Computational and experimental evidence of through-space NMR spectroscopic J coupling of hydrogen atoms

Article abstract of DOI:10.1002/chem.201102272

J coupling in NMR spectroscopy is conventionally associated with covalent bonds. A noncovalent contribution often called through-space coupling (TSC) has been observed for heavy atoms. In this study, the TSC was detected and analyzed for the more common <

Full text of DOI:10.1002/chem.201102272

FULL PAPER
DOI: 10.1002/chem.201102272
Computational and Experimental Evidence of Through-Space NMR
Spectroscopic J Coupling of Hydrogen Atoms
Martin Dracˇꢀnsky,* Petr Jansa,* and Petr Bourˇ*[a]
´
Abstract: J coupling in NMR spectros-
copy is conventionally associated with
covalent bonds. A noncovalent contri-
bution often called through-space cou-
pling (TSC) has been observed for
heavy atoms. In this study, the TSC
was detected and analyzed for the
The nature and magnitude of the phe-
nomenon were also analyzed by densi-
ty functional computations. Calculated
carbon- and hydrogen-coupling maps
and perturbed electronic densities sug-
gest that the aromatic system strongly
participates in the noncovalent contri-
bution. Unlike covalent coupling,
which is usually governed by the Fermi
contact, TSC is dominated by the dia-
magnetic term comprising interactions
of nuclei with the electron orbital an-
gular momentum. The computations
further revealed a strong distance and
conformational dependence of TSC.
This suggests that the through-space
coupling can be explored in molecular
structural studies in the same way as
the covalent one.
1
1
ꢀ
more common H H coupling as well.
In synthesized model molecules the hy-
drogen positions could be well con-
trolled. For several coupling constants
the through-space mechanism was even
found to be the predominant factor.
Keywords: conformations · density
functional calculations · NMR spec-
troscopy · through-space coupling ·
weak interactions
Introduction
an unexpectedly large coupling between two atoms close in
space but separated by several bonds.[5] TSC was observed
for fluorine–fluorine,[6] fluorine–carbon, fluorine–nitrogen,[7]
fluorine–hydrogen,[6d,8] phosphorus–phosphorus,[9] carbon–
phosphorus,[10] and rarer metallic nuclear pairs.[11]
Studies of TSC in van der Waals complexes without any
covalent interaction are least frequent. It is very difficult to
detect the coupling for such systems in the same manner as
for the hydrogen-bound case because the lifetime of the dis-
persion (van der Waals) complexes is usually too short to
allow for a conventional measurement. A sizable magnitude
of TSC was also predicted in several theoretical studies for
xenon[12] and helium[13] dimers; HF·CH4 and HF·CH3F com-
Isotropic spin–spin (scalar) J coupling of nuclear magnetic
momenta is normally thought of as a proof of a strong cova-
lent link between two atoms. The relationship between the
vicinal coupling and the torsion angles in peptides and
sugars, for example, became famous as the Karplus equa-
tion.[1] But molecular structure, constitution, and configura-
tion can also be elucidated from the coupling information
contained in the NMR spectra.[1b,c,2]
J coupling is mediated by electrons, and their covalent
distribution is not necessary for the phenomenon. Indeed,
measurable scalar couplings of nuclei not connected by con-
ventional chemical bonds have been recently observed in a
variety of systems. Typically, such “through-space” coupling
(TSC) occurs for nuclei involved in hydrogen bonding, in
which the covalent contribution is minor.[3,4]
plexes;[14]
methane–benzene
and
benzene–benzene
dimers;[15] and the CH3CN·C6F6 complex.[16] Experimentally,
to the best of our knowledge, TSC in a van der Waals com-
plex has been confirmed only for dithallium cryptate, with
Intramolecular TSC has been observed as well. The
through-space character can be inferred, for example, from
JACTHNGUTERNNUG
(Tl,H)=17 Hz.[17]
The electronic origin of TSC was analyzed by Bagno
et al.[15b] Quantum chemical calculations verified that the
electronic cloud could produce the spin–spin coupling be-
tween two nuclei regardless of whether there was a covalent
link or not.[13,14b,18] Similar results were obtained by density
functional theory (DFT)[19] and wavefunction method-
s.[5,14a,19b,20] We chose the DFT methodology with the B3LYP
functional as it provides a good balance between computa-
tional cost and accuracy, and describes all the main physical
factors involved in the coupling.[21]
We studied the TSC effect on model compounds 1–7
(Scheme 1), in which the spatial arrangement of interacting
nuclei could be controlled. For example, in the [2,2]paracy-
clophane derivatives 1–3 the distance between the pseudo-
ˇ
´
ˇ
[a] Dr. M. Dracꢀnsky, Dr. P. Jansa, Prof. P. Bour
Institute of Organic Chemistry and Biochemistry
Academy of Sciences
ˇ
Flemingovo nꢁmestꢀ 2
166 10 Prague (Czech Republic)
Fax : (+420)220183578
E-mail: dracinsky@uochb.cas.cz
jansa@uochb.cas.cz
bour@uochb.cas.cz
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102272. It contains further
synthetic and computational details, including the compound charac-
terization.
