Thermoresponsive Alignment Media in NMR Spectroscopy: Helix Reversal of a Copolyaspartate at Ambient Temperatures

Article abstract of DOI:10.1002/chem.201803540

Poly(aspartic acid esters) are known to form either right-or left-handed α-helices depending on the ester group in the side chain, on solvent and/or on temperature. Polyphenethyl-l-aspartates (PPLA) exhibit a helix reversal from the right- to the left-handed form with increasing temperature. We have recently reported the application of polyphenethylaspartates as helically chiral alignment media. The thermoresponsivity observed for these polymers offers the possibility to measure different orientations of analytes before and after helix reversal of the alignment medium at 373 K. Herein we present a synthesized copolymer of phenethyl- and benzylaspartate as a new alignment medium undergoing this helix reversal at 303–313 K. Thus, the measurement of residual dipolar couplings (RDC) before and after the helix reversal is allowed for at ambient temperatures. A complete sign change of all ¹H–¹³C RDCs was observed, which is close to the highest possible difference in NMR spectra.

Full text of DOI:10.1002/chem.201803540

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Accepted Article
Title: Thermoresponsive Alignment Media in NMR spectroscopy: Helix
Reversal of a Copolyaspartate at Ambient Temperatures
Authors: Mira Schwab, Volker Schmidts, and Christina Thiele
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Thermoresponsive Alignment Media in NMR spectroscopy:
Helix Reversal of a Copolyaspartate at Ambient Temperatures
Mira Schwab, Volker Schmidts, Christina M. Thiele[a]*
Abstract: Poly(aspartic acid esters) are known to form either right-or
left-handed α-helices depending on the ester group in the side chain,
on solvent and/or on temperature. Polyphenethyl-L-aspartates
(PPLA) exhibit a helix reversal from the right- to the left-handed form
with increasing temperature. We have recently reported the applica-
tion of polyphenethylaspartates as helically chiral alignment media.
The thermoresponsivity observed for these polymers offers the
possibility to measure different orientations of analytes before and
after helix reversal of the alignment medium at 373 K. Herein we
present a synthesized copolymer of phenethyl- and benzyl-aspartate
as new alignment medium undergoing this helix reversal at 303 K-
313 K. Thus the measurement of residual dipolar couplings (RDCs)
before and after helix reversal is allowed for at ambient temperatures.
1
A complete sign change of all H-13C RDCs was observed, which is
close to the highest possible difference in NMR spectra.
Figure 1. Overview of the general principle of enantiodifferentiation, which is
based on different diastereomorphous interactions between chiral analyte and
chiral helix. For each enantiomer in one helix configuration different orienta-
tions and therefore different order tensors should be obtained. The difference
is usually described by the generalized cosine of the enclosed angle β which is
1 if the tensors are collinear (enantiomorphous cases) and close to zero if they
are perpendicular.
Residual dipolar couplings (RDCs) have become an important
tool in organic structure elucidation[1-3] as they complement
structural information from conventional NMR-methods like the
nuclear Overhauser effect[4-6] (NOE) or the 3J-couplings.[7-8]
RDCs are anisotropic NMR-parameters requiring a partial
alignment of the analyte which is commonly achieved by me-
chanically strained gels[9-12] or by lyotropic liquid crystalline (LLC)
phases.[13-17] If the alignment medium is furthermore chiral, en-
antiodifferentiation is possible (see Fig. 1).[18-20] This property
holds the potential of determining the absolute configuration in
the future.[21] To achieve this, however, the diastereomorphous
interactions between chiral solute and chiral alignment medium
need to be understood. With a few notable exceptions[22-24], gels
are usually achiral, while LLC phases may be based on a num-
ber of well-established chiral mesogenes and are therefore
much better suited for studies focusing on the specific interac-
tions of chiral analytes with the chiral medium. Since the pio-
neering work of Courtieu and Lesot,[18] the development of fur-
ther alignment media based on helically chiral polymers was
aspired.[13-17] Aiming at the compatibility with various organic
solvents, the introduction of different orientations and enan-
tiodifferentiating abilities, chiral LLC phases of polyguanidines,[15]
polyisocyanides[25] and poly-acetylenes[16-17] have been invented
for the RDC analysis.
enantiodifferentiating abilities, they possess the intrinsic property
to undergo a temperature induced helix reversal without perturb-
ing the nematic phase.[27] This thermoresponsivity based on one
polymer in two different helix conformations enables the meas-
urement of different orientations of an analyte in the very same
sample, under alignment conditions as close to each other as
possible. However, for poly-β-phenethylaspartates the tempera-
ture at which the helix reversal occurs is at 373 K. Imada et al.
