, Gaussian09, Revision D.01; Gaussian, Inc.:
Wallingford CT, 2013. b) L. A. Curtiss, P. C. Redfern, K.
Computed geometries of all monomers and dimers were optimized at
ωB97X-D/aug-cc-pVDZ,[15] and the calculated H-bonding dimerization
energies include counterpoise corrections. Vibrational analyses verified
the nature of all computed minima. The ωB97X-D/aug-cc-pVDZ level has
been shown to produce H-bonding interaction energies comparable to
results computed at the CCSD(T)/CBS level.[16] NICS(1)zz values at
Raghavachari, V. Rassolov, J. A. Pople, J. Chem. Phys. 1999, 110. c)
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temperature coefficients were optimized as parameters to fit equation
S1 to the experimental data. Here they are corrected to 298.15 K for
the sake of comparision. b) The aromatic hydrogens of compounds 1
and 2 were assigned by NOE. The assignment of compound 1 was
also confirmed by HMBC. All spectra used are presented in the SI.
11] a) L. Meschede, D. Gerritzen, H.-H. Limbach, Berichte der
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assessed
changes in the aromatic character of the monomers and dimers. For the
nonplanar monomer 2, ΔNICS(1)zz values were computed on both faces
of the five-membered ring (1.36 and 2.13 ppm) and averaged to account
for differences in the π-electron density on the two sides. Monomer dipole
moments were obtained from single point energy calculations at the
MP2/aug-cc-pVTZ level of theory[18] (shown to predict experimental dipole
[
moments well)[19] based on frozen monomer geometries taken from the C
i
or C2h forms of 1dimer, 1’dimer, 2dimer, and 2’dimer
.
[
[
Acknowledgements
12] M. Findeisen, T. Brand, S. Berger, Magn. Reson. Chem. 2007, 45,
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Research at Michigan State University (MSU) was supported by
the National Science Foundation under award CHE-1362812, and
for computing resources, the High Performance Computing
Center at MSU. TK and JEJ would like to thank Dr. Chrysoula
Vasileiou for her comments on the Table of Contents.
7
512–7515.
[
[
[
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Krishnan, J. S. Binkley, R. Seeger, J. A. Pople, J. Chem. Phys. 1980,
72, 650–654.
Keywords: aromaticity • aromaticity-modulated hydrogen
bonding • hydrogen bonding • high-field NMR spectroscopy
[
18] a) M. J. Frisch, M. Head-Gordon, J. A. Pople, Chem. Phys. Lett. 1990,
1
66, 275–280. b) M. J. Frisch, M. Head-Gordon, J. A. Pople, Chem.
[
[
1] a) J. I. Wu, J. E. Jackson, P. v. R. Schleyer, J. Am. Chem. Soc. 2014,
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Angewandte Chemie International Edition
10.1002/anie.201705023
COMMUNICATION
COMMUNICATION
Tayeb Kakeshpour, John P. Bailey,
Madison R. Jenner, Darya Howell,
Richard J. Staples, Daniel Holmes, Judy
I. Wu,* and James E. Jackson*
Page No. – Page No.
High-Field NMR Spectroscopy
Reveals Aromaticity-Modulated
Hydrogen Bonding in Heterocycles
Fine-tuning hydrogen bonding via aromaticity: High-field NMR spectroscopy
measurements show that hydrogen bonding strength of heterocycles is effectively
modulated by perturbations their aromaticity upon hydrogen bonding in solution.
Quantum chemical investigations show that these aromaticity perturbations are
dominant, overweighting hybridization or dipole effects.
This article is protected by copyright. All rights reserved.