Chem. Eur. J. 2012, 18, 981 – 986
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981

ble in compound 6 (compare with the spectrum in Figure S1
of the Supporting Information), in which the two benzene
rings are not kept together by the covalent link. The same
coupling behavior as for compounds 1 and 6 was observed
for closed and opened mononitro derivatives 2 and 7. As an
alternate confirmation we performed long-range COSY ex-
periments (e.g., the aromatic region of 2D long-range
COSY of compound 2 is shown in Figure S2 in the Support-
ing Information).
A similar coupling pattern was observed in the benzophe-
nanthrene derivatives 4 and 5 for hydrogen atom H-12,
close to the methyl group or H-1, respectively (Figure S3 in
the Supporting Information). In 4, the TSC is detectable be-
tween hydrogen atoms that are separated by seven bonds,
similarly as for 1–3, whereas no coupling is observed be-
tween the methyl-group hydrogen atoms and H-6 or H-7
separated by the same number of covalent bonds. In com-
pound 5 the “six-bond” TSC between H-1 and H-12 is de-
tectable, unlike analogous six-bond couplings JACHTUNGERTN(NUNG H1,H6) or J-
AHCTUNGTREG(NNUN H1,H7). The absolute values of the constants were ob-
Scheme 1. Structure and atom numbering of the model compounds. Mol-
ecules 6 and 7 are formally open forms of compounds 1 and 2 (the struc-
ture of which is close to 3); therefore, analogous numbering is main-
tained within 1–3 and 6 and 7. TSC was observable in 1–5.
tained from comparison of off- and on-resonance selective
decoupling of the coupled nucleus. Because of their small
ipso-hydrogen atoms is 3.1 ꢃ.[22] The ring rotations are
completely blocked at room temperature. In the benzo-
phenanthrene derivatives 4 and 5 the hydrogen atom at
the 12-position is close to the hydrogen atoms of the C-1
methyl group (4) or to the H-1 hydrogen atom (5). Com-
pounds 6 and 7 were prepared as systems in which the
TSC is supposed to be minimal. Otherwise they are chem-
ically similar to and can be thought of as open forms of
derivatives 1 and 2.
Results and Discussion
NMR spectroscopy experiment: As the primary model
compound, we investigated the pseudo-meta-heteroannu-
lar-disubstituted derivative of [2,2]paracyclophane (1).
The 1D COSY and 1D NOE spectra, in which the signal
of hydrogen A3 was selectively irradiated, are plotted in
Figure 1. Note that in the COSY experiment (Figure 1b)
one can observe signals of hydrogen atoms that couple
with the irradiated atom. In the NOE spectra (Figure 1c),
the signals correspond to hydrogen atoms close in space
to A3.
Figure 1. a) The aromatic region of the 1H NMR spectrum of compound
1, b) selective 1D COSY, and c) selective differential 1D NOE experi-
ments with the irradiation of the signal of hydrogen A3.
magnitude, the small TSCs do not result in line splitting, but
only in a broadening. The coupling constant thus were eval-
uated by the usual simulation of spectral shape.[23] Neverthe-
less, rather long acquisition times, substantial zero filling,
and strong windowing had to be applied to obtain sufficient
spectral resolution.
The spectra in Figure 1 thus reveal significant TSC (for-
mally seven-bond) J
ACHTUNGTRENNUNG
and five-bond couplings (J
N
ACHTUNGTRENNUNG
benzene ring. These results are in agreement with the previ-
ous selective decoupling experiment on compound 1, which
indicated the magnitude of the heteroannular coupling of
0.3–0.4 Hz.[23] Analogous “seven-bond” coupling between
hydrogen atoms that are not close in space, such as J-
Comparison to calculated J couplings: The experimental
magnitudes of TSC agree very well with the calculated
values (Table 1). As discussed before,[24] reliable computa-
ACHTUNGTRENNUNG(A3,B3), is absent. Nor is the seven-bond coupling observa-
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Chem. Eur. J. 2012, 18, 981 – 986

J Coupling of Hydrogen Atoms
FULL PAPER
Table 1. Calculated (B3LYP/6-311++GACTHNUTRGNE(UNG 2df,2pd), B3LYP/6-31+G** geometry) and
experimental TSC constants (in Hz) for compounds 1–7.
and DSO terms. This can be explained by the delo-
calized character of TSC. The electron spin–nuclear
spin interactions (giving the FC and SD terms) are
not so important, probably because of an electron-
spin pairing within a large part of the molecule.
