Organic Letters
Letter
generate the computed IR spectrum. The agreement between
the experimental and computed IR spectra verified that
B3LYP/6-311++G(d,p) is appropriate to compute IR and
VCD spectra (Figure 3A). We measured the VCD traces of
Figure 4. Molecular structure from the X-ray analysis of diquinine salt
(−)-5. Only hydrogens at the stereogenic centers and those forming
ionic hydrogen bonds (in orange) are shown. A cocrystallized water
molecule was omitted for clarity. Thermal ellipsoids are set at the 50%
probability level.
Figure 3. Assignment of the AC of 1 by VCD. (A) Experimental
(neat; black) and computed (B3LYP/6-311++G(d,p); gas phase, 6
cm−1 simulated line width, scaled by 0.98; red) IR spectra of 1. (B)
Experimental (neat; black) and computed (B3LYP/6-311++G(d,p);
gas phase, 8 cm−1 line width, scaled by 0.98; red) VCD spectra of
(+)-1 and (R,R)-1, respectively.
spectroscopies: The first is the crystalline sponge method
developed by Fujita and coworkers,32−39 although the
applicability of the method to alkanes has yet to be seen.
The second technique is the visual inspection of single
molecules by microscopic techniques such as scanning
tunneling microscopy (STM)40−43 and atomic force micros-
copy (AFM).44,45 We recently demonstrated that low-temper-
ature AFM with a CO-functionalized tip provided images of
individual [123]tetramantanea chiral, rigid alkane consisting
of four adamantane unitsadsorbed on a copper surface.46
The approach differentiated the two enantiomers along with
their orientations on the surface and enabled the AC
assignment by direct visualization of the single molecules.
Because the surface temperature is as low as 15 K, even volatile
compounds such as 1 can be suitable analytes for this method.
Our next step will be the visualization of single molecules of 1
to further expand the scope of our AFM-based AC assignment.
(+)-1 and, for baseline corrections and the elimination of
systematic errors, also that of ( )-1. Figure 3B shows the
experimental and computed (B3LYP/6-311++G(d,p), scaled
by 0.98) VCD spectra of (+)-1 and (R,R)-1, respectively, in
the spectroscopically viable region of 1400−800 cm−1. The
excellent agreement confirms that the AC of (+)-1 is indeed
(R,R).
Finally, X-ray crystallographic analysis provided further
evidence of our AC determination of 1 on the basis of single
crystals of diquinine salt (−)-5 (Figure 4). Because the AC for
quinine is known, the AC of resolved dicarboxylic acid (−)-4
was assigned to (S,S). Because our synthetic route does not
involve transformations that affect the two adjacent stereogenic
centers, the AC of our synthetic (+)-1 must indeed be (R,R).
Even today, many chemists execute AC assignments by
means of laborious compound derivatizations and total
syntheses using a material of known AC. As demonstrated
here, such synthetic efforts only for the purpose of AC
determination are not necessary; we synthesized enantiomeri-
cally pure 1 only because of the extreme difficulty to separate
the two enantiomers. Our results showcase that chiroptical
spectroscopies combined with readily executed computations
are reliable approaches to the AC determination of even the
most challenging and fundamental organic molecules. Because
conformationally flexible alkanes often belong to a class of
crypto-optically active compounds whose ACs are extremely
difficult to determine, the unambiguous assignment of the AC
of 1, consisting of multiple conformers, is comforting.
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
Full experimental procedures, compound character-
ization, X-ray crystallographic data, and computational
Accession Codes
CCDC 1988737 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Note that (R,R)-(+)-1 is an oily material; in fact, chiroptical
spectroscopies could be the only methods currently available
to determine the AC of molecules in such physical states.
There are two emerging technologies that rival chiroptical
C
Org. Lett. XXXX, XXX, XXX−XXX