Polyisocyanides as a new alignment medium to measure residual dipolar couplings for small organic molecules

Article abstract of DOI:10.1021/ol202547y

Polyisocycanides were found to give anisotropic molecular alignment in the magnetic field and are useful to measure residual dipolar couplings (RDCs) from analytes, e.g. strychnine. They show less quadrupolar splitting of the deuterated solvent signal com

Full text of DOI:10.1021/ol202547y

ORGANIC
LETTERS
2012
Vol. 14, No. 1
241–243
Polyisocyanides As a New Alignment
Medium To Measure Residual Dipolar
Couplings for Small Organic Molecules
Murali Dama and Stefan Berger*
Institute for Analytical Chemistry, University of Leipzig, Johannisallee 29, D-04103
Leipzig, Germany
stberger@rz.uni-leipzig.de
Received November 9, 2011
ABSTRACT
Polyisocycanides were found to give anisotropic molecular alignment in the magnetic field and are useful to measure residual dipolar couplings
(RDCs) from analytes, e.g. strychnine. They show less quadrupolar splitting of the deuterated solvent signal compared with other liquid crystal
systems such as Poly-γ-benzyl-L-glutamate (PBLG) and hence less undesired line broadening.
Residual dipolar couplings (RDCs) are an important
parameter in organic structure determination.1a These
RDCs are useful in configuration, conformation and
constitutional analysis of molecules and support or even
replace NOE information due to their rÀ3 dependence.1b
RDCs can be observed by NMR when molecules are
anisotropically oriented in a solution. For high resolution
structure calculation the degree of anisotropy should be
small.2
Liquid crystals,3 bicelles,4 micelles,5À7 bacteria phages,8,9
and paramagnetic lanthanide tags10,11 have been devel-
oped as anisotropic media to enhance the magnetic
orientation of biomolecules, but these methods are not
well suited for small organic molecules due to the require-
ment of water as a solvent.
For water insoluble organic molecules, stretched poly-
mer gels12 and liquid crystals such as Poly-γ-benzyl-L/
D-glutamate (PBLG/PBDG),13À15 or Poly-γ-ethyl-L/
(1) For recent reviews, see: (a) Thiele, C. M. Eur. J. Org. Chem. 2008,
5673. (b) Gil, R. R. Angew. Chem., Int. Ed. 2011, 50, 7222.
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1997, 73, 3337.
(7) Klochkov, V. V.; Baikeev, R. F.; Skirda, V. D.; Klochkov, A. V.;
Muhamadiev, F. R.; Baskyr, I.; Berger, S. Magn. Reson. Chem. 2009, 47,
57.
(8) Hansen, M. R.; Mueller, L.; Pardi, A. Nat. Struct. Biol. 1998, 5,
1065.
(10) Swarbrick, J. D.; Ung, P.; Su, X.-C.; Maleckis, A.; Chhabra, S.;
Huber, T.; Otting., G.; Graham, B. Chem. Commun. 2011, 47, 7368.
(11) Pintacuda, G.; John, M.; Su, X.-C.; Otting, G. Acc. Chem. Res.
2007, 40, 206.
(12) Luy, B.; Kobzar, K.; Kessler, H. Angew. Chem., Int. Ed. 2004,
43, 1092.
(13) Thiele, C. M.; Berger, S. Org. Lett. 2003, 5, 705.
(14) Madiot, V.; Gree, D.; Gree, R.; Lesot, P.; Courtieu, J. Chem.
Commun. 2000, 169.
(15) Klochkov, V. V.; Khairutdinov, B. I.; Klochkov, A. V.; Tagirov,
M. S.; Thiele, C. M.; Berger, S.; Vershinina, I. S.; Stoikov, I. I.; Antipin,
I. S.; Konovalov, A. I. Russ. Chem. Bull. Int. Ed. 2004, 53, 1.
(16) Poliks, M. D.; Park, Y. W.; Samulski, E. T. Mol. Cryst. Liq.
Cryst. 1987, 153, 321.
(9) Zweckstetter, M.; Bax, A. J. Biomol. NMR 2001, 20, 365.
r
10.1021/ol202547y
2011 American Chemical Society
Published on Web 12/13/2011