Nevertheless, the PSO and DSO terms have oppo-
site signs and partially cancel. Only the relative
contribution of the SD component is consistently
minor in both coupling types.
Another insight into the spatial coupling provides
visualization of the diamagnetic coupling density,
and Fermi contact and paramagnetic perturbations
(Figure S5 in the Supporting Information), obtained
Compound Coupling Calcd Exptl Compound Coupling Calcd
Exptl
1
1
2
2
2
3
3
3
A3,B5
A5,B3
A3,B3
A5,B5
A6,B6
A3,B3
A5,B5
A6,B6
0.37
0.34
0.36
0.34
0.33
0.38
0.34
0.36
0.37
0.33
0.45
0.54
4
5
6
6
7
7
7
12,CH3
1,12
0.56 0.38
ꢀ0.42 0.55[b]
A3,B5
A5,B3
A3,B3
A5,B5
A6,B6
0.13
0.14
0
0
0
0
0
[a]
–
ꢀ0.03
ꢀ0.04
ꢀ0.05
0.34
0.60
[a]
–
[a] Immeasurable because of signal overlap. [b] Absolute value.
tion of J coupling requires a large basis set of atomic orbi-
tals. We noticed that adding polarization or diffuse functions
on heavy atoms had a particularly dramatic effect on com-
puted TSC (Table S1 and Figure S4 in the Supporting Infor-
mation). Also, the double!triple zeta basis change (6-
using the sum-over-states (SOS) approximation.[26] The den-
sity plots indicate that the aromatic system enhances TSC
by providing many electrons that interact with the nuclei.
Nucleus-free TSC maps (Figure S6 in the Supporting Infor-
mation) indicate a significant role of the benzene ring, and a
strong directional, geometrical dependence of the phenom-
enon.
31++G**!6-311++G**) typically caused
a significant
drop (up to 50%) of the calculated constants. For converged
results it was further important to include the f orbitals. The
6-311++G
(2df,2pd) basis set finally provided coupling
Molecular dynamics and conformational dependence of the
coupling: Starting from the DFT-optimized geometry of
compound 1, we performed Born–Oppenheimer (BO) mo-
lecular dynamic runs to investigate the influence of molecu-
lar flexibility on TSC. The linear distance dependence of the
constants simulated during the MD run (Figure 3) is some-
values very close to the supposedly most accurate aug-cc-
pVTZ ones, but with significantly less computational effort
(Table S2 in the Supporting Information). On the other
hand, when the conductor-like polarizable continuum model
(CPCM) solvent correction was added, the coupling con-
stants changed less than 0.01 Hz (Table S1 in the Supporting
Information). Likewise, inclusion of the DFT dispersion cor-
rection (Table S3 in the Supporting Information) for the ge-
ometries led to a minor (ꢁ10%) change of the calculated
constants. Thus we attribute most of the remaining error to
the inaccuracy of the B3LYP method, and a lack of anhar-
monic and dynamical averaging.[25]
Components of TSC constants: Individual terms contribu-
ting to the coupling (Fermi contact (FC), spin dipolar (SD),
paramagnetic spin–orbit (PSO), and diamagnetic spin–orbit
(DSO))[21,24] ratios are very different from those in the usual
through-bond J coupling. As exemplified in Figure 2 (and
more in Table S4 in the Supporting Information), the Fermi
contact term, which usually dominates the covalent cou-
pling,[24,26] is relatively small for TSC, in favor of the PSO
Figure 3. Calculated (B3LYP/6-31+G**) dependence of the through-
space JACTHNURTGNEU(GN H,H) coupling on the distance, obtained from 24 BOMD snap-
*
shots for compound 1. The dynamics was performed at 300 K. =A5–
!
B3; =A3–B5.
what surprising because of the much steeper rꢀ3 term in the
conventional magnetic dipole–dipole interaction opera-
tor.[21a] However, a similar dependence was previously found
in the simpler systems and covalent J coupling.[27] Clearly,
for larger distances, the coupling quickly disappears.[15b] The
large dispersion of TSC (ꢁ0.4–1.2 Hz, Figure 3) suggests
that the correlation with the distance can be potentially
used in structural studies, in a same way as the NOE.