showed that the reversal temperature can be lowered by jointing
two opposite screw sense regimes.[28] Poly-
L-aspartic acid esters
are known to be versatile and therefore being able to form either
a right- or left-handed α-helix depending on the ester group.[29]
Poly-β-phenethyl-
handed helices whereas Poly-β-benzyl-
L
-aspartate (PPLA) is known to form right-
-aspartate (PBLA)
L
preferably forms left-handed helices.[30] By incorporation of BLA
residues in PPLA, copolymers of PPLA and PBLA are obtained
which show a much lower helix reversal temperature than mere
PPLA. For copolymers comprising 51% PLA and 49% BLA the
transition temperature can be lowered down to approximately
40 °C, as determined by circular dichroism and NMR spectros-
copy.[28] Based on these findings of Imada and our previous
investigation of PPA alignment media, we were wondering
whether this copolymer can be used as a new helically chiral
enantiodifferentiating alignment medium and whether the helix
reversal at ambient temperatures can be used to induce different
orientations.
Recently, we started to investigate LLC phases of high molecu-
lar weight poly-β-phenethylaspartates (PPA) as new helically
chiral alignment media.[26] In addition to displaying
[a] M. Schwab, Dr. V. Schmidts, Prof. Dr. C.M. Thiele
Clemens-Schöpf Institut für Organische Chemie und Biochemie
Technische Universität Darmstadt
Alarich-Weiss-Straße 4, 64287 Darmstadt, Germany
E-mail: cthiele@thielelab.de
The synthesis of the copolymer of PLA and BLA, as well as the
enantiomeric
D
-configured copolymer – termed in the following
Supporting information for this article is given via a link at the end of
the document.
as -copo and
L
D-copo, respectively, was achieved by synthesiz-
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ing the corresponding N-carboxyanhydrides and (statistically)
copolymerizing them in chloroform under an inert atmosphere
(for detailed information: see Supporting Information (SI)). After
successful synthesis, we were able to prepare LLC phases
between 9% w/w and 15% w/w copolymer in tetrachloroethane-
d2 (TCE-d2), chloroform-d1 and dichloromethane-d2. This was
monitored by the quadrupolar splitting of the solvent.
So far, we showed the enantiodifferentiating alignment proper-
ties of the copolymers within one temperature regime. As a next
step the helix inversion and the corresponding RDCs were in-
vestigated by recording 2H-spectra (Fig. 3), 2H-images and
CLIP-HSQCs with increasing temperature (see SI). The sign of
the quadrupolar splitting ∆νQ was obtained by Q.E.COSY-
spectra.[37]
To examine the copolymers’ orientational properties as well as
its enantiodifferentiating abilities, β-pinene[31], which has been
previously used as an analyte in several RDC analyses, was
added to LLC phases of the copolymer. All four sample combi-
From Figure 3 it is apparent that around 306 K the quadrupolar
splittings
change
drastically
from
∆νQ ~ +215 Hz
to
∆νQ ~ -420 Hz indicating the helix reversal. Moreover, the curve
progression of the quadrupolar splittings can be divided into five
different domains. Domain (A) before the helix reversal, domain
(B) at the helix reversal, domain (C) between 308 K and 315 K
with a relatively constant quadrupolar splitting after the helix
reversal, domain (D) with a drastic decrease of quadrupolar
splittings between 315 K and 327 K and domain (E) with slightly
increasing quadrupolar splittings between 327 K and 340 K.
Based on these observations we determined RDCs in domains
(C), (D) and (E) after the reversal, at the representative tempera-
tures 312 K, 320 K and 330 K. Due to the decent CLIP-HSQC-
spectra, RDCs with small errors are observed (for NMR-spectra
see SI). Furthermore we calculated the corresponding order
tensors for all four samples containing each combination of (+)-
nations of (+)-β-pinene in
D- and L-copolymer as well as (-)-β-
pinene in - and -copolymer have been prepared.
D
L
To showcase the suitability of the copolymers as alignment
media, one-bond residual dipolar couplings (1DCH) were meas-
ured with CLean InPhase (CLIP)-HSQC[32] spectra. High-quality
NMR-spectra with narrow lines were obtained (Figure 2 and SI),
with experimental RDCs ranging between -10 and +10 Hz, con-
firming the desired weak alignment.
