Synthesis and Stereochemical Assignment of Crypto-Optically Active 2H6-Neopentane

Article abstract of DOI:10.1002/anie.201505349

The determination of the absolute configuration of chiral molecules is at the heart of asymmetric synthesis. Here we probe the spectroscopic limits for chiral discrimination with NMR spectroscopy in chiral aligned media and with vibrational circular dichroism spectroscopy of the sixfold-deuterated chiral neopentane. The study of this compound presents formidable challenges since its stereogenicity is only due to small mass differences. For this purpose, we selectively prepared both enantiomers of ²H₆-1 through a concise synthesis utilizing multifunctional intermediates. While NMR spectroscopy in chiral aligned media could be used to characterize the precursors to ²H₆-1, the final assignment could only be accomplished with VCD spectroscopy, despite the fleetingly small dichroic properties of 1. Both enantiomers were assigned by matching the VCD spectra with those computed with density functional theory.

Full text of DOI:10.1002/anie.201505349

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International Edition: DOI: 10.1002/anie.201505349
German Edition: DOI: 10.1002/ange.201505349
Chiral Discrimination Very Important Paper
Synthesis and Stereochemical Assignment of Crypto-Optically Active
2H6-Neopentane
Ahmad Masarwa, Dennis Gerbig, Liron Oskar, Aharon Loewenstein, Hans Peter Reisenauer,
Philippe Lesot,* Peter R. Schreiner,* and Ilan Marek*
Dedicated to Professor Duilio Arigoni
Abstract: The determination of the absolute configuration of
chiral molecules is at the heart of asymmetric synthesis. Here
we probe the spectroscopic limits for chiral discrimination with
NMR spectroscopy in chiral aligned media and with vibra-
tional circular dichroism spectroscopy of the sixfold-deuter-
ated chiral neopentane. The study of this compound presents
formidable challenges since its stereogenicity is only due to
small mass differences. For this purpose, we selectively
(clockwise) or “À” (counterclockwise) optical rotation.[1]
However, in some very special cases of chirality, due to the
electronic properties of the chiral molecule, the optical
rotation is not measurable.[2] The determination of the
absolute configuration of these cryptochiral[3]—better called
crypto-optically active[4]—compounds remains therefore
extremely challenging. For instance, a suitable prototype of
a crypto-optically active molecule is appropriately deuterated
neopentane (excluding its carbon isotopologues), C(CH3)-
2
prepared both enantiomers of H6-1 through a concise syn-
2
thesis utilizing multifunctional intermediates. While NMR
spectroscopy in chiral aligned media could be used to
characterize the precursors to 2H6-1, the final assignment
could only be accomplished with VCD spectroscopy, despite
the fleetingly small dichroic properties of 1. Both enantiomers
were assigned by matching the VCD spectra with those
computed with density functional theory.
(CH2 H)(CH2H2)(C2H3), henceforth referred to as 2H6-1,
which is the smallest chiral compound possessing a quaternary
carbon stereogenic center. This crypto-optically active mol-
ecule owes its chirality exclusively to an asymmetric distri-
bution of the masses of the nuclei, whilst having virtually the
same electron distribution as all-1H-neopentane.[5] As
a matter of fact, within the commonly invoked Born–
Oppenheimer (BO) approximation, 2H6-1 is electronically
achiral and BO computations of its optical rotation return
a zero value. Even dynamic computations beyond the BO
approximation deliver, at best, vanishingly small values that
could not be measured reliably.[6] The preparation as well as
the experimental assignment of the absolute configuration of
the enantiomers of 2H6-1 therefore poses a formidable
analytical challenge and was (so far) exclusively achieved
for its R enantiomer through matching of the experimentally
determined Raman optical activity (ROA) spectra with
density functional theory (DFT) computations.[7] Following
these elegant studies, a complementary technique would be
vibrational circular dichroism (VCD) spectroscopy, whose
T
he creation of new molecular entities and subsequent
exploitation of their properties is central to a broad spectrum
of research disciplines ranging from medicine to materials.
One of these important properties, overlapping many
branches in the sciences, e.g., chemistry, physics, and math-
ematics, is a symmetry property called chirality. Molecules are
chiral if they cannot be superimposed on their miror images.