Figure 2. A typical composition of the through-bond (FC-term-dominat-
ed) and through-space (DSO-term-dominated) couplings, obtained for
compound 5 at the 6-311++G
ACHTUNGTREN(NGNU 2df,2pd) level.
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983

ˇ
ˇ
´
P. Bour, P. Jansa, and M. Dracꢀnsky
effects will play an increasing role in structural studies of
molecules and their complexes. Similarly to NOE, for exam-
ple, TSC can monitor noncovalent contacts in molecules and
their complexes.
Experimental Section
Synthesis: Compounds 1, 3–5, and 1,2-di-p-tolylethane were obtained
from Sigma Aldrich. To synthesize 6–9, a solution of 1,2-di-p-tolylethane
(420 mg, 2 mmol) in acetonitrile (100 mL) was purged with argon and
cooled with an ice bath. Nitronium tetrafluoroborate (265 mg, 2 mmol)
was slowly added at 08C and the reaction mixture was stirred without
further cooling for 5 h. After evaporation, the products were separated
by column chromatography (silica gel, hexane/ethyl acetate). Phases con-
taining the desired products were purified on preparative TLC sheets.
After evaporation, 1-methyl-4-(4-methylphenethyl)-2-nitrobenzene (7;
37 mg),
1-methyl-4-(4-methyl-2-nitrophenethyl)-2-nitrobenzene
(8;
46 mg), and 1,2-bis(4-methyl-3-nitrophenyl)ethane (9; 114 mg) of a high
purity were isolated (Scheme 2).
Figure 4. Calculated (B3LYP/6-31+G**) dependence of the H–H dis-
tance, and components of the H12–methyl hydrogen TSC on the CH3-
!
*
group rotation in compound 4. =H–H distance in ꢃ; =J (H–H) in
~
&
^
Hz; =FC; =PSO; =DSO.
Even more surprising is the conformational dependence
of the TSC modeled for compound 4 plotted in Figure 4.
The coupling does weakly correlate with the distance of cou-
pled atoms; however, it is much more dependent on the tor-
Scheme 2. The synthesis of compound 7.
sion angle. For example, J
tance of 2 ꢃ (torsion angle ꢀ608) is smaller than J-
(H,H12)=1.1 Hz obtained for the larger distance of 2.3 ꢃ
(H,H12)=ꢀ0.7 Hz for the dis-
ACHTUNGTRENNUNG
The preparation of 7 by nitration of 1,2-di-p-tolylethane appeared to be
very challenging. In the beginning we used various nitration reagents
such as nitric acid, acetyl nitrate, a mixture of nitric and sulfuric acid, or
a mixture of acetic and nitric acid. As verified by GC-MS, these reagents
produced mixtures containing dinitro isomers and other byproducts, typi-
cally with molecular weights smaller by 2 or 4 than the dinitro com-
pounds. We explain this by the oxidation of the ethane bridge, which
forms double or triple bonds between two benzene rings. The nitronium
tetrafluoroborate, however, suppressed the oxidation, in accord with the
known properties of this mild nitration reagent.[28] Reaction of 1,2-di-p-
tolylethane with nitronium tetrafluoroborate (Scheme 2) afforded a mix-
ture of three major products, which were isolated by repeated chromato-
graphic purifications, and were identified as 7, 8, and 9.
(torsion angle of ꢀ108), and so forth. Clearly, the sole FC
term is responsible for most of the angular dependence. A
more detailed analysis (Figure S7 in the Supporting Infor-
mation) reveals that the measurable average J coupling be-
tween the three methyl and H12 hydrogen atoms is depen-
dent on the rotation in a similar manner, and that the aro-
matic residue attached to the CH3 group is not so important
for this dependence.
Conclusion
NitroACTHNUTRGNE[NUG 2,2]paracyclophane (2) was obtained by the reaction of [2,2]paracy-
clophane (416 mg, 2 mmol) and nitric acid (1.94 g, 65%, 20 mmol) in
acetic acid (50 mL) at reflux for 10 min. After evaporation, the product
was purified by column chromatography (silica gel, hexane/ethyl acetate)
The NMR spectroscopy experiments on model compounds
confirmed the presence of TSC for spatially closed hydrogen
atoms. The obtained coupling constants could be well repro-
duced by the density functional calculations. Unlike for the
covalent case, the Fermi contact term is relatively small in
TSC, whereas the DSO term is unusually large, followed by
the PSO interaction.