To examine the copolymers’ enantiodifferentiating properties,
the orientational differences in the enantiomorphous cases (e.g.
between (+)-β-pinene in
in the diastereomorphous cases (e.g. between (+)-β-pinene in
copo and (-)-β-pinene in -copo), as depicted in Figure 1, were
L-copo and (-)-β-pinene in D-copo) and
L
-
L
and (-)-β-pinene in
D- and
L-copolymer. In the diastereomor-
determined at 300 K. Therefore the corresponding order tensors
were calculated using the software RDC@hotFCHT.[33-34] Follow-
ing approaches from literature, the collinearity of a pair of order
tensors is usually described by the generalized cosine of the
enclosed angle β,[24, 35-36] which is used to quantify enantiodiffer-
entiation. Consequently, for the enantiomorphous cases (see
Figure 1) β = 1° is obtained, demonstrating the accuracy of this
method since the orientations should be the same and thus
β ~ 0° is expected. For the diastereomorphous case β = 49.6° is
obtained, confirming higher enantiodifferentiation than for other
known polypeptides like PBLG or PELG (for RDCs and all corre-
sponding β-angles see SI). Furthermore, essentially identical
tensor orientations are obtained upon repeated measurement of
a sample after 18 months again confirming reproducibility and
stability of the phases.
phous case of (+)-β-pinene in
L
-copo and (-)-β-pinene in -copo
L
at 312 K β = 44.5°, at 320 K β = 24.6° and at 330 K β = 11.3° is
obtained. It is expected that with increasing temperature also
mobility increases. We assume this to be the reason for the
observed change in orientation and the decreasing enan-
tiodifferentiation with increasing temperature.
To further understand the helix reversal and the change in enan-
tiodifferentiation with increasing temperature, we plotted the
obtained RDCs for (+)-β-pinene in
(Fig. 4). The plot reveals an unusual finding of a zero crossing,
when all RDCs become zero. One could assume that this point
enables the measurement of isotropic couplings. Unluckily, this
is impeded by the broad signals observed. Splittings, which are
in accordance with isotropic couplings can be read off; the error
is unreasonably high though (see SI).
D-copo against temperature
Figure 3: Quadrupolar splitting ∆νQ of TCE-d2 in an LLC phase containing
15% w/w D
-copolymer with increasing temperature monitored by 2H-spectra.
The curve can be divided into five domains: ∆νQ before the helix reversal (A),
∆νQ at helix reversal (B), ∆νQ directly after helix reversal (C), strongly decreas-
ing ∆νQ (D) and a slightly increasing ∆νQ (E).
Figure 2. Sections of the CLIP-HSQC spectrum of (+)-β-pinene in an LLC
phase of 15% w/w D-copo in TCE-d2 (red) showing the correlations of C10-
H10a, C10-H10s, C3-H3a, C3-H3s, C4-H4a/s, C5-H5, C1-H1 and of the
isotropic spectrum of (+)-β-pinene in TCE-d2 (black) measured at a 700 MHz-
spectrometer at 300 K.
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Figure 4. Course of RDCs with increasing temperature of (+)-β-pinene in
15% w/w
306 K.
L-copolymer with the helix reversal from P- to M-helix occurring at
Throughout the entire temperature range a stable LLC-phase is
present. This is in accordance with literature,[28, 38-39] confirming
the rod-like state throughout the entire temperature range. In our
previous report on thermoresponsive polyphenethylaspartates,
we did not observe such a zero crossing at the reversal temper-
ature. This suggests that the phenomenon is due the intrinsic
conformational properties of the copolymer which is based on
Figure 5. 1H-13C RDCs obtained from CLIP-HSQC spectra of all four samples
containing (+)- and (-)-β-pinene in D- and L-copolymer at 300 K before the helix
reversal (top) and RDCs obtained at 312 K directly after the helix reversal
(bottom) with complete sign inversion, indicating remarkable differentiation. If
RDCs are scaled with the respective ∆νQ, nearly identical absolute values are
observed. This is shown exemplarily in Table SI-6.
the poly-γ-benzyl-
opposite screw-sense than poly-β-phenethyl-
L
-aspartate portion possessing the actual
L
-aspartate.[30]
What this zero crossing and the accompanied sign change in
RDCs means in terms of macromolecular ordering needs to be
examined in further investigations.
