C-HETSERF: distinction of cis/trans-isomers and measurement of long rangecouplings between chemically equivalent nuclei in polycyclic aromatichydrocarbons{

Sachin R. Chaudhari, Nilamoni Nath{ and N. Suryaprakash*

Received 22nd August 2012, Accepted 24th October 2012

DOI: 10.1039/c2ra21898d

The scalar couplings between chemically equivalent protons in symmetric molecules are not reflected

in the NMR spectrum. The present study reports the utility of our previously reported two

dimensional spin selective correlation experiment to measure the short and long range homo- and

hetero-nuclear scalar couplings in such systems. In weakly coupled spin systems, the experiment also

yields the relative signs of the couplings. The relative configurations of double bonded symmetrically

disubstituted isomers could be determined from the measured long range vicinal proton-proton

couplings (3JHH), owing to the fact that these couplings are consistently larger for trans isomers. The

study also reveals that long range 2JCH cannot be utilized as an exclusive parameter for the

identification of symmetrically disubstituted cis/trans isomers. The application of the methodology

for the determination of couplings between the chemically equivalent protons in polycyclic aromatic

hydrocarbons and in bigger molecules such as porphyrin, has also been demonstrated. The study,

carried out on large number of molecules, shows the generality and wide applicability of the

C-HETSERF experiment.

Introduction

There has been a growing importance in the study of naturally

occurring C2 symmetric molecules and polycyclic aromatic

hydrocarbons (PAHs) owing to their environmental and

biological activities.1 Consequently, the identification of indivi-

dual components from a mixture of symmetric molecules and

their separation are of profound importance. Furthermore, the

presence of two or more equivalent sub-units in symmetric

molecules often creates very difficult analytical problems.

Among the various analytical techniques generally employed in

determining the structures of such molecules, NMR spectro-

scopy has played a dominant role.2 A serious limitation in the

analysis of NMR spectra of such molecules is the detection of

very few transitions due to chemical equivalence, hindering their

assignment and subsequent structure elucidation. On the other

hand, the vicinal proton–proton scalar coupling (3JHH) has been

demonstrated to be an important spectral parameter for the

distinction of cis- and trans-isomers as, for example, in

symmetrically disubstituted alkenes. However, the inherent

problem is the scalar couplings between chemically equivalent

protons in such symmetric systems, as although they exist, they

are not reflected in the conventional one dimensional (1D) 1H

NMR spectrum. In favourable situations, they could be

extracted from the well-resolved and non-overlapped 13C

satellites of the 1D proton spectrum.3 In bigger molecules, the

identification of satellites and the extraction of this information

is formidable since, many a times, the satellite peaks are masked

by the intense signals from the 12C bound protons. The precise

assignment of the cis/trans-isomers in symmetrically disubsti-

tuted ethylenes, (R9RCLCRR9), employing the nuclear

Overhauser effect (nOe) experiment, though feasible, is also a

challenging task. One may encounter situations where there is

overcrowding of the spectral lines or peaks, which is due to the

absence of coupling fine structures in the NOESY spectra,

restricting their analyses.4

Although a plethora of 2D experiments have been reported for

the study of symmetric molecules, they do not facilitate the

measurement of long-range heteronuclear scalar couplings

(nJXH).5–9 On the other hand, nJXH (n = 2, 3) has emerged as

reliable parameters in the assignment of relative configurations

and conformations.10 Earlier their utilization was limited due to

the non-availability of appropriate NMR experimental techni-

ques to measure such couplings, which are usually small, with the

required accuracy. The recent developments of several two

dimensional experimental methodologies have drastically

improved this scenario.10d In the present study, we have applied

the sign-sensitive C-HETSERF experiment to derive both short

NMR Research Centre and Solid State and Structural Chemistry Unit,Indian Institute of Science, Bangalore 560 012, India.E-mail: nsp@nrc.iisc.ernet.in; http://nrc.iisc.ernet.in/nsp;Fax: +91 80 23601550; Tel: +91 80 22933300, +91 98 45124802{ Electronic supplementary information (ESI) available: Description ofC-HETSERF experiment, experimental and processing parameters andrelated references. See DOI: 10.1039/c2ra21898d{ Present Address: Dept. of NMR-based Structural Biology, Max-PlankInstitute for Biophysical chemistry, Gottingen, Germany.