D-glutamate (PELG/PEDG),16 have been used as align-
ment media. Extraction of RDCs in these liquid crystal
alignment media happens to be complicated, due to the
relatively large degree of orientation in these media and
since the systems become unaligned below a certain LC
concentration. Helically chiral nonracemic polymers are
capable of foming lyotropic LC phases. These one-hand-
ed polymers such as polyisocyanates,17 polyacetylenes,18
polyisocyanides,19 and polyguanidines20 have potential
applications in enantiomer separations, chirality sensing,
and asymmetric catalysis. Polyguanidines have been used
as chiral orienting media for organic molecules by the
group of Reggelin et al.21 They show well separated
enantiomers, but the degree of orientation is too large.
After considerable unsuccessful work with low mole-
cular weight organogelators (LMOG) we expected that
polyisocyanides19 will give a suitable degree of orienta-
tion and can separate enantiomers. Because of its chir-
ality, and because of the side chain being similar to LMOG’s,
we chose helical poly(phenylisocyanide) Poly-L-1 as an or-
ienting medium for organic molecules and report here on
our initial findings.
Figure 1. Quadrupolar deuterium splitting of CDCl3 in the
presence of 17.9% Poly-L-1.
We also found that Poly-L-1 exhibits liquid crystalline
phases in tetrahydrofuran (THF) and CD2Cl2 solutions
at a concentration of 17.9% w/w with a quadrupolar
splitting of the solvent signal of 99 Hz for THF and 106
Hz for CD2Cl2. We first measured RDCs in these two
liquid crystalline phases for the pyridine molecule. The
observed RDCs (Table 1) and 13C-gated decoupled NMR
spectra for pyridine (Figure 2) for the liquid crystalline
system in CD2Cl2 are presented below.
We then selected strychnine as an analyte to study the
alignment properties of Poly-L-1 in CDCl3 and to com-
pare the results with our previous work with PBLG.13
For these experiments 170 mg of Poly-L-1, 50 mg of
strychnine, and 950 mg of CDCl3 were weighed into an
NMR tube.
The polyisocyanide investigated here, Poly-L-1, is known
to form liquid crystalline phases in concentrated chloro-
form solutions due to their main chain stiffness. Synthesis
of Poly-L-1 was achieved according to the literature.19
The polymer Poly-L-1 was obtained by polymerization of
the monomer with NiCl2 6H2O as a catalyst. (Scheme 1).
3
Scheme 1. Final Step in the Synthesis of Poly-L-1
Table 1. 13C Chemicals Shifts, 1JCH Spin Coupling Constants,
Total Spin Coupling Constants TCH, and RDC Values DCH in
Pyridine
carbon no.
δc
JCH (Hz)
TCH (Hz)
DCH (Hz)
2/6
4
149.9
135.8
123.7
177.2
162.1
162.8
199.3
152.6
185.5
11.1
À4.8
11.3
3/5
We determined the number average molecular weight Mn
to be 185k Da, the weight average molecular weight Mw
to be 265k Da, and a polydispersity index of 1.43 through
GPC. We found that Poly-L-1 exhibits a liquid crystalline
phase at a critical concentration of 17.9% w/w in CDCl3
(monitored by observation of concentration dependent
2H spectra) with a quadrupolar splitting of the deuterium
solvent CDCl3 signal of 272 Hz (Figure 1).
(17) Green, M. M.; Park, J. W.; Sato, T.; Teramoto, A.; Lifson, S.;
Selinger, R. L. B.; Selinger, J. V. Angew. Chem., Int. Ed. 1999, 38, 3138.
(18) Maeda, K.; Yashima, E. Top. Curr. Chem. 2006, 265, 47.
(19) Kajitani, T.; Okoshi, K.; Sakurai, S. I.; Kumaki, J.; Yashima, E.
J. Am. Chem. Soc. 2006, 128, 708.
(20) Tian, G.; Lu, Y.; Novak, B. M. J. Am. Chem. Soc. 2004, 126 (22),
4082.
(21) Arnold, L.; Marx, A.; Thiele, C. M.; Reggelin, M. Chem.;Eur.
J. 2010, 16, 10342.
Figure 2. Gated decoupled 13C NMR spectra of pyridine in
CD2Cl2 (bottom) and CD2Cl2/Poly-L-1 (top).
242
Org. Lett., Vol. 14, No. 1, 2012

