Quantifying weak hydrogen bonding in uracil and 4-cyano-4′- ethynylbiphenyl: A combined computational and experimental investigation of NMR chemical shifts in the solid state

Article abstract of DOI:10.1021/ja075892i

Weak hydrogen bonding in uracil and 4-cyano-4′-ethynylbiphenyl, for which single-crystal diffraction structures reveal close CH...O=C and C≡CH...N≡C distances, is investigated in a study that combines the experimental determination of ¹H, ¹³C, and ¹⁵N chemical shifts by magic-angle spinning (MAS) solid-state NMR with first-principles calculations using plane-wave basis sets. An optimized synthetic route, including the isolation and characterization of intermediates, to 4-cyano-4′-ethynylbiphenyl at natural abundance and with ¹³C≡¹³CH and ¹⁵N≡C labeling is described. The difference in chemical shifts calculated, on the one hand, for the full crystal structure and, on the other hand, for an isolated molecule depends on both intermolecular hydrogen bonding interactions and aromatic ring current effects. In this study, the two effects are separated computationally by, first, determining the difference in chemical shift between that calculated for a plane (uracil) or an isolated chain (4-cyano-4′-ethynylbiphenyl) and that calculated for an isolated molecule and by, second, calculating intraplane or intrachain nucleus-independent chemical shifts that quantify the ring current effects caused by neighboring molecules. For uracil, isolated molecule to plane changes in the ¹H chemical shift of 2.0 and 2.2 ppm are determined for the CH protons involved in CH...O weak hydrogen bonding; this compares to changes of 5.1 and 5.4 ppm for the NH protons involved in conventional NH...O hydrogen bonding. A comparison of CH bond lengths for geometrically relaxed uracil molecules in the crystal structure and for geometrically relaxed isolated molecules.reveals differences of no more than 0.002 A, which corresponds to changes in the calculated ¹H chemical shifts of at most 0.1 ppm. For the C≡CH...N=C weak hydrogen bonds in 4-cyano-4′-ethynylbiphenyl, the calculated molecule to chain changes are of similar magnitude but opposite sign for the donor ¹³C and acceptor ¹⁵N nuclei. In uracil and 4-cyano-4′- ethynylbiphenyl, the CH hydrogen-bonding donors are sp² and sp hybridized, respectively; a comparison of the calculated changes in ¹H chemical shift with those for the sp³ hybridized CH donors in maltose (Yates et al. J. Am. Chem. Soc. 2005, 127, 10216) reveals no marked dependence on hybridization for weak hydrogen-bonding strength.

Full text of DOI:10.1021/ja075892i

Published on Web 01/01/2008
Quantifying Weak Hydrogen Bonding in Uracil and
4-Cyano-4′-ethynylbiphenyl: A Combined Computational and
Experimental Investigation of NMR Chemical Shifts in the
Solid State
Anne-Christine Uldry,† John M. Griffin,‡ Jonathan R. Yates,§ Marta Pe´rez-Torralba,|
M. Dolores Santa Mar´ıa,| Amy L. Webber,‡ Maximus L. L. Beaumont,‡
Ago Samoson, Rosa Mar´ıa Claramunt,| Chris J. Pickard,† and Steven P. Brown*,‡
School of Physics and Astronomy, UniVersity of St Andrews, North Haugh, St Andrews KY16
9SS, U.K., Department of Physics, UniVersity of Warwick, CoVentry CV4 7AL, U.K., TCM
Group, CaVendish Laboratory, UniVersity of Cambridge, 19 J J Thomson AVenue, Cambridge
CB3 OHE, U.K., Departamento de Qu´ımica Orga´nica y Bio-Orga´nica, UNED, Senda del Rey 9,
28040 Madrid, Spain, and National Institute for Chemical Physics and Biophysics,
Akadeemia Tee 23, Tallinn, Estonia
Received August 6, 2007; E-mail: S.P.Brown@warwick.ac.uk
Abstract: Weak hydrogen bonding in uracil and 4-cyano-4′-ethynylbiphenyl, for which single-crystal
diffraction structures reveal close CH‚‚‚OdC and CtCH‚‚‚NtC distances, is investigated in a study that
combines the experimental determination of 1H, 13C, and 15N chemical shifts by magic-angle spinning (MAS)
solid-state NMR with first-principles calculations using plane-wave basis sets. An optimized synthetic route,
including the isolation and characterization of intermediates, to 4-cyano-4′-ethynylbiphenyl at natural
abundance and with 13Ct13CH and 15NtC labeling is described. The difference in chemical shifts calculated,
on the one hand, for the full crystal structure and, on the other hand, for an isolated molecule depends on
both intermolecular hydrogen bonding interactions and aromatic ring current effects. In this study, the two
effects are separated computationally by, first, determining the difference in chemical shift between that
calculated for a plane (uracil) or an isolated chain (4-cyano-4′-ethynylbiphenyl) and that calculated for an
isolated molecule and by, second, calculating intraplane or intrachain nucleus-independent chemical shifts
that quantify the ring current effects caused by neighboring molecules. For uracil, isolated molecule to
1
plane changes in the H chemical shift of 2.0 and 2.2 ppm are determined for the CH protons involved in
CH‚‚‚O weak hydrogen bonding; this compares to changes of 5.1 and 5.4 ppm for the NH protons involved
in conventional NH‚‚‚O hydrogen bonding. A comparison of CH bond lengths for geometrically relaxed
uracil molecules in the crystal structure and for geometrically relaxed isolated molecules reveals differences
of no more than 0.002 Å, which corresponds to changes in the calculated 1H chemical shifts of at most 0.1
ppm. For the CtCH‚‚‚NtC weak hydrogen bonds in 4-cyano-4′-ethynylbiphenyl, the calculated molecule
to chain changes are of similar magnitude but opposite sign for the donor 13C and acceptor 15N nuclei. In
uracil and 4-cyano-4′-ethynylbiphenyl, the CH hydrogen-bonding donors are sp2 and sp hybridized,
respectively; a comparison of the calculated changes in 1H chemical shift with those for the sp3 hybridized
CH donors in maltose (Yates et al. J. Am. Chem. Soc. 2005, 127, 10216) reveals no marked dependence
on hybridization for weak hydrogen-bonding strength.
1. Introduction
considered the importance of C-H‚‚‚O hydrogen bonding in
protein-ligand binding and drug design,3,4 transmembrane helix
interactions,5-7 and the stability of helical or â-sheet polypeptide
structures.8,9 Moreover, C-H‚‚‚O interactions have been shown
to play key roles in asymmetric synthesis,10 the mixing of
The role of weak C-H‚‚‚X hydrogen bonding1 in determining
the molecular-level structure and hence a particular property of
a material or function of a biological molecule is being
increasingly recognized.2 For example, recent discussion has
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† University of St Andrews.
‡ University of Warwick.
§ Cambridge University.
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| UNED Madrid.
NICPB, Tallin.