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and long range homo- and hetero-nuclear scalar couplings (nJXH,

where X = 13C/1H, n . 1).11–13 Subsequently the 3JHH and nJCH

(n . 1) obtained from the 2D C-HETSERF spectrum are

employed for the assignment of cis/trans-isomers. In addition,

the utility of the method has been demonstrated by the

measurement of short and long-range J-couplings among the

chemically equivalent nuclei in bigger molecules, such as

porphyrin and PAHs.

Experimental section

The experiments have been carried out on three mixtures of

isomers, viz., cis and trans-stilbene (1 and 2, respectively),

fumaric acid (3) and maleic acid (4), cis and trans-dichloroethene

(5 and 6, respectively) and other symmetric molecules, such as,

but-2-yne-1,4-diyl bis(perfluorophenyl) dicarbonate (7), phenan-

threne (8), pyrene (9) and porphyrin (10). The chemical

structures of the investigated molecules are reported in

Scheme 1. The one and two dimensional spectra were recorded

either on a Bruker DRX 500 MHz or AVANCE-400 MHz NMR

spectrometer equipped with a TXI probe. The temperature was

regulated at 298 K by using a BVT 3000 temperature control

unit. The C-HETSERF pulse sequence,11–13 given in Fig. 1, was

employed to obtain both homo- and hetero-nuclear couplings. A

diagrammatic illustration of the information derivable10,13 from

the diagonal and cross peaks of a weakly coupled three spin

system of the type AMX is also given in Fig. 1.

In summary, it is a correlation experiment that connects 13C

edited proton magnetization in both the dimensions. The anti-

phase proton magnetization (2IxSz) is allowed to evolve under

both short and long range proton–proton and proton–carbon

couplings in both dimensions, facilitating their determination.

The diagonal peaks yield one bond proton–carbon couplings and

homonuclear couplings, whereas the cross peaks provide long

range proton–carbon couplings in addition to proton–proton

couplings. Since the pattern of the cross peaks is of the E-COSY

type,14,15 the methodology also provides information on the

relative signs of the couplings in weakly coupled spin systems

from the slopes of the displacement vectors of the cross peaks.

As far as the strongly coupled spin systems are concerned, the

question of determination of relative signs of the couplings does

not arise. A detailed description of the spin dynamics during the

pulse sequence is provided in the ESI.{ The delay ‘‘D’’

responsible for creation of the 13C-bound proton signal, other

experimental and data processing parameters for all the

experiments is tabulated in the ESI.{

Results and discussion

Assignment of symmetrically disubstituted cis-, trans-isomers

In symmetric molecules viz., Ha–12C–12C–Hb, containing two

chemically equivalent protons, Ha and Hb, the chemical shift

difference between Ha and Hb is zero and therefore individual

chemical shifts are unobservable in the NMR spectrum.

Although coupling between Ha and Hb exists, it does not get

reflected in the spectrum, thereby hindering its measurement.

Since JHaHbis much larger than DdHaHb

(= 0), it constitutes a

strongly coupled AA9 two spin system. On the other hand, if Ha

is directly bonded to a 13C, spin (X), the spin symmetry is broken

and can be treated as an ABX system. The transformation of the

AA9 spin system to ABX is schematically illustrated for a

symmetrically disubstituted ethylene molecule in Fig. 2.

Though the coupled protons and the 13C (i.e., Ha–13C–12C–

Hb) form a spin system of the type ABX, even in this situation

the chemical shift difference between the two protons arising due

Scheme 1 Chemical structures of investigated molecules, cis-stilbene (1), trans-stilbene (2), fumaric acid (3), maleic acid (4), cis-dichloroethene (5),

trans-dichloroethene (6), but-2-yne-1,4-diyl bis(perfluorophenyl) dicarbonate (7), phenanthrene (8), pyrene (9) and porphyrin (10).

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to isotopic effects by the inclusion of naturally abundant 13C is

negligibly small [DdHaHb(= 0)] and is unobservable. Therefore, a

single peak is detected even for this spin system in the 1H

spectrum. On the other hand, the low intensity 13C satellite

signals of Ha (Ha1 and Ha2) appear on either side of the Ha peak

(attached to 12C), and the peak Ha1 gets separated from the Hb

chemical shift by the distance 1JCH/2. As a consequence of

coupling between Ha and Hb, the peak Ha1 splits into a doublet,

enabling the direct measurement of JHaHb.