After we scrutinized the orientational properties within each
temperature domain (300 K, 312 K, 320 K and 330 K), an inter-
temperature comparison was performed, comparing the orienta-
tion before the helix reversal with the orientation after the helix
reversal. Here it should be noted that the helix conformation
varying the ratio of purple membrane to salt concentrations Sass
et al. were able to achieve a range of RDC data sets and molec-
ular orientations, exhibiting generalized angles β = 0.8 to
32.9°.[35] While these studies use β to characterize the difference
changes from e.g. P- to M-helix but the amino acid configuration
in tensor orientations in a general sense, we and others also use
remains the same. In our previous paper[26] we demonstrated
that polyaspartates before and after helix reversal are diastere-
omeric alignment media, thus furnishing β-angles very different
from zero. For the copos this becomes quite evident when com-
paring RDCs obtained at 300 K with RDCs obtained at 312 K
(Fig. 5). All 1H-13C RDCs undergo a sign change. Thus the orien-
tation of the solute changes drastically. This large change in the
experimentally observed RDCs is also observed for the ∆νQ of
the solvent (see above). It is furthermore evident in the axial
components of the alignment tensors changing from
Da = -2.95·10-4 to Da = 6.31·10-4. Concomitantly, also the rhom-
bicity, expressed as Dr = -1.58·10-4 changes to Dr = 3.15·10-4.
A related occurrence is described by Gayathri et al.[11] in a
PMMA gel and by Sass et al.[35, 40] in oriented purple membranes
or in polyacrylamide gels. Gayathri et al. obtained mostly posi-
tive RDCs in the stretched gel whereas compressing the gel
resulted in negative RDCs. They suggested that this is primarily
based on the fundamental difference between a stretched and
compressed gel leading to a rotation of the molecular order
matrix accompanied by changes in the rhombicities. Similarly, by
26, 31, 41]
β to quantify enantiodifferentiation.[16,
To reflect the
symmetry properties of enantiodifferentiation, values are com-
monly limited to a range of β = 0 .. 90° in this context. Using β
over other methods of comparison (Euler angles, eigenvector
spheres, etc.) brings the advantage of not only reporting on
changes in tensor orientation, but also subsuming changes in
tensor shape. The peculiarities of this parameter become appar-
ent, when comparing the tensors determined before and after
helix inversion. The two states exhibit a different sign of Da simi-
lar to the situation, where a perpendicular relative tensor orienta-
tion was observed in stretched vs. compressed gels. However,
when calculating the generalized angle of these two tensors for
our system, the value is determined as β = 7.8° (in the limited
notation), suggesting basically no difference in tensor orientation.
Both interpretations do not reflect the observed differentiation in
experimental RDCs.
While limiting the range of the generalized angle β gives a useful
quantity to express enantiodifferentiation and differences in
tensor orientation accompanied by only small changes in tensor
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shape, it is apparently not appropriate when both tensor orienta-
tion and shape change to a degree as seen here before and
after the helix inversion, as it does not reflect the differences
observed in the experimental RDCs and thus doesn’t allow for a
quantitative analysis. Thus we suggest using the full range for β
(0° .. +180°) in such cases. In the previous example, the proper
result would thus be β = 172.2°, indicating an almost anti-parallel
tensor orientation in 5D,[42] again with a small orientational dif-
ferentiation. As noted above, however, this value does not nec-
essarily encode solely for a large difference in tensor orientation,
but is a composite of differences in all tensor parameters (see SI
for further explanation).
In contrast to this rather small difference in orientation in 5D
before and after helix reversal (domains (A) and (C),
respectively), we obtained a significant difference of β = 44°
when comparing the orientations of the analyte in the domains
(C) and (E) after the helix reversal (see Figure 3 and SI).
Furthermore, we were interested in solute compatibility and
whether the same behavior can also be observed for other com-
pounds. Thus we examined various analytes with a wide range
of functional groups like isopinocampheol (IPC), carvone, cam-
phor, camphorsultam and perillic acid. All allow for RDC extrac-
tion and display similar results concerning the inter-temperature
comparison (including the sign change in 1H-13C RDCs and
rhombicities after helix reversal (for details see SI)). Additionally,
we investigated a non-racemic mixture of both enantiomers of
IPC. For some of the signals, the high enantiodifferentiation and
spectra quality allows for a direct observation of baseline sepa-
rated multiplets (for details see SI).
Fährmann for synthesizing
like to thank the DFG and FOR1583 for financial support.
D
-copolymer. The authors would also
Keywords: polyaspartates • LLC phase • helix reversal • residual dipolar
couplings • NMR spectroscopy • alignment media
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Mirror RDCs in one sample: We
present a copolyaspartate as new
helically chiral enantiodifferentiating
alignment medium which undergoes a
helix reversal at 306 K resulting in a
maximum difference in NMR-spectra
and parameters before and after the
helix reversal. The RDCs obtained
within one sample at different temper-
ature are almost mirror images.
Mira Schwab, Volker Schmidts, Christina
M. Thiele*
Page No. – Page No.
Thermoresponsive Alignment Media
in NMR spectroscopy: Helix Reversal
of a Copolyaspartate at Ambient
Temperatures
Layout 2:
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Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
Text for Table of Contents
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