Figure 4. Molecular formula of strychnine.
Figure 3. Gated decoupled 13C NMR spectra in the aromatic/
olefinic region of strychnine in CDCl3 (bottom), in CDCl3/Poly-
L-1 (middle) and in CDCl3/PBLG (top).
Table 2. 13C Chemicals Shifts, 1JCH Spin Coupling Constants,
Total Spin Coupling Constants TCH, and RDC Values DCH in
Strychnine in CDCl3/Poly-L-1
carbon no.
δc
JCH (Hz)
TCH (Hz)
DCH (Hz)
Figure 5. Plot of calculated vs experimental RDC values for
strychnine in CDCl3/Poly-L-1.
1
122.3
124.2
128.6
116.2
60.1
159
229.0
159.6
122.8
247
35.0
À0.5
À18.4
39.5
2
160.9
159.6
168
3
4
aliphatic region in the presence of the hydrogen-contain-
ing side chain of Poly-L-1.
8
145.4
126.3
135.9
146.2
133.4
136.8
144.3
137.2
134
À5.7
5.5
11R
11β
16
17R
18R
23R
23β
42.5
137.3
157.3
133.4
132.4
85.25
105.5
109.9
In summary, we have presented a member of a new
class of alignment medium for organic molecules based
on helically chiral polyisocyanides. It is useful for not only
molecules which are soluble in chloroform but also mole-
cules which are soluble in THF or CD2Cl2. The deuterium
quadrupolar splitting for this Poly-L-1 liquid crystal sys-
tem is nearly 272 Hz for chloroform and 99 and 106 Hz for
10.7
60.3
42.9
50.4
64.6
À6.4
À0.5
À25.8
À19.4
À13.7
2
THF and CD2Cl2 respectively at a 61.4 MHz H NMR
This sample mixture was allowed to equilibrate over-
night with no further preparation efforts such as intensive
shaking or centrifugation compared to PBLG mixtures.
RDCs were calculated from the difference of isotropic
and anisotropic 13C gated decoupled NMR spectra for
strychnine (Figure 3).
We observed 12 RDCs (Table 2) for the strychnine
molecule in the Poly-L-1/CDCl3 liquid crystal system.
These RDCs were back calculated by using the program
package PALES,22 which uses the mathematical concept
of singular value decomposition (SVD) to determine the
alignment tensor from a given structure. A crystal struc-
ture of strychnine (Figure 4) was used as an input struc-
ture. The back calculated RDCs DCalc and experimental
DCH are shown in Figure 5. There is a good agreement
between calculated and observed RDCs, with a small
deviation at C-16, which may be due to its position in the
frequency. For PBLG (poly-γ-benzyl-L-glutamate) the
deuterium quadrupolar splitting was 423 Hz on the same
spectrometer in CDCl3.13
Polyisocyanides therefore show a smaller degree of align-
ment, when compared to PBLG. They may be of potentially
better use if we succeed in deuterating the aliphatic side
chain of Poly-L-1 to get good resolution in the aliphatic
region of the NMR spectra. We also will focus on the use of
this alignment medium to discriminate enantiomers.
Acknowledgment. This work was supported by the
Graduate School BUILDMONAof the German Research
Council.
Supporting Information Available. Experimental pro-
cedure and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(22) Zweckstetter, M. Nat. Protoc. 2008, 679.
Org. Lett., Vol. 14, No. 1, 2012
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