For the purpose of demonstrating the utility of C-HETSERF

experimental methodology both for the determination of short

and long range couplings and their utility for the assignment of

relative configurations of double bonded symmetrically disub-

stituted molecules, a prepared 1 : 1 mixture of cis-stilbene (1)

and trans-stilbene (2) was chosen. Non-aromatic protons of each

of these molecules pertain to an AA9 spin system. The well-

resolved 13C satellites, marked with red arrows, shown for the

trans-isomer in Fig. 3, provide 3JHH. The measurement of 3JHH

for the cis-isomer by identification of satellites corresponding to

this molecule facilitates the distinction between the cis- and

trans-isomers, since it is well established that (3JHH)trans .

(3JHH)cis. The measurement of long-range 2JCH is, however, not

possible from this spectrum as they are masked by the proton

signals arising from the molecules attached to the abundant 12C

spin. Consequently, for the simultaneous measurement of 3JHH

and 2JCH, and their subsequent utilization for unambiguously

distinguishing the isomers, the C-HETSERF experiment has

been implemented. In C-HETSERF, the natural abundant 13C is

introduced as a spy nucleus in the chemically equivalent proton

spin system.12 This results in the breaking down of the symmetry

of the AA9 spin system, and the three spin system then pertains

to an ABX type, as schematically depicted in Fig. 2, where A and

Fig. 1 (a) Pulse sequence utilized for the C-HETSERF experiment. The delay D responsible for the polarization transfer that depends on the factor 1/

(4 6 1JCH). (b) Pictorial depiction of the extraction of different couplings from the C-HETSERF experiment in an AMX spin system when the selective

pulse is applied on A spin; (A) The diagonal peaks of the 2D spectrum yielding the one bond heteronuclear coupling (1JAX). It is the frequency

difference between the 13C-bound proton signals at their |13Ca. or |13Cb. spin states in both the dimensions, (B) The cross peaks yielding the long

range heteronuclear coupling (2JXM). The F2 cross-section of the 13C-attached proton signals at either |13Ca. or |13Cb. spin states provides the

homonuclear coupling between A and M (3JAM). In the all present experiments, a non-selective 90u pulse is applied on protons instead of a selective

pulse before the t1 evolution.

Fig. 2 The schematic illustration of coupled proton two spin system of

the type AA9 getting transformed into the ABX type with the inclusion of

one naturally abundant 13C spin.

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B are chemically non-equivalent protons and X is the 13C nucleus

directly bonded to proton A. The scalar couplings measurable

from the cross-peaks of the C-HETSERF spectrum reported in

Fig. 4 are; 1JCH, 2JCH and 3JHH. The frequency difference

between the displaced a/b-cross peaks along the direct dimension

(marked as ‘a’ and ‘b’ for molecules 2 and 1, respectively)

provides 2JCH. The frequency difference between two adjacent

cross peaks in the same cross-section provides 3JHH (marked as

‘c’ and ‘d’ for 2 and 1, respectively). The separation ‘c’ and ‘d’

measured from the spectrum are 16.2 Hz and 12.2 Hz,

respectively. The spectrum with a larger coupling (3JHH = 16.2

Hz) is assigned to the trans-isomer, unambiguously distinguish-

ing it from its cis-counterpart. Therefore, 2JCH, pertaining to

separations ‘b’ (2.7 Hz) and ‘a’ (3.8 Hz) could be assigned to the

cis- and trans-isomers respectively.

The relative slopes of the displacement vectors of the cross

peaks (indicated by the tilted brown coloured arrows in Fig. 4)

along the direct dimension indicate that the relative signs of2JCH, in both the molecules 1 and 2, are identical. For

demonstrating the wider utility of this experiment, investigations

were carried out on other mixtures of symmetrically disubsti-

tuted molecules, such as 3 and 4, and 5 and 6. The homo- and

hetero-nuclear couplings determined for these molecules are

reported in Table 1.

Can 2JCH be an indicator for the assignment of cis- and trans-

isomers?