The absolute configuration of enantiomers, defined either as
“R” (rectus) or “S”(sinister) according to the Cahn–Ingold–
Prelog (CIP) rules, determines the direction in which an
enantiomer rotates the plane of polarized light, namely “ + ”
2
application to both enantiomers of H6-1 has been examined
[*] Dr. A. Masarwa, L. Oskar, Prof. Dr. A. Loewenstein, Prof. Dr. I. Marek
The Mallat Family Laboratory of Organic Chemistry
Schulich Faculty of Chemistry and the Lise Meitner-Minerva Center
for Computational Quantum Chemistry
theoretically but not yet experimentally. When using VCD,
several questions arise. For instance, could one discern the
individual contributions of the nine possible conformers of
2H6-1 that present minima (i.e., rotamers) on the correspond-
ing rotational potential energy surface (PES) to the VCD
spectra? Is it possible to match the spectra with quantum
mechanical computations to assign absolute stereochemistry?
On the basis of such computations it was concluded that the
contributions of the individual rotamers would very signifi-
cantly reduce the overall VCD intensities but should in
principle, although not yet demonstrated, be measureable in
the 700–1400 cmÀ1 range.[5]
Technion-Israel Institute of Technology
Haifa, 32000 (Israel)
E-mail: chilanm@tx.technion.ac.il
Dr. D. Gerbig, Dr. H. P. Reisenauer, Prof. Dr. P. R. Schreiner
Institute of Organic Chemistry, Justus-Liebig University
Heinrich-Buff-Ring 58, 35392 Giessen (Germany)
E-mail: prs@uni-giessen.de
Prof. Dr. P. Lesot
ICCMMO (RMN en Milieu OrientØ)
UniversitØ Paris-Sud, CNRS UMR 8182, Bât. 410
15 rue Georges Clemenceau, 91405 Orsay (France)
E-mail: philippe.lesot@u-psud.fr
As the assignment of absolute configurations of chiral
molecules is in principle more reliable with ROA and VCD
techniques than with CD and optical rotatory dispersion
(ORD) alone,[8] it is essential to determine whether current
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201505349.
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experimental and theoretical approaches can indeed be
trustworthy to the degree that they can replace the (current)
ultimate proof of stereochemical identity, namely the syn-
thesis of a target structure from a natural product with
established absolute configuration, a very tedious and time-
consuming strategy.
Another alternative for spectropically separating the
signals of enantiomers of 2H6-1 should be NMR experiments
using deuterium as a nuclear probe and chiral liquid crystals
(CLC) as oriented NMR solvents. This approach ideally
complements vibrational spectroscopy, even if the determi-
nation of the absolute configuration (of chiral molecules with
a single-stereogenic center) is impossible, without the a priori
knowledge of the Saupeꢀs order tensors.[9] It has never been
utilized for a chiral molecule as challenging as 2H6-1, and is, as
we will demonstrate, not yet capable of spectral enantiodis-
crimination of an essentially unfunctionalized molecule such
as 2H6-1.
DnQ(R) ¼ DnQ(S), when nuclei of spin I = 1 (such as deute-
rium) are used as nuclear probes.[17] Due to the high sensitivity
of the quadrupolar interaction (HQ) to small variations of
ordering of the C-D vector, the method is particularly
efficient in discriminating between enantiomers of chiral
molecules (isotopically enriched or at natural-abundance
deuterium level), including compounds that are chiral by
virtue of isotopic substitution such as 2.[18–20] The presence of
two quadrupolar doublets (j DnQ j= 8 and 15 Hz) in the
2H-{1H} spectrum of (Æ)-2H3-2 recorded in the CLC shows
that spectral discrimination does occur (Figure 1A, top); the
determination of peak surfaces performed by deconvoluting
2
the H signals in the enantioenriched series indicate that the
enantiomeric ratio is higher than 98:2 (Figure 1A, bottom).
When (S)-2H3-2 is treated with the Negishi reagent,[21] the
À
combined zirconocene-mediated allylic C H bond activation
À
followed by selective C C bond cleavage and deuteration of
the resulting bismetalated species with 2H3O+ gives (R)-2H5-3
on gram scale in 91% yield. As the stereogenic quaternary
center is at no risk of racemization in the process, the optical
purity is identical throughout the rest of the synthesis
(Scheme 1). Subsequent oxidative cleavage of the double
bond followed by the in situ reduction with NaBD4
leads to the volatile neopentanol which must be
protected in situ to give the tosylate adduct (R)-2H5-4
in 89% yield. The final reduction was performed with
LiAl2H4 in Oct2O to give the expected gaseous (S)-
2H6-1 in quantitative yield. The opposite enantiomer
(R)-2H6-1 was similarly prepared from the alkylidene-
cyclopropane (R)-2H3-2.[16]
Our strategy for the preparation of both enantiomers of
2H6-1 (Scheme 1) was to promote the transformation of the
easily accessible w-ene cyclopropanes[10] as well as alkylide-
necyclopropanes[11] into acyclic molecular fragments by
The structure of 2H6-1 was definitively established
2
by H NMR spectroscopy with and without proton
decoupling in an isotropic solvent (Figure 1B, top and
bottom). Thus, the presence of three 2H resonances in
the H-{1H} 1D spectrum with a relative intensity of
2
Scheme 1. Synthesis of (S)-2H6-1.