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9
10.1021/ja075892i CCC: $40.75 © 2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 945-954
945

A R T I C L E S
Uldry et al.
polymers in a blend,11 and the activation of alkane C-H bonds
in heterogeneous catalysis.12 While the existence of some
specific weak C-H‚‚‚X hydrogen bonding interactions has been
demonstrated by spectroscopic techniques, e.g., pioneering gas-
phase infrared measurements13,14 as well as recent Fourier
transform infrared (FTIR) experiments on lipid bilayers15 and
a gas-phase photoelectron spectroscopic investigation of ali-
phatic carboxylate molecules,16 most evidence for the existence
of weak C-H‚‚‚X hydrogen bonds has been provided by
analysis of high-resolution crystal structures obtained by X-ray
or neutron diffraction.17 In particular, the widespread occurrence
of short C-H‚‚‚X distances in molecular crystals6,18-21 is taken
to represent strong support for such close C-H‚‚‚X contacts
constituting bonding interactions. The question, however,
remains as to whether these close contacts between potential
donors and acceptors are indeed bonding interactions that
contribute to stabilizing the structure or are merely accidental,
as a result of other packing constraints.22 For example, an
experimental study of the thermodynamic stability of the
membrane protein bacteriorhodopsin showed that mutations
which remove a putative CH‚‚‚O hydrogen bond (CHO angle
) 117° and C-O distance ) 3.4 Å) did not cause significant
destabilization.23
The Nuclear Magnetic Resonance (NMR) chemical shift is
a sensitive indicator of the local electronic environment, thus
suggesting its suitability as a probe of weak hydrogen bonding.
Indeed, in solution-state NMR, an investigation of serine
protease catalysis revealed that the C1ꢀ-1Hꢀ1 proton chemical
shift for the catalytic histidine is shifted by ∼0.6 to 0.8 ppm
downfield because of C-H‚‚‚O hydrogen bonding,24 while Sola`
et al.10 have observed a downfield shift of 2.1 ppm of a CH 1H
resonance between the syn and anti conformers of an organo-
metallic complex, with intramolecular C-H‚‚‚O hydrogen
bonding only being possible in the former case. Moreover,
Cordier et al. have measured h3JCRC′ couplings of 0.2 to 0.3 Hz
across CRsHR‚‚‚OdC hydrogen bonds in â-sheet regions of a
small protein.25 In the solid state, it has been shown that the 1H
NMR chemical shift is a powerful probe of the intermolecular
interactions, notably hydrogen bonding and π-π interactions,
that control the self-assembly of organic molecules in the solid
state.26 Specifically, proton-proton proximities are identified
in two-dimensional 1H double-quantum (DQ) correlation spectra
recorded under fast magic-angle spinning (MAS)27,28 or using
a combined rotation and multiple-pulse sequence (CRAMPS)
approach,29-31 with applications including the study of structure
and dynamics in hydrogen-bonded polymers32 and the biological
molecule bilirubin,33 π-π stacked polycyclic aromatic systems,34-36
polyoxoniobate materials,37 proton-conducting materials,38 and
surface organometallic species.39,40 Moreover, it is being
increasingly recognized that valuable insight is provided by
combining experiment with chemical shift calculations.41-64 In
the context of weak hydrogen bonding, Yates et al. showed,
for the case of maltose anomers, that the strength of weak Cs
H‚‚‚O hydrogen bonding can be quantified by determining the
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946 J. AM. CHEM. SOC. VOL. 130, NO. 3, 2008

H-Bonding in Uracil and 4-Cyano-4
′
-ethynylbiphenyl
A R T I C L E S
Scheme 1
1
difference in H chemical shift between calculations for the
periodic crystal structure and an isolated molecule.51 A key result
from this study was the observation of a clear correlation
between large chemical shift differences (up to 2 ppm) and both
short intermolecular H‚‚‚O distances and bonding angles larger
than 130°. This observation is consistent with the finding by
Yohannan et al.23 that a CH‚‚‚O contact with a short H‚‚‚O
distance, but an unfavorable CHO angle (117°), did not make
a significant contribution to the stability of bacteriorhodopsin.
In 1963, Allerhand and Schleyer postulated that the strength
of a weak hydrogen bonding interaction depends on the
hybridization of the CsH donor group, i.e., C(sp)sH >
C(sp2)sH > C(sp3)sH.1,13,17 In this paper, the effect of
hybridization is investigated by applying a combined experi-
mental and computational approach to two compounds, uracil
1 and 4-cyano-4′-ethynylbiphenyl 2. In uracil, the weak
bonding donors are sp3 hybridized with OH hydroxyl moieties
as acceptor groups. A further important aspect of this work is
the presentation of computational methods for separately
determining the contribution to the NMR chemical shift of
intermolecular hydrogen bonding and intermolecular ring current
effects, as is required for uracil and 4-cyano-4′-ethynylbiphenyl,
where, as is commonly the case, the molecules contain aromatic
moieties as well as hydrogen-bonding groups.
2. Experimental and Computational Details
2.1. Materials and Synthesis. Natural abundance and 15N-labeled
(>99%) uracil (1) was obtained from Sigma-Aldrich, U.K., and
Cambridge Isotope Laboratories, Andover, MA, USA, respectively, and
used without further purification. While the preparation and charac-
terization of 2 at natural abundance has been reported in ref 65, the
synthetic procedure was not described in detail, with specifically no
details being given concerning either the isolation or characterization
of the intermediate compound 4 (see Scheme 1); the authors simply
stated that it was obtained according to the Hagihara et al. conditions.67
We describe here an optimized synthetic route to unlabeled and labeled
2 according to the three-step method depicted in Scheme 1. Specifically,
4-(15N)cyano-4′-iodobiphenyl (15N-3) was obtained by reaction of
commercially obtainable 4,4′-diiodobiphenyl with (15N)-cuprous cyanide
in dimethylformamide68 and subsequently treated with trimethylsilyl-
(13C2)acetylene in the presence of catalytic amounts of bis[triph-
enylphosphine]palladium(II) dichloride and copper(I) iodide in trieth-
ylamine to afford 4-(15N)cyano-4′-[(trimethylsilyl)(13C2)ethynyl]biphenyl
(15N-13 C2-4). Final hydrolysis with dilute aqueous potassium hydroxide
in methanol gives rise to (15N-13C2-2). Full details are given in the
Supporting Information, where IUPAC nomenclature for each com-
pound has also been included.
2.2. Solid-State NMR. 13C and 15N cross-polarization (CP) MAS
experiments were performed on a Varian Infinity Plus spectrometer
operating at H, 13C, and N Larmor frequencies of 300, 75.5, and
30.4 MHz, respectively, using a Bruker 4 mm double resonance probe
at a MAS frequency of 8.5 kHz. Ramped cross polarization69,70 from
1H was used to create transverse 13C and 15N magnetization, with contact
times of 1.0 and 3.0 ms, respectively. The 1H 90° pulse length was of
duration 2.5 µs. TPPM decoupling71 at a 1H nutation frequency of 100
kHz was applied during acquisition, using pulse lengths of 4.67 µs
and a relative phase shift of 11.2° (as determined by a direct spectral
1
15
hydrogen bond donors are sp2 CsH groups with CdO carbonyl
oxygens as acceptors; indeed, uracil was included in the
pioneering systematic crystallographic investigation of Cs
H‚‚‚O interactions in purine and pyrimidine systems by Sutor
in 1963.14 In 4-cyano-4′-ethynylbiphenyl, for which IR spec-
troscopy shows evidence for weak hydrogen bonding,65 the
donors are sp hybridized alkyne CsH groups and the acceptors
are CtN groups. As noted by Langley et al.,65 the CtCH‚‚‚
NtC synthon is identical to that observed in cyanoacetylene
in 1958.66 In this way, this investigation complements our initial
work on the maltose anomers,51 where the CsH‚‚‚O hydrogen
(67) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N. Synthesis 1980,
627.