The analysis of the distant and torsional dependence addi-
tionally revealed that the through-space coupling, similarly
to the covalent one, provides very specific information
about local molecular geometry. As the precision of NMR
spectroscopy instruments grows, we thus suppose that TSC
to give the nitroACTHNUTRGNEUNG[2,2]paracyclophane (246 mg, 49%).
2-Methyl-5-(4-methyl-3-nitrophenethyl)aniline (6) was prepared by the
selective reduction of compound 9. The hydrazine hydrate (2 mg,
0.04 mmol) in methanol (5 mL) was added with cooling and vigorous stir-
ring to a mixture containing 9 (12 mg, 0.04 mmol), charcoal (100 mg),
and FeCl3 (1 mg, 0.06 mmol) in methanol (20 mL) under argon for 2 h.
The temperature was maintained at 20–258C. The reaction mixture was
then vigorously stirred at room temperature for an additional 4 h. The
crude product was purified by preparative TLC (silica gel, hexane/ethyl
acetate) to give the desired product 6 (8 mg, 75%). It may be useful to
note that a selective reduction of one of the two nitro group in 9 was suc-
cessful only under particular conditions, previously described also for a
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J Coupling of Hydrogen Atoms
FULL PAPER
ˇ
´
1,3,5-trinitrobenzene reduction by hydrazine hydrate in the presence of
iron chloride and charcoal.[29] An alternative procedure using SnCl2 in
HCl[30] failed in this case.
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NMR spectroscopy experiments: NMR spectra were measured on a
Bruker Avance II 500 and/or Avance II 600 spectrometer (500 or
1
600 MHz for H and 126 or 151 MHz for 13C). All spectra were acquired
for samples in CDCl3 and referenced to TMS. Signals of all hydrogen and
carbon atoms were assigned by using a combination of 1D and 2D (H,H-
COSY, H,C-HSQC, H,C-HMBC, and H,H-ROESY) techniques. The
long-range COSY (LR COSY) experiment was recorded by using the
standard magnitude-mode COSY sequence and setting the delay for evo-
lution of long-range couplings to 500 ms. The small through-space cou-
plings were obtained from selective 1D homonuclear decoupling experi-
ments, in which the data were reproduced iteratively by simulations with
different constant values.
Density functional computations: The geometries of compounds 1–7
were optimized at the DFT level of theory, using the Gaussian 09 pro-
gram,[31] B3LYP functional,[32] and 6-31+G** basis set. Harmonic vibra-
tional frequencies were calculated for all of the optimized structures to
confirm a minimum at the potential-energy surface. For the equilibrium
geometries and selected atoms, J coupling constants were calculated by
using Gaussian with the 6-31G, 6-31G*, 6-31G**, 6-31+G**, 6-
31++G**, 6-311++G**, 6-311++G
Gaussian basis sets. The IGLOIII[33] basis set, and the COSMO[34] solvent
correction with the 6-311++G(2df,2pd) basis set were also tested; for
ACHTUNGTRENN(UNG 2df,2pd), and aug-cc-pVTZ standard
AHCTUNGTRENNUNG
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some derivatives, the BPW91[35] and B97D[36] functionals, and IGLOII[33]
basis were tried. The nuclear selection appeared extremely important for
savings of computer time, especially for the larger basis sets. By using
our program interfaced to Gaussian, the diamagnetic coupling density,
Fermi contact, and paramagnetic perturbations of the electronic density
were visualized within the SOS approximation.[26] The B3LYP hybrid
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Born–Oppenheimer molecular dynamics (BOMD): By using the DFT-op-
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BOMD[38] runs to investigate the influence of molecular flexibility on the
through-space coupling. Note that we used the periodic boundary condi-
tions and the GGA/plane wave methodology[38] for a single molecule to
save computer time. For example, BOMD with Gaussian and the B3LYP
functional would be unreasonably slow. Within the Car–Parrinello molec-
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Born–Oppenheimer dynamics, apart from the default CPMD) the mole-
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10 ps, using a time step of 0.38704 fs, energy cutoff of 25 Rydberg, the
BLYP[32a] functional, Vanderbilt ultra-soft pseudopotentials,[40] and the
fictitious electron mass of 600 atomic units. A temperature of 300 K was
maintained by using a Nosꢅ–Hoover bath.[41] Trajectory snapshots were
saved every 1000 time steps (within 0.39 ps intervals), and the coupling
constants were calculated by Gaussian at the B3LYP/6-31+G** level.
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Received: July 23, 2011
Published online: December 14, 2011
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