3:2:1 indicates the discrimination of mono-, di-, and
2
trideuterated methyl groups on the basis of their H
merging two modes of chemical activation.[12] Indeed, through
the use of a unique organometallic species, successive allylic
À
À
C H bond activations followed by a selective C C bond
cleavage and selective functionalization with two different
electrophiles,[10] complex molecular architectures possessing
a quaternary carbon stereogenic center[13] were readily
constructed from common starting materials.[14,15] We there-
fore predicted that the control of both modes of activation
could be successfully used for the direct and expedient
preparation of both (R)- and (S)-1 from the easily accessible,
enantiomerically enriched alkylidenecyclopropane (2H3-2,
Scheme 1, e.r. 98:2).[16]
The enantiomeric ratio of enantioenriched 2H3-2 was
determined using proton-decoupled deuterium NMR
(2H-{1H}) techniques using a polypeptide lyotropic CLC
made of poly-g-benzyl-l-glutamate (PBLG) and chloroform
as an organic aligning NMR solvent,[17] whereas the absolute
configuration was determined by analogy to our previous
work.[11] This NMR approach dedicated to the determination
of enantiopurity is based on the difference of residual
quadrupolar couplings (RQC) of an enantiomeric pair,
2
2
Figure 1. A) Determination of the e.r. of H3-2 by H-{1H} NMR
analysis (14 T/cryoprobe) in the chiral liquid crystal PBLG (top:
racemic series; bottom: enantiomerically enriched series). B) 2H
2
assignment (d and J) of H6-1 in liquid (pyridine). Note the scalar
coupling patterns when 1H decoupling is off (bottom).
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chemical shifts d(2H). This assignment is also unambiguously
2
confirmed by the H fine structures (a triplet, a doublet, and
a singlet, centered at 0.793, 0.785, and 0.755 ppm in pyridine,
respectively) due to intramethyl geminal 2H–1H scalar (J)
1
couplings when the H decoupling is turned off (see also the
Supporting Information). Considering the positive results for
the determination of the enantiomeric ratio of (S)-2H3-2, and
previous studies on isotopic enantiodiscrimination,[19] 2H-{1H}
NMR in PBLG mesophases, we applied the same technique
again to differentiate the enantiomeric signals of (rac)-2H6-1,
with the goal of assessing the enantiopurity of enantioen-
riched (S)-2H6-1. Interestingly, small but spectrally resolved
quadrupolar doublets (j DnQ j< 2 Hz) associated with the
mono- and dideuterated methyl groups (see the Supporting
Information) indicate that this asymmetric (C1 point group)
molecule is slightly oriented in this weakly aligning lyotropic
chiral mesophase. Unfortunately, all attempts to discriminate
the enantiomers based on RQC differences failed, irrespec-
tive of the temperature (in a range of 30 K) and the polarity of
the cosolvent (CHCl3 or pyridine). It appears that the overall
shape recognition mechanisms involved in the chiral discrim-
ination phenomenon[22] are in the case of PBLG unable to
differentiate the extremely small topological differences
between the mono-, di-, and trideuterated methyl groups
around the stereogenic carbon atom of 2H6-1.
From the perspective of the CDP, the absence of visible
discriminations in this challenging example emphasizes the
limits of efficiency of overall shape recognition mechanisms
with this particular chiral liquid crystals.[23] The challenging
assignment of the absolute configuration of (S)-2H6-1 thus at
this time directly relies on the combination of highly sensitive
vibrational spectroscopy with high-level theory.
2
The experimental infrared (IR) spectrum of H6-1 agrees
well with the spectrum computed at the CCSD(T)/-cc-pVTZ
level of theory (unscaled, Figure 2A; see Figure S5 for
enlarged details), which is considered the “gold standard”[24]
of currently available ab initio methods. Note that the nine
rotamers have approximately equal statistical weight[5] as
their energy difference at this level amounts to less than
10À4 kcalmolÀ1 only due zero-point vibrational energy con-
tributions. As the rotational barrier in 1 derived from IR
measurements in the crystalline state[25] or in the gas phase[26]
only amounts to 4.3 kcalmolÀ1, the nine conformers of
2H6-1 must be essentially equally populated in the gas phase
at room temperature. The computed rotational barrier only
amounts to 3.7 kcalmolÀ1 at CCSD(T)/cc-pVTZ//B3LYP/aug-
cc-pVTZ + ZPVE. Such a relatively small rotational barrier
implies that at 0–258C there is essentially free internal
rotation.