(68) McNamara, J. M.; Gleason, W. B. J. Org. Chem. 1976, 41, 1071.
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Chem. Phys. Lett. 1994, 223, 283.
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(71) Bennett, A. E.; Rienstra, C. M.; Auger, M.; Lakshmi, K. V. J. Chem. Phys.
1995, 103, 6951.
(65) Langley, P. J.; Hulliger, J.; Thaimattam, R.; Desiraju, G. R. New J. Chem.
1998, 22, 1307.
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9
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A R T I C L E S
Uldry et al.
optimization approach).72-74 Recycle delays of 16 s (1), 16 s (2, 13C),
and 128 s (2, 15N) were used.
relaxed crystal structure. Keeping the atoms in their crystal positions,
i.e., without further geometric relaxation, the distance between single
planes was progressively increased until the shieldings converge to
within 0.04 ppm, effectively isolating one plane from another. This
occurred at a separation of 31 Å, which corresponds to ∼10 times the
size of the original unit cell along the out-of-plane direction. The single
molecule was put into a 8000 Å3 cell, such that intermolecular
interactions with its neighbors are negligible. For 4-cyano-4′-ethynyl-
biphenyl, shieldings were calculated for isolated chains and molecules.
Four distinguishable chains were first taken out of the relaxed crystal
structure. The molecules in the chains were then spaced out so as to
effectively isolate each one from external influence. Specifically, the
chains were calculated in a 25 × b × 25 Å3 cell, where b is the original
crystal lattice parameter of the side along which the chains are aligned.
The separated molecules were put in a 25 × 27 × 25 Å3 cell.
1
The rotor-synchronized two-dimensional H double-quantum (DQ)
MAS experiments26-28 were performed on a Bruker Avance II+
1
spectrometer, operating at a H Larmor frequency of 600 MHz. The
experiments were performed at a MAS frequency of 40 kHz, using a
specially developed 1.8 mm double-resonance probe.75 (The probe is
fitted with a cooling port, such that the additional frictional temperature
increase, as has been previously calibrated, is only +15 °C.) The pulse
sequence and coherence-transfer pathway diagram for the employed
z-filtered DQ MAS experiment is shown in Figure 7 of ref 26. One
cycle of the BABA76 dipolar recoupling sequence was used to create
DQ coherence. The 1H 90° pulse length was of duration 2.5 µs. A 16-
step phase cycle was used to select ∆p ) (2 on the DQ excitation
pulses (4 steps) and ∆p ) -1 (4 steps) on the z-filter 90° pulse, where
p is the coherence order. Sign discrimination in the indirect dimension
was achieved using the States77 protocol. 16 transients were coadded
for each of 88 (1) or 144 (2) t1 slices. Recycle delays of 10 and 40 s
were used for 1 and 2, respectively.
1H and 13C chemical shifts are indirectly referenced relative to neat
tetramethyl silane (Si(CH3)4), using the CH3 resonance of powdered
L-alanine (1.1 ppm (1H) and 20.5 ppm (13C)) as an external reference,
equivalent to adamantane 13C resonances at 29.5 and 38.5 ppm.78,79
15N chemical shifts are indirectly referenced relative to neat liquid CH3-
NO2, by using the 15N resonance of powdered glycine at -347.4 ppm
as an external reference. To convert to the chemical shift scale
frequently used in protein NMR, where the reference is liquid ammonia
at -50 °C, it is necessary to add 379.5 to the given values.
2.3. Computational Details. The first-principles calculations were
performed with the academic release version 4.1 of the CASTEP80
software package, which implements density functional theory using a
plane-wave basis set. The calculations of the shielding tensor utilize
the gauge-including projector augmented-wave method81 (GIPAW) with
“ultrasoft” pseudopotentials,82 as developed by Yates et al.83
The crystal structures of uracil and 4-cyano-4′-ethynylbiphenyl were
obtained from the Cambridge Crystal Database84 (database reference
code URACIL and JOQSEN, respectively). Geometry optimizations
were performed using the PBE85 exchange-correlation functional and
ultrasoft pseudopotentials with a basis set cutoff at 1200 eV and a 2 ×
2 × 4 Monkhorst-Pack grid for uracil, and 522 eV with a 2 × 1 × 1
Monkhorst-Pack grid for 4-cyano-4′-ethynylbiphenyl. The high cutoff
chosen for uracil is required by the presence of the oxygen, for which
even the ultrasoft pseudopotential is relatively hard. Note however that
a lower level of convergence would not affect significantly the
conclusions drawn in this work. Since non-negligible residual forces
remained on the other atoms after first relaxing only the protons (up to
1.2 eV/Å for uracil and 4.7 eV/Å for 4-cyano-4′-ethynylbiphenyl), all
the atoms in the unit cell were subsequently relaxed.
For both uracil and 4-cyano-4′-ethynylbiphenyl, the effect of
intermolecular interactions on the bond lengths was investigated by
relaxing the isolated molecules (starting with the isolated molecule
arrangements described above). In uracil, all atoms were relaxed. For
4-cyano-4′-ethynylbiphenyl, the values cited in the main text are those
obtained by relaxing the protons only. (A full relaxation of all the atoms
was however also performed, the results of which are given in the
Supporting Information.) The geometry-optimizations were performed
with the cutoff energy at 1100 eV (uracil) or 600 eV (4-cyano-4′-
ethynylbiphenyl) and a single k-point at the fractional coordinate (0.25,
0.25, 0.25).
For the geometrically relaxed arrangements described above, shield-
ing tensors were calculated for all atoms. For the uracil crystal the
parameters used were a Brillouin zone sampling defined by a 3 × 3 ×
8 Monkhorst-Pack grid and a plane-wave cutoff at 1100 eV. This
corresponded to the values of the isotropic shielding σiso being
converged to (0.01 ppm for the protons and (0.05 ppm for the other
atoms. Shieldings in 4-cyano-4′-ethynylbiphenyl were obtained with a
3 × 2 × 2 Monkhorst-Pack grid and a cutoff energy of 560 eV. For
the isolated planes/chains and molecules, a single k-point at the
fractional coordinate (0.25, 0.25, 0.25) was found to be sufficient with
a plane-wave energy cutoff of 1100 eV (uracil) or 600 eV (4-cyano-
4′-ethynylbiphenyl).
Nucleus-Independent Chemical Shifts86 (NICSs) were determined
in order to estimate the contribution from aromatic ring currents on
neighboring molecules. The shieldings in CASTEP are obtained from
the calculation of the first-order-induced current that is generated by
the application of the magnetic field.81 The induced current is computed
in reciprocal space, and the shielding can thus be obtained at any point
of the real space. It is therefore straightforward to calculate the NICSs,
defined as -σiso, anywhere in the unit cell. In this work, the NICSs
were calculated within the isolated uracil plane, and within the isolated
4-cyano-4′-ethynylbiphenyl chains, using the same calculation param-
eters as those used for the shielding values at the nuclei. Note that, for
the compounds under consideration in this work, only the nearest rings,
within a plane or a chain, give a significant contribution (which from
ring currents are expected to drop off with distance as 1/r3). This is
evident from the calculations performed on the isolated molecules. In
the case of 2, the single molecules are fully isolated from one another
when the ethynyl proton and the closest neighbor’s ring is 17 Å apart.