As a consequence of the determination of long range hetero-

nuclear couplings (2JCH) by C-HETSERF, an intriguing ques-

tion that remains to be answered is, whether this parameter can

also be employed as an indicator for the assignment of cis- and

trans-isomers, either exclusively or in conjunction with 3JHH.

Hence a systematic study was carried out on the pairs of

symmetrically disubstituted cis- and trans-isomers. From the

derived parameters reported in Table 1, it was observed that in

fumaric (3) and maleic acid (4), similar to cis/trans-stilbene (1/2),

the 2JCH for the trans-isomer (3) is consistently larger than its cis-

counterpart (4). On the other hand for cis- and trans-

dichloroethene (5 and 6, respectively), the situation gets reversed.

In molecules 5 and 6, the 2JCH is larger for the cis-isomer than

the trans-isomer. Therefore, it evidently establishes the fact that

unlike 3JHH, the 2JCH can neither be construed as an exclusive

parameter nor be utilized in conjunction with 3JHH for

identification of cis/trans-isomers.

Application of C-HETSERF to symmetric molecules

The approach reported in this work is not only confined to the

study of cis/trans-isomers but is also applicable to other types of

symmetric isomers possessing methyl, methylene and methine

groups. As an example, the analysis of NMR spectra of a

symmetric molecule, such as but-2-yne-1,4-diyl bis(perfluoro-

phenyl) dicarbonate (structure is given in Scheme 1), using

routinely employed techniques, such as HSQC, HMQC, etc., is

very difficult.3 Furthermore, the nOe experiment cannot be

applied as this is not detectable between the homotopic

methylene protons. On the other hand, the analysis of the

spectrum and subsequent extraction of the couplings is possible

using the C-HETSERF experiment (the C-HETSERF spectrum

is given in the ESI{). The 1H-NMR signals of but-2-yne-1,4-diyl

bis(perfluorophenyl) dicarbonate comprises of a triplet due to

the five bond long-range coupling (5JHH) with two other protons.

The 5JHH thus determined is 1.8 Hz. It is very interesting to note

that in this symmetric molecule, we could precisely determine the4JCH of 1.2 Hz, which otherwise would have been impossible

from the conventional 1H spectrum.

Application to polycyclic aromatic hydrocarbons (PAHs) and

porphyrin

Another interesting application of C-HETSERF is in the

determination of couplings between identical segments of

polycyclic aromatic hydrocarbons. As an example, the protons

marked He and Hf in the phenanthrene molecule (8) (Fig. 5) are

Fig. 3 500 MHz 1H spectrum of the mixture of cis- and trans-stilbene in

the solvent CDCl3. The two 13C satellites for the trans-isomer are marked

by red arrows. It may be noted that many satellites are hidden below the

strong peaks from the 12C protons, severely hampering their identifica-

tion.

Fig. 4 400 MHz 2D C-HETSERF spectrum corresponding to the

prepared mixture of samples 1 and 2. Selected cross-peaks regions are

shown. The separations ‘e’ and ‘f’, along the indirect dimension, provide1JCH, whereas separations ‘a’ and ‘b’ (displacement of cross peaks), along

the direct dimension, provide 2JCH. Since the relative slopes of the

displacement vectors are identical (as marked by brown arrows) the

relative signs of the 2JCH values are the same in both molecules 1 and 2.

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equivalent and appear as a singlet at 7.81 ppm, rendering it

possible to determine the coupling between them. However, the

C-HETSERF spectrum reported in Fig. 5 exhibits the coupling

between them. The separations giving couplings 3JHeHfand

2JC10Hfare marked as ‘a’ and ‘b’ in the spectrum and their

measured values are 8.6 Hz and 0.2 Hz, respectively. This brings

out another immediate advantage of the C-HETSERF experi-

ment, wherein the coupling of such a small magnitude could be

measured accurately as they are measured from the displacement

of cross peaks in the direct dimension (they are separated by1JCH in the indirect dimension).

An additional example is the molecule pyrene (9). In this

system the coupling between the symmetric protons (marked Ha

and Ha9 given in Fig. 6) cannot be determined by conventional

NMR experiments. However, the C-HETSERF cross peaks at

Ha, reported in Fig. 6, provides the coupling between them. The

measured couplings 3JHaHa9and 2JC1Ha

(marked as ‘a’ and ‘b’ in

Fig. 6) are 8.7 Hz and 0.2 Hz, respectively. In an identical

manner, the method can be extended to measure the couplings

between the symmetric units in other reasonably bigger PAHs.