Despite the large and readily discernible IR signals in the
C-H/2H absorption region, the B3LYP/aug-cc-pVTZ com-
puted VCD spectrum of (S)-2H6-1 (simulated with 3 cmÀ1
linewidth) is remarkably poor in terms of spectroscopic
features (Figure 2B), as predicted.[5] In the range of about
1500–3000 cmÀ1 virtually all signal intensities of the nine
rotamers cancel so that there is essentially no VCD signal in
this range and one is left with the typically less intense and less
well resolved fingerprint region. An additional challenge is
the fact that 2H6-1 is a good Raman scatterer but a rather poor
Figure 2. A) Computed (CCSD(T)/cc-pVTZ; orange) and experimental
matrix IR spectrum (Ar, 8 K; black) of (S)-2H6-1. B) Spectral region for
2
VCD measurements of H6-1. C) Cancellation of VCD signals of the
nine (S)-2H6-1 rotamers. D) Matching of experimental VCD (Ar, 8 K;
black) and computed (B3LYP/aug-cc-pVTZ, 3 cmÀ1 linewidth; orange)
VCD spectrum of (S)-2H6-1 (difference of (S)- and (R)-2H6-1 VCD
traces).
IR absorber.[5] As a consequence, the range left accessible for
VCD measurements of 1000–1500 cmÀ1 is of very low
intensity because a larger number of signals with opposite
contributions to the total intensity coincide (for a color-coded
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distribution of the individual rotamers see Figure 2C), lead-
ing to reduced total band intensities. All of this poses major
challenges on compound purity and handling, and the
required spectral resolution.
Keywords: chirality · cryptochirality · neopentane ·
NMR spectroscopy · vibrational circular dichroism
How to cite: Angew. Chem. Int. Ed. 2015, 54, 13106–13109
Angew. Chem. 2015, 127, 13298–13302
We sought to counteract this problem by employing the
matrix isolation technique, in which the target compound is
isolated in a dilute and rigid matrix of a gaseous host material
under cryogenic conditions. Both the absence of intermolec-
ular interactions, owing to the high dilution of the isolated
species, as well as the very low temperature usually below
15 K afford narrow signal profiles, which greatly aid spectro-
scopic investigations. This advantage is, however, slightly
diminished due to the lower concentration of the target
compound in matrix environment, so that great care has to be
taken to determine the optimal conditions for VCD experi-
ments.
[1] G. P. Moss, Pure Appl. Chem. 1996, 68, 2193.
[2] H. Wynberg, G. L. Hekkert, J. P. M. Houbiers, H. W. Bosch, J.
Am. Chem. Soc. 1965, 87, 2635 – 2639.
[3] K. Mislow, P. Bickart, Isr. J. Chem. 1976, 15, 1 – 6.
[4] A. de Meijere, A. F. Khlebnikov, R. R. Kostikov, S. I. Kozhush-
kov, P. R. Schreiner, A. Wittkopp, D. S. Yufit, Angew. Chem. Int.
Ed. 1999, 38, 3474 – 3477; Angew. Chem. 1999, 111, 3682 – 3685.
[5] W. Hug, J. Haesler, Int. J. Quantum Chem. 2005, 104, 695 – 715.
[6] A. G. Csµszµr, W. D. Allen, H. F. Schaefer, J. Chem. Phys. 1998,
108, 9751 – 9764.
[7] J. Haesler, I. Schindelholz, E. Riguet, C. G. Bochet, W. Hug,
Nature 2007, 446, 526 – 529.
[8] T. D. Crawford, Theor. Chem. Acc. 2005, 115, 227 – 245.
[9] a) R. Berger, R. J. Courtieu, R. R. Gil, C. Griesinger, M. Kçck, P.
Lesot, B. Luy, D. Merlet, A. Navarro-Vµzquez, M. Reggelin,
U. M. Reinscheid, C. M. Thiele, M. Zweckstetter, Angew. Chem.
Int. Ed. 2012, 51, 8388 – 8391; Angew. Chem. 2012, 124, 8512 –
8515; b) L. Ziani, P. Lesot, A. Meddour, J. Courtieu, Chem.
Commun. 2007, 4737 – 4739.
[10] A. Vasseur, L. Perrin, O. Eisenstein, I. Marek, Chem. Sci. 2015, 6,
2770 – 2776.
[11] S. Simaan, A. Masarwa, E. Zohar, A. Stanger, P. Bertus, I.
Marek, Chem. Eur. J. 2009, 15, 8449 – 8464.