In the chain configuration, the second nearest neighbor’s ring is 22 Å
away, excluding therefore any contribution from that ring. As for the
uracil, it will be seen that even the nearest neighbor rings do not
contribute significantly.
For uracil, shielding tensors were calculated (see below) for isolated
planes and isolated molecules as well as for the fully geometrically
(72) De Paepe, G.; Hodgkinson, P.; Emsley, L. Chem. Phys. Lett. 2003, 376,
259.
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Ser. A 1995, 113, 131.
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286.
(78) Earl, W. L.; VanderHart, D. L. J. Magn. Reson. 1982, 48, 35.
(79) Morcombe, C. R.; Zilm, K. W. J. Magn. Reson. 2003, 162, 479.
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Refson, K.; Payne, M. C. Z. Kristallogr. 2005, 220, 567.
(81) Pickard, C. J.; Mauri, F. Phys. ReV. B 2001, 63, 245101.
(82) Vanderbilt, D. Phys. ReV. B 1990, 41, 7892.
The chemical shift δiso ) σref - σiso is given with respect to a
1
reference (e.g., TMS for H and 13C). The references for carbon and
(86) Sebastiani, D. Chem. Phys. Chem. 2006, 7, 164.
(83) Yates, J. R.; Pickard, C. J.; Mauri, F. Phys. ReV. B 2007, 76, 024401.
(84) Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J. Chem. Inf. Comput. Sci.
1996, 36, 746.
(85) Perdew, J. P.; Burke, K.; Enzernhof, M. Phys. ReV. Lett. 1999, 77, 3865.
(87) Gervais, C.; Dupree, R.; Pike, K. J.; Bonhomme, C.; Profeta, M.; Pickard,
C. J.; Mauri, F. J. Phys. Chem. A 2005, 109, 6960.
(88) Yates, J. R.; Pickard, C. J.; Payne, M. C.; Dupree, R.; Profeta, M.; Mauri,
F. J. Phys. Chem. A 2004, 108, 6032.
9
948 J. AM. CHEM. SOC. VOL. 130, NO. 3, 2008

H-Bonding in Uracil and 4-Cyano-4
′
-ethynylbiphenyl
A R T I C L E S
Figure 1. Crystal structure adopted by uracil. (a) Planar arrangement. (b)
Conventional N-H‚‚‚O and weak C-H‚‚‚O hydrogen bonding within a
plane. Color coding: C black, O red, N blue, H gray. The XHY angle, the
H‚‚‚X distance (in red), and the XY distance (in brackets) are indicated.
hydrogen were determined in uracil (similarly to procedures adopted
1
in ref 51,53,87, and 88) and found to be σref ) 29.7 ppm for H and
σref ) 167.8 ppm for 13C. The same reference shieldings were used for
4-cyano-4′-ethynylbiphenyl. More details on how the references are
obtained are given in the Supporting Information. The shielding
references for 17O (water) and 15N (nitromethane) were taken from ref
87, namely σref ) -154.3 for 15N and σref ) 261.5 for 17O. Note that
these reference values were obtained using Trouiller-Martins norm-
conserving pseudopotentials,89 and hence care should be exercised when
considering the 15N and 17O chemical shifts tabulated here. It is to be
emphasized, however, that the changes in chemical shifts that are of
primary interest in this study are independent of the reference value.
It should be noted that the NMR shielding contains, in principle, a
contribution dependent on the sample shape arising from the effect of
the bulk magnetic susceptibility. In common with previous GIPAW
studies the shielding is computed for the case of a spherical sample.
For such a geometry the observed shielding is independent of the bulk
susceptibility. This is the most natural arrangement to quantify the
intermolecular interactions; furthermore, it is directly applicable to
magic-angle spinning experiments which eliminate the isotropic bulk
magnetic susceptibility.90
Figure 2. (a) 13C (300 MHz) CP MAS (8.5 kHz), (b) 15N (300 MHz) CP
MAS (8.5 kHz), and (c) 1H (600 MHz) DQ MAS (40 kHz) spectra of uracil
(a,c) at natural abundance and (b) with 15N labeling. The base contour is at
26% of the maximum intensity.
3. Results and Discussion
slightly closer to the ideal 180° than the CHO bond angles. Note
that the bond lengths and angles given in Figure 1b are those
obtained after geometry optimization, as described in the
Computational Details (section 2.3).
3.1. C-H‚‚‚O Weak Hydrogen Bonding in Uracil. As
shown in Figure 1, the X-ray single-crystal diffraction structure
of uracil91 reveals a layered structure of planes stacked along
(001) at a separation of 3.136 Å. There is one molecule in the
asymmetric unit cell, with Figure 1b showing the intermolecular
hydrogen bonding within each plane. Specifically, there are two
distinct N-H‚‚‚O hydrogen bonds to one carbonyl acceptor and
two distinct C-H‚‚‚O hydrogen bonds to the second carbonyl
acceptor, with the H‚‚‚O distances being 20-25% longer for
the latter weak hydrogen bonds. The NHO bond angles are also
Figure 2 presents a (a) 13C CP MAS, (b) 15N CP MAS, and
1
(c) rotor-synchronized two-dimensional H DQ MAS NMR
spectrum of uracil (a,c) at natural abundance and (b) with 15N
labeling. Such a DQ spectrum displays DQ peaks for pairs of
1
dipolar-coupled H nuclei, where the DQ frequency is given
by the sum of the single-quantum frequencies of the two
involved protons, i.e., ωDQ ) ωSQ1 + ωSQ2. To a first
approximation, the DQ peak intensity is proportional to the
dipolar coupling squared; this corresponds to a 1/r6 distance
dependence, and hence, for a typical organic solid, DQ peaks
are only observed for pairs of protons with a close spatial
(89) Trouiller, N.; Martins, J. L. Phys. ReV. B 1991, 43, 1993.
(90) Harris, R. K.; Becker, E. D.; Cabral de Menezes, S.; Goodfellow, R.;
Granger, P. Pure Appl. Chem. 2001, 73, 1795.
(91) Stewart, R. F.; Jensen, L. H. Acta Crystallogr. 1967, 23, 1102.
9
J. AM. CHEM. SOC. VOL. 130, NO. 3, 2008 949

A R T I C L E S
Uldry et al.