Another commonly encountered problem is that other methods,

such as COSY and NOESY, are insufficient to assign all the

chemical shifts in the 1H and 13C NMR spectrum of PAHs.9a

However, the long range correlations (nJCH) could be determined

from this experiment and utilized to assign closely resonating 13C

chemical shifts.17

Table 1 Determined scalar coupling constants (3JHH and 2JCH in Hz) for the investigated molecules. The accuracy of determination of 3JHH and 2JCH

are given by LW/SN, where LW is the line width and SN the signal-to-noise ratio.16 For molecules 8 and 9, it may be pointed out that J values are verymuch less than the digital resolution. These values are not measured from a single cross section. They are measured from the displacement of crosssections arising due to spin state selection and are accurate

System 3JHH (in Hz) Accuracy in the measurement 2JCH (in Hz) Accuracy in the measurement

cis-Stilbene (1) 12.2 0.041 2.7 0.041trans-Stilbene (2) 16.2 0.031 3.8 0.031cis-Dichloroethene (5) 5.2 0.003 10.6 0.003trans-Dichloroethene (6) 12.3 0.004 0.6 0.004Maleic acid (cis-isomer) (4) 12.0 0.05 2.3 0.05Fumaric acid (trans-isomer) (3) 15.7 0.028 4.2 0.028Phenanthrene (8) 8.6 0.037 0.2 0.037But-2-yne-1,4-diyl bis(perfluorophenyl) dicarbonate (7) 5JHH = 1.8 0.039 4JCH = 1.2 0.039Pyrene (9) 8.7 0.029 0.2 0.029Porphyrin (10) 4.1 0.051 4.0 0.051

Fig. 5 400 MHz 1H spectrum of phenanthrene in the solvent CDCl3. Expanded region of the C-HETSERF spectrum corresponding to the cross peak

at chemical shift of proton marked He.

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Fig. 6 (Left) 400 MHz 1H spectrum of pyrene in the solvent CDCl3. (Right) The region of the C-HETSERF spectrum corresponding to the chemical

shift of the proton marked Ha.

Fig. 7 400 MHz 1H spectrum of porphyrin in the solvent CDCl3. Assignments of chemical shifts to different protons are marked with letters. The

region of the C-HETSERF spectrum corresponding to chemical shift of proton marked Ha.

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Another advantage of this methodology is exploited in the

study of porphyrin molecules, where the coupling between the

symmetric protons of the pyrrole moiety cannot be measured from

the conventional one dimensional spectrum. The cross peak of the

C-HETSERF spectrum pertaining to these protons is reported in

Fig. 7. The measured couplings 3JHH and 2JCH (marked as ‘a’ and

‘b’ in Fig. 7) are 4.1 Hz and 4.0 Hz, respectively.

Conclusions

The utility of the C-HETSERF experiment in the measurement

of long-range proton–proton and carbon–proton scalar cou-

plings and also in achieving the distinction between symmetri-

cally disubstituted double bonded isomers is demonstrated on

the basis of 3JHH. However, unlike the well known concept of

(3JHH)trans . (3JHH)cis, an anomalous pattern is encountered in

the 2JCH couplings, that are not consistently large for one type of

isomer, establishing that 2JCH cannot be construed as an

exclusive parameter or be used in conjunction with 3JHH for

the assignment of symmetrically disubstituted cis/trans-isomers.

The couplings of smaller magnitudes, that are generally hidden

within the line widths in the one dimensional proton spectrum,

could be accurately determined from the displacement of a/b

cross peaks in the direct dimension. In weakly coupled spin

systems, the direction of displacement of the cross sections can

be utilized to obtain the relative signs of the couplings. The wider

utility of the C-HETSERF experiment in the determination of

couplings between the chemically equivalent protons in larger

polycyclic aromatic hydrocarbons, and in porphyrin, has also

been demonstrated.

Acknowledgements

SRC would like to thank the UGC for the SRF, and NN thanks

the IISc for a research associateship. NN thanks Dr Suresh

Kumar Vasa for useful discussions. NS gratefully acknowledges

the generous financial support of the Science and Engineering

Research Board, New Delhi (grant no. SR/S1/PC-42/2011).

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