[12] A. Masarwa, D. Didier, T. Zabrodsky, M. Schinkel, L. Acker-
mann, I. Marek, Nature 2014, 505, 199 – 203.
[13] J. P. Das, I. Marek, Chem. Commun. 2011, 47, 4593 – 4623.
[14] Y. Minko, M. Pasco, L. Lercher, M. Botoshansky, I. Marek,
Nature 2012, 490, 522 – 526.
[15] I. Marek, Y. Minko, M. Pasco, T. Mejuch, N. Gilboa, H. Chechik,
J. D. Das, J. Am. Chem. Soc. 2014, 136, 2682 – 2694.
[16] S. Simaan, A. Masarwa, P. Bertus, I. Marek, Angew. Chem. Int.
Ed. 2006, 45, 3963 – 3965; Angew. Chem. 2006, 118, 4067 – 4069.
[17] P. Lesot, J. Courtieu, Prog. Nucl. Magn. Reson. Spectrosc. 2009,
55, 128 – 159.
[18] P. Lesot in Encyclopedia of Magnetic Resonance (eMagRes)
Vol. 2 (Eds.: R. K. Harris, R. E. Wasylishen), Wiley, Hoboken,
2013, pp. 315 – 334.
Indeed, we note the vanishingly small absorbance values
in Figure 2D of only about 10À5 absorbance units in our
experiments, in which both enantiomers of 2H6-1 were
isolated in Ar at only 8 K. To be able to discern individual
signals for the low-intensity spectrum of the S enantiomer, we
subtracted from it the VCD trace of the R enantiomer,
thereby increasing the signal-to-noise ratio and hence the
overall quality; alternatively, we subtracted from the VCD
traces of the S and R enantiomers, respectively, the VCD
trace of (rac)-2H6-1 as the baseline. The resulting VCD
spectra (see Figure S6) indeed appear as mirror images. The
agreement between experiment and theory of all acquired
spectral data both in the IR and VCD spectra is remarkably
good and warrants the assignment of the absolute config-
urations of both enantiomer by comparison with the com-
puted VCD spectra.
Despite the earlier notion that “Vibronic effects in the
vacuum ultraviolet circular dichroism might reveal that the
molecule is chiral, but the presence of nine rotamers would
make it extremely difficult to interpret the spectra, because
the spatial arrangement of the rotamersꢀ nuclei resembles that
of enantiomers…”,[7] we clearly point out here that the
assignment of even one of the most challenging chiral
molecules can be successfully achieved through a combination
of sophisticated experimental and theoretical techniques. As
such, the title structure with an essentially centrosymmetric
electron distribution and multiple close-lying rotamers whose
optical activities almost perfectly cancel is a stringent test case
for the current arsenal of experimental and theoretical
methods available for the determination of structures and
absolute configurations of chiral molecules.
[19] P. Lesot, C. Aroulanda, H. Zimmermann, Z. Luz, Chem. Soc.
Rev. 2015, 44, 2330 – 2375.
[20] a) A. Meddour, I. Canet, A. Loewenstein, J. M. Pechine, J.
Courtieu, J. Am. Chem. Soc. 1994, 116, 9652 – 9656; b) M.
Sarfati, C. Aroulanda, J. Courtieu, P. Lesot, Tetrahedron:
Asymmetry 2001, 12, 737 – 744; c) M. Sarfati, J. Courtieu, P.
Lesot, Chem. Commun. 2000, 1113 – 1114.
[21] E. Negishi, T. Takahashi, Synthesis 1998, 1 – 19.
[22] P. Lesot, O. Lafon, J. Courtieu, P. BerdaguØ, Chem. Eur. J. 2004,
10, 3741 – 3746.
[23] P. Lesot, Z. Serhan, C. Aroulanda, I. Billault, Magn. Reson.
Chem. 2012, 50, S2 – S11.
[24] R. J. Bartlett, WIREs Comput. Mol. Sci. 2012, 2, 126 – 138.
[25] J. R. Durig, S. M. Craven, J. Bragin, J. Chem. Phys. 1970, 52,
2046 – 2052.
Acknowledgements
[26] S. Weiss, G. E. Leroi, Spectrochim. Acta Part A 1969, 25, 1759.
This research was supported by a grant from the German–
Israeli Project Cooperation (DIP 597/19-1) between I.M. and
P. R.S. and the Minerva Foundation in Munich. P. L. is grateful
to CNRS and UniversitØ de Paris Sud for the continued
funding and Dr. C. Aroulanda for the access to a gas-transfer
ramp.
Received: June 11, 2015
Published online: September 7, 2015
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