Table 1. Comparison of Experimental Solid-State NMR and
Table 2. Comparison of C-H and N-H Bond Lengths Obtained
from a Geometry Optimization of Uracil within Its Period Crystal
Structure and as an Isolated Molecule
Computed 1H Chemical Shifts for Uracil
calcda [ppm]
bond lengths (in Å)
plane
iso
-mol
donor
expt
∆δ
NICS
[ppm]
rel. mol.a
mol.b
rel. mol.c
[ppm]
bond
cryst.
and site
[ppm]
cryst.
plane
N1-H1
N2-H2
C3-H3
C4-H4
1.047
1.046
1.090
1.087
1.024
1.020
1.088
1.086
N-H H1
N-H H2
C-H H3
C-H H4
11.2
10.8
7.5
11.7
11.2
7.2
12.5
11.9
8.1
7.4
6.5
6.1
4.1
6.7
5.8
6.1
4.0
5.1
5.4
2.0
2.2
0.1
0.01
0.2
0.3
6.0
5.5
6.3
a All atoms relaxed.
a δiso ) σref - σiso, where σref(1H) ) 29.7 ppm. b Geometry as that in
optimized crystal structure. c Geometry after all atoms are relaxed.
geometric optimization). The 1H chemical shift differences
between the crystal and an isolated plane are less than 1 ppm,
as is to be expected for the weak aromatic character of uracil.94
These small changes are to be compared with previously
reported calculated 1H chemical shift differences due to
intermolecular ring currents of up to 6 ppm for benzene,
naphthalene, hexabenzocoronene, and imidazole aromatic
moieties.41-43,56,57,59,64
proximity (less than 3.5 Å).26,28,92 In Figure 3c, pairs of cross-
peaks are observed at 6.0 + 7.5 ) 13.5 and 7.5 + 10.8 ) 18.3
ppm corresponding to the intramolecular proximity of the H3
and H4 (2.53 Å, dipolar coupling constant djk ) 7.4 kHz) and
H2 and H3 (2.35 Å, djk ) 9.2 kHz) protons, respectively. In
addition, a diagonal peak at 11.2 + 11.2 ) 22.4 ppm (2.44 Å,
djk ) 8.3 kHz) corresponding to the intermolecular proximity
of two H1 protons is observed, while a pair of cross-peaks at
6.0 + 10.8 ) 16.8 ppm (2.69 Å, djk ) 6.2 kHz) corresponding
to the intermolecular proximity of the H2 and H4 protons is
also observed. The extension to two dimensions thus allows
the assignment of the distinct H1 and H2 resonances that are
not resolved in a one-dimensional spectrum.
In order to separate out the effect of interplane aromatic ring
currents, a comparison is made here between calculations for
an isolated molecule and an isolated plane of molecules. The
plane-mol
plane
-
iso
molecule to plane differences defined by ∆δ
) δ
iso
mol
1
δ
are listed for the NH and CH H nuclei in Table 1. Of
iso
plane-mol
iso
particular interest is a comparison of the ∆δ
values for
Table 1 compares the experimental 1H solid-state NMR
chemical shifts with the results of first-principles calculations.
Note that it is absolute shieldings that are determined in such
first-principles calculations. To allow comparison with experi-
mental chemical shifts, the calculated chemical shifts presented
in Table 1 and elsewhere in this paper are determined with
respect to a reference shielding, whose calculation is described
in the Computational Details section. (The calculated absolute
shieldings are given in the Supporting Information.) The
experimental and calculated chemical shifts for the periodic
crystal structure are in good agreement, with the largest
discrepancies ((0.5 ppm) seen for the lowest and highest values.
This is a common observation for such calculations, which is
linked to the fact that currently used density functionals are
believed to overestimate the paramagnetic contribution to the
chemical shift.93
the NH protons, H1 and H2, involved in conventional NH‚‚‚O
hydrogen bonding interactions, with those for the CH protons,
H3 and H4, involved in weak CH‚‚‚O hydrogen bonding
1
interactions. It is well-known that the H chemical shift is a
sensitive indicator of hydrogen-bonding strength,95-97 and hence
plane-mol
iso
the ∆δ
values of over 5 ppm for the NH protons are
unsurprising. A similar change has been noted by Schmidt
et al. for a NH proton of L-histidine‚HCl‚H2O involved in
NH‚‚‚O intermolecular hydrogen bonding.56 For the CH protons
involved in weak CH‚‚‚O hydrogen bonding interactions,
plane-mol
iso
∆δ
values of over 2 ppm are calculated, i.e., the
changes are ∼40% of those for the conventional NH‚‚‚O
hydrogen bonding interactions. This will be surprising to many
NMR spectroscopists, since there is very little discussion of the
effect of weak hydrogen bonding on NMR chemical shifts in
the literature.10,24,51,98 These ∆δipsloane-mol values of 2.0-2.2 ppm
are slightly larger than the biggest molecule to crystal changes
While solid-state NMR chemical shifts can only be deter-
mined experimentally for the case of powdered crystallites (or
single crystals) corresponding to the periodic crystal structure,
much greater flexibility is possible with calculations. For
example, ref 51 compares 1H chemical shifts of maltose anomers
as calculated for, on the one hand, the full crystal structure and,
on the other hand, isolated molecules extracted from the crystal
1
in the H chemical shift as calculated for the CH protons in
maltose anomers (1.9 ppm)51 that also exhibit CH‚‚‚O weak
hydrogen bonding.
plane-mol
iso
The ∆δ
values in Table 1 are calculated by com-
parison to the case of an isolated molecule extracted from the
geometrically optimized crystal structure without further geo-
metric optimization. In this way, the above method does not
consider the effect of intermolecular hydrogen-bonding interac-
tions on the YH bond lengths. In order to address this, Table 2
compares the YH bond lengths for uracil molecules for the case
of geometric optimizations of the periodic crystal structure or
an isolated molecule (see computational details). It is observed
that while the N-H bonds are ∼0.02 Å longer for the periodic
1
structure; the isolated molecule to crystal changes in the H
chemical shift were shown to be a quantitative measure of the
relative strength of CH‚‚‚O weak hydrogen-bonding interactions.
For uracil, insight into the effect of intermolecular interactions
on the NMR chemical shifts is provided by a comparison of
calculated 1H chemical shifts (see Table 1) for the full periodic
crystal with those calculated for an isolated plane or an isolated
molecule (for the latter two cases, the isolated plane or molecule
were extracted from the geometrically optimized crystal struc-
ture, and the chemical shifts were calculated without further
(94) Vernon, G. S. B.; Fleumingue, J.-M. J. Mol. Model. 2001, 7, 334.
(95) Berglund, B.; Vaughan, R. W. J. Chem. Phys. 1980, 73, 2037.
(96) Jeffrey, G. A.; Yeon, Y. Acta Crystallogr. 1986, B42, 410.
(97) Harris, R. K.; Jackson, P.; Merwin, L. H.; Say, B. J.; Hagele, G. J. Chem.
Soc., Faraday Trans. 1988, 84, 3649.
(98) Scheffer, J. R.; Wong, Y.-F.; Patil, A. O.; Curtin, D. Y.; Paul, I. C. J. Am.
Chem. Soc. 1985, 107, 4898.
(92) Schnell, I.; Spiess, H. W. J. Magn. Reson. 2001, 151, 153.
(93) Buhl, M.; Kaupp, M.; Malkina, O. L.; Malkin, V. G. J. Comput. Chem.
1999, 20, 91.
9
950 J. AM. CHEM. SOC. VOL. 130, NO. 3, 2008

H-Bonding in Uracil and 4-Cyano-4
′
-ethynylbiphenyl
A R T I C L E S
Table 3. Comparison of Experimental Solid-State NMR and
crystal as opposed to the relaxed isolated molecule, the C-H
bonds change by no more than 0.002 Å. Note that similar
observations have been made from geometrical data calculated
in quantum-chemical studies that compare uracil in the gas phase
with either a uracil-uracil dimer (UU7)99 or a cluster represent-
ing the uracil periodic crystal.100 The 1H chemical shifts
determined for the geometrically relaxed isolated molecule are
also listed in Table 1. It is evident that while the ∼0.02 Å change
in the NH bond length leads to a 0.7 ppm change for the NH
protons as compared to the calculation for an isolated molecule
extracted from the crystal structure without further optimization,
there is virtually no change (<0.1 ppm) for the CH protons
Computed 13C, 15N, and 17O Chemical Shifts for Uracil
calcdb shift [ppm]
plane
iso
[ppm]
-mol
expt
[ppm]
∆δ
NICS
[ppm]
site
cryst.
plane
mol.c
rel. mol.d
C1 CdO
C2 CdO
C3 CsH
C4 CsH
170.9
151.7
147.0
99.9
169.6
149.8
149.1
100.0
170.3
150.7
148.3
99.2
165.0
148.2
138.4
100.7
159.9
147.0
137.6
101.7
5.3
2.5
9.9
0.6
0.4
0.3
0.3
-1.5
N1
N2
-185.2 -209.2 -209.6 -208.9 -211.6
-207.3 -225.2 -226.8 -244.2 -245.7
-0.7
0.5
0.3
1.0
0.6
17.4
O1 (NH) 275a
274.4
257.6
273.2
256.0
407.8
286.0
379.0 -134.6
274.8 -30.0
O2 (CH)
245a
a Reference 100. δiso ) σref - σiso, where σref(13C) ) 167.8 ppm,
b
associated with only a 0.002 Å change in the CH bond length.
15
( N) ) -154.3 ppm (ref 87), and σref (17O) ) 261.5 ppm (ref 87).
plane-mol
iso
σ
ref
While the calculation of ∆δ
excludes ring current
c Geometry as that in optimized crystal structure. d Geometry after all atoms
are relaxed.
effects caused by the other planes above and below, there
plane-mol
iso
remains potential contributions to ∆δ
arising from ring
currents in neighboring, in-plane molecules. One approach that
has been previously employed to untangle hydrogen bonding
and aromatic ring current effects is the modeling of the latter
as a single-point dipole. White et al.101 used this approach
together with a set of susceptibility data to interpret experi-
1
mentally observed H chemical shifts of zeolite OH protons
involved in hydrogen bonding to pi-rich adsorbates such as
acetylene and ethylene. In the context of the present work a
first-principles approach is however to be preferred, and the
ring current contributions can be easily evaluated by calculating
the in-plane Nucleus Independent Chemical Shifts (NICSs). By
definition, the NICS is minus the isotropic shielding, which in
principle can be calculated at any site, whether the site is
occupied by a nucleus or not. NICS calculations are finding
increasing application in the interpretation of solid-state NMR
parameters.56,63,86,102-104 For the uracil NICS calculations, one
molecule was removed from the unit cell for the plane, and the
NICSs due to the other three molecules were calculated at the
positions of the removed molecule. The corresponding NICSs
at the hydrogen sites are given in the last column of Table 1.
While the in-plane NICSs values are small (at most 0.3 ppm),
plane-mol
iso
their sign indicates that ∆δ
tends to overestimate
slightly the strength of the intermolecular hydrogen bonding
interactions in uracil.
Table 3 presents the results of analogous chemical shift
calculations for the 13C, 15N, and 17O nuclei. Note that the stated
calculated chemical shifts were again determined with respect
to a reference shielding (see Computational Details). While the
plane-mol
1
∆δ
values for the H nuclei are positive (see Table 1),
iso
plane-mol
the ∆δ
values are negative for the hydrogen-bond
iso
acceptor 17O nuclei (Table 3), i.e., corresponding to a substantial
increase in shielding when comparing the shieldings for an
isolated molecule to that for a plane. Moreover, the molecule
to plane change for the acceptor of two conventional NH‚‚‚O
hydrogen bonds, O1, is about 4.5 times bigger than that for
O2, which participates in two CH‚‚‚O weak hydrogen bonds.
This marked difference in 17O chemical shifts has been noted
Figure 3. Packing of 4-cyano-4′-ethynylbiphenyl molecules in the solid
state, as determined by X-ray single-crystal diffraction.65 (a) The four
molecules of the asymmetric unit cell are labeled. (b) View of the four
distinct chains. (c) Postulated C-H‚‚‚N weak hydrogen bonding. Color
coding: C black, N blue, H gray. The CHN angle, the HN distance (in
red), and the CN distance as obtained after geometry optimization (see
Computational Details (section 2.3)) are indicated.
previously by Ida et al. who compared quantum-chemical
calculations for clusters of uracil molecules with that for an
isolated uracil molecule.100 The sensitivity of the 17O chemical
shift and also quadrupolar interaction to hydrogen bonding has
been noted by Wu and co-workers also for secondary amides,
benzamide, urea,105-107 and guanine and guanosine deriva-
tives.108 For the ring carbon and nitrogen atoms, there are no
(99) Pavel, H.; Sˇponer, J.; Cubero, E.; Orazco, M.; Luque, F. J. J. Phys. Chem.
B 2000, 104, 6286.
(100) Ida, R.; De Clerck, M.; Wu, G. J. Phys. Chem. A 2006, 110, 1065.
(101) White, J. L.; Beck, L. W.; Haw, J. F. J. Am. Chem. Soc. 1992, 114, 6182.
(102) Rapp, A.; Schnell, I.; Sebastiani, D.; Brown, S. P.; Percec, V.; Spiess, H.
W. J. Am. Chem. Soc. 2003, 125, 13284.
(103) Facelli, J. C. Magn. Reson. Chem. 2006, 44, 401.
(104) Ma, Z.; Halling, M. D.; Solum, M. S.; Harper, J. K.; Orendt, A. M.; Facelli,
J. C.; Pugmire, R. J.; Grant, D. M.; Amick, A. W.; Scott, L. T. J. Phys.
Chem. A 2007, 111, 2020.
9
J. AM. CHEM. SOC. VOL. 130, NO. 3, 2008 951

A R T I C L E S
Uldry et al.
clear trends in the molecule to plane changes in chemical shifts;
this is presumably a consequence of the delocalization of the
electrons in the uracil ring.
3.2. C-H‚‚‚N Weak Hydrogen Bonding in 4-Cyano-4′-
ethynylbiphenyl. The above section considered weak hydrogen
bonding between an sp2 hybridized aromatic CH donor and a
CdO carbonyl acceptor; this section considers 2, where the
X-ray single-crystal structure65 suggests weak hydrogen bonding
between an sp hybridized CtCH donor and a CtN acceptor.
As shown in Figure 3a, the packing is centro-symmetric, with
four molecules in the asymmetric unit cell, labeled 1-4 in
Figure 3a. The crystal structure shows that the molecules pack
as four repeating chains (see Figure 3) corresponding to the
four molecules of the asymmetric unit cell; the chains are all
aligned along (010), noting that chain 4 is oriented in the
opposite direction. Reference 65 indicates significant orienta-
tional disorder for chain 2, with a stated probability of 40% for
the chain to be oriented in the opposite direction to that in the
structure deposited in the Cambridge Crystal Database.84 The
H‚‚‚N and CN distances, as well as the CHN angles for the
postulated intermolecular C-H‚‚‚N weak hydrogen bonds
corresponding to the four chains are indicated in Figure 3c. The
stated distances and angles are those determined after full
geometry optimization (see section 2.3).
1
Experimental H, 13C, and 15N MAS NMR spectra of 2 are
presented in Figures 4 and 5. Specifically Figure 4 presents (a,b)
13C and (d) 15N CP MAS spectra of 2 at (a) natural abundance
and (b, d) with 13Ct13CH and Ct15N labeling, while Figure 5
presents (a) a one-dimensional MAS and (b) a two-dimensional
1
DQ MAS H spectrum of 2. The horizontal bar in Figure 5b
indicates DQ coherences between an ethynyl proton (H9) and
an aromatic proton; the selected slices extracted at different DQ
frequencies shown in Figure 5c indicate a range of positions of
the peak maxima corresponding to the ethynyl proton (H9), as
is to be expected for the presence of four distinct molecules in
the crystal structure.
The 1H, 13C, and 15N chemical shifts were calculated for the
periodic crystal structure (after geometric optimization) of 2.
Specifically, Tables 4 and 5 list the calculated 1H, 13C, and 15
N
chemical shifts (again presented as relative shieldings with
respect to the same calculated reference shieldings as used for
uracil; see Computational Details) for the CH donor and N
acceptor atoms of the CtCH‚‚‚NtC hydrogen bonding ar-
rangements (a full listing of the calculated absolute shieldings
is given in the Supporting Information). Simulated spectra
corresponding to the calculated 13C and 1H chemical shifts for
the 15 carbon and 9 hydrogen atoms in each of the four distinct
molecules are shown in Figures 4c and 5a (dashed line),
respectively. Reasonable agreement between experiment and
calculation is observed. For the ethynyl proton, H9, the
calculated chemical shifts of 4.6, 4.0, 4.9, 4.8 ppm for molecule
1 to 4, respectively, are overestimated as compared to the
experimental distribution of 3.3 to 3.8 ppm (see Figure 5b,c).
Several factors potentially contribute to this overestimation: One
may be the problem of DFT overestimating the paramagnetic
contribution93 noted above in the discussion of Table 1 for uracil;
Figure 4. Experimental (a,b) 13 C and (d) 15 N CP MAS (8.5 kHz) NMR
(300 MHz) spectra of 4-cyano-4′-ethynylbiphenyl (a) at natural abundance
and (b, d) with 13Ct13CH and Ct15N labeling. The simulated spectrum
(c) corresponds to the calculated chemical shifts for the 15 carbon nuclei
in each of the four distinct molecules (tabulated in the Supporting
Information) using Lorentzian lines with full width at half-maximum height
of 0.5 ppm.
Another is the stated disorder in the crystal structure, upon which
(after geometrical optimization) the chemical shift calculations
are based.
In the following, an analogous approach to that employed
for the case of uracil is adopted in order to quantify the effect
of CtCH‚‚‚NtC weak hydrogen bonding on the NMR chemi-
cal shifts for 4-cyano-4-ethynylbiphenyl, focusing first on the
(105) Yamada, K.; Dong, S.; Wu, G. J. Am. Chem. Soc. 2000, 122, 11602.
(106) Wu, G.; Yamada, K.; Dong, S.; Grondey, H. J. Am. Chem. Soc. 2000,
122, 4215.
(107) Dong, S.; Ida, R.; Wu, G. J. Phys. Chem. A 2000, 104, 11194.
(108) Kwan, I. C. M.; Mo, X.; Wu, G. J. Am. Chem. Soc. 2007, 129, 2398.
1
ethynyl H9 H chemical shifts. As noted above, the crystal
structure reveals the formation of four distinct chains due to
9
952 J. AM. CHEM. SOC. VOL. 130, NO. 3, 2008

H-Bonding in Uracil and 4-Cyano-4
′
-ethynylbiphenyl
A R T I C L E S
Table 4. Computed 1H Chemical Shifts of H9 (CtCH) in
4-Cyano-4′-ethynylbiphenyl
calcda shift [ppm]
chain
iso
-mol
∆δ
NICS
[ppm]
mol label
cryst.
chain
mol.b
rel. mol.c
[ppm]
1
2
3
4
4.6
4.0
4.9
4.8
4.5
4.4
4.6
4.8
3.3
3.3
3.4
3.4
3.1
3.2
3.2
3.2
1.2
1.1
1.2
1.4
-0.9
-0.8
-0.9
-1.0
a δiso ) σref - σiso, where σref(1H) ) 29.7 ppm (uracil reference).
b Geometry as that in optimized crystal structure. c Geometry after protons
are relaxed.
Table 5. Computed C and N Chemical Shifts of C15 (Ct13CH)
and 15N1 (13Ct15N) in 4-Cyano-4′-ethynylbiphenyl
calcda shift [ppm]
chain
iso
-mol
mol and
∆δ
NICS
[ppm]
site label
cryst.
chain
mol.b
rel. mol.c
[ppm]
1 C15
2 C15
3 C15
4 C15
92.0
90.4
90.5
91.1
93.0
80.3
80.8
80.7
81.5
80.0
80.5
80.4
81.3
10.2
9.8
10.4
11.5
-0.3
-0.3
-0.3
-0.3
90.2
91.6
92.2
1 N1
2 N1
3 N1
4 N1
-103.0
-101.7
-101.1
-99.8
-95.0
-94.9
-95.6
-96.6
-82.8
-83.2
-83.1
-83.2
-82.9
-83.3
-83.2
-82.2
-12.2
-11.6
-12.4
-13.5
0.2
0.2
0.2
0.2
a δiso ) σref - σiso, where σref(13C) ) 167.8 ppm (uracil reference) and
15
σ
ref
( N) ) -154.3 ppm (ref 87). b Geometry as that in optimized crystal
structure. c Geometry after protons are relaxed.
is consistent with a packing that exposes the CtCH moieties
to minimal interchain ring current effects. As shown in the
Supporting Information, larger chain to crystal changes in the
1H chemical shift (up to 2.6 ppm) are observed for hydrogen
atoms on the benzene rings.
1
Table 4 also lists the H9 H chemical shifts calculated for
the case of extracting the four distinct isolated molecules from
the geometrically optimized crystal structure. Calculations were
performed without and with further geometric optimization of
the isolated molecule structures. Such further geometric opti-
mization resulted in changes in the CH bond length from 1.078,
1.076, 1.078, 1.078 Å (without optimization) to 1.069, 1.069,
1.070, 1.069 Å (optimized); as shown in Table 4, such small
changes of <1% in the CH bond length led to changes of at
1
most only 0.2 ppm in the H9 H chemical shifts. For the H9
chain-mol
chain
-
iso
proton, the molecule to chain changes, ∆δ
) δ
iso
δmisool, are between 1.1 and 1.4 ppm. For the other hydrogen
Figure 5. (a, solid line) A one-dimensional MAS and (b) a two-dimensional
DQ MAS1H (600 MHz) NMR spectrum of 4-cyano-4′-ethynylbiphenyl,
recorded at a MAS frequency of 40 kHz. In (a), the dashed line is a simulated
spectrum that corresponds to the calculated chemical shifts for the nine
hydrogen nuclei in each of the four distinct molecules (tabulated in the
Supporting Information), using Lorentzian lines with full width at half-
maximum height of 0.5 ppm. The horizontal bar in (b) indicates DQ
coherences between an ethynyl proton (H9) and an aromatic proton; selected
slices extracted at different DQ frequencies are indicated in (c), with the
positions of the peak maxima corresponding to the ethynyl proton (H9)
being specified.
chain-mol
atoms on the benzene rings, |∆δ
| is at most 0.1 ppm
iso
(see Supporting Information).
While interchain ring current effects are excluded by calculat-
ing the chemical shifts for the isolated chain, it is necessary to
consider any ring current effects due to adjacent molecules
within each chain. To this end, every other molecule was
removed from each chain and the intrachain NICSs were
calculated at the relevant position in the removed molecule. As
shown in Table 4, the intrachain NICSs for H9 range from 0.8
to 1 ppm. These intrachain NICSs are larger in magnitude and
of different sign, i.e., positive as opposed to negative, as
compared to the in-plane NICSs calculated for uracil (see Table
the linking together of the individual molecules via intermo-
lecular weak hydrogen bonding. It is, therefore, informative to
consider chemical shifts calculated for the four isolated chains
(as extracted from the geometrically optimized crystal structure,
with the chemical shifts being calculated without further
geometric optimization). Table 4 reveals only small differences
1). For 4-cyano-4′-ethynylbiphenyl, the calculated intrachain
chain-mol
iso
NICSs for H9, thus, indicate that ∆δ
underestimates
the chemical shift change due to intermolecular weak hydrogen
bonding by about 1 ppm.
1
in the calculated crystal and chain H9 H chemical shifts; this
9
J. AM. CHEM. SOC. VOL. 130, NO. 3, 2008 953

A R T I C L E S
Uldry et al.
Table 6. A Comparison of CH‚‚‚X Weak Hydrogen Bonding in
Maltose, Uracil, and 4-Cyano-4′-ethynylbiphenyl
results for the two strongest weak hydrogen bonds found in the
crys-mol
maltose anomers (∆δ
) studied in ref 51. For uracil and
iso
∆δiso(1H)
4-cyano-4′-ethynylbiphenyl, it is necessary to take into account
the contribution of intermolecular ring currents to the 1H
chemical shift: the estimated corrections listed in the final
column of Table 6 correspond to the negative of the intraplane
and intrachain NICS values (see Tables 1 and 4). Note that there
are no aromatic moieties in maltose and such a correction is,
thus, not required. When these ring-current corrections are
included, it is observed that the largest corrected ∆δiso (1H)
values are found for the weak hydrogen bonds in the sp
hybridized case of 4-cyano-4′-ethynylbiphenyl. While this agrees
with the predicted dependence on hybridization, i.e., C(sp)-H
g C(sp2)-H g C(sp3)-H,1,13,17 the ∆δiso (1H) values are in
fact very similar (∼2 ppm) for all the considered weak CH‚‚‚X
hydrogen bonds, suggesting only a weak dependence on
hybridization (at least for the small set of compounds considered
in this study).
dist. [Å]
dist. [Å]
CX
(deg)
CHX
(estim. corr.d)
[ppm]
donor
acceptor
H‚‚‚X
aC(sp3)sH
aC(sp3)sH
OH
OH
2.479
2.479
3.564
3.564
167
168
1.9
1.9
bC(sp2)sH
bC(sp2)sH
CdO
CdO
2.161
2.246
3.212
3.291
161
161
2.0 (-0.2)
2.2 (-0.3)
cC(sp)sH
cC(sp)sH
cC(sp)sH
cC(sp)sH
CtN
CtN
CtN
CtN
2.157
2.205
2.207
2.251
3.234
3.277
3.276
3.311
177
173
171
168
1.4 (+1.0)
1.2 (+0.9)
1.2 (+0.9)
1.1 (+0.8)
a Maltose, ∆δiso ) δcrys - δmisool, from ref 51. b Uracil, ∆δiso ) δplane
-
iso
iso
mol
iso
δ
.
c 4-Cyano-4-ethynylbiphenyl, ∆δiso ) δchain - δmol d -NICS.
.
iso
iso
In 4-cyano-4′-ethynylbiphenyl, each CtCH donor and each
CtN acceptor are only involved in one weak hydrogen bond;
this coupled with the fact that the donor and acceptor groups
All the weak CH‚‚‚X hydrogen bonds considered here
correspond to short H‚‚‚X distances (<2.5 Å) and CHX angles
close to linearity (>160°). For such favorable weak hydrogen-
bonding geometries, the bonding interactions make a significant
contribution (∼2 ppm for 1 H, >10 ppm for 13C, 15N, and 17O)
to the observed chemical shift that must be taken account of
when interpreting NMR spectra. Where geometries are less
favorable, the chemical shift changes due to weak hydrogen-
bonding could still be significant, but a careful case-by-case
investigation is to be recommended.
are well separated within each molecule means that the chain
chain-mol
to molecule changes ∆δ
for the heteroatoms are also
iso
expected to be clearly interpretable measures of the strength of
the weak hydrogen-bonding interactions. The calculated 13C and
15N chemical shifts for the CH donor and N acceptor atoms of
the CtCH‚‚‚NtC hydrogen bonding arrangements are listed
chain-mol
in Table 5. ∆δ
for the CH carbon C15 (attached to H9)
iso
chain-mol
varies from 9.8 to 11.5 ppm; this compares to ∆δ
for
iso
the other carbon nuclei of less than 3.4 ppm (see Supporting
Information). For the 15N nuclei of the hydrogen-bond acceptor
chain-mol
C3N, ∆δ
are of similar magnitude but of opposite sign,
iso
chain-mol
Acknowledgment. Funding from EPSRC (U.K.) is acknowl-
edged, including the use of the EPSRC Chemical Database
Service. Computational work was carried out at the Centre for
Scientific Computing at the University of Warwick (SRIF
funded) and the EaStCHEM Research Computing Facility at
the University of St Andrews. Support from the Estonian
Science Foundation and EU FP6 UPMAN project is acknowl-
edged.
varying from -11.6 to -13.5 ppm. Negative ∆δ
iso
values were also observed for the 17O nuclei of the hydrogen-
bond acceptor carbonyl groups in uracil (see Table 3). Note
that the intrachain NICSs (magnitudes of less than 0.3 ppm) in
chain-mol
iso
Table 5 are observed to be small as compared to the ∆δ
values.
4. Conclusions
Weak CH‚‚‚X hydrogen bonding in uracil and 4-cyano-4′-
ethynylbiphenyl involves sp2 and sp hybridized CH donor
groups, respectively. Table 6 compares the relevant changes in
Supporting Information Available: Tables of all calculated
absolute shieldings (PDF) and geometrically optimized crystal
structures (plain text). This material is available free of charge
via the Internet at http://pubs.acs.org.
1
the calculated H chemical shift that are indicative of weak
plane-mol
hydrogen-bonding strength for uracil (∆δ
) and 4-cy-
iso
chain-mol
ano-4′-ethynylbiphenyl (∆δ
). The table also lists the
JA075892I
iso
9
954 J. AM. CHEM. SOC. VOL. 130, NO. 3, 2008