Double chirality transmission in trityl amines: Sensing molecular dynamic stereochemistry by circular dichroism and DFT calculations

Article abstract of DOI:10.1002/chem.201101699

Con-figured out: The tert-butyl group can be formally seen as "less" sterically demanding (M) than the methyl group (L). This is the case when a CD-active trityl group at the nitrogen atom is used to report the chirality of the carbon substituent with two

Full text of DOI:10.1002/chem.201101699

DOI: 10.1002/chem.201101699
Double Chirality Transmission in Trityl Amines: Sensing Molecular Dynamic
Stereochemistry by Circular Dichroism and DFT Calculations
[a]
´
Jacek Sciebura and Jacek Gawron´ski*
The dynamic stereochemistry of chiral molecules is one of
the major challenges of contemporary structural chemistry
and biochemistry.[1] Sensitive issues regarding absolute con-
figuration and conformation can now be dealt with by ap-
plying spectroscopic (in particular, chiroptical) methods and
computational methods, especially those based on density
functional theory. Despite their importance, amines (secon-
dary and tertiary) present a still unsolved problem in the de-
termination of their absolute configuration at the nitrogen.
This configuration is subject to dynamic inversion at the ni-
trogen, and the inversion rate approaches 106 sÀ1.[2] Pre-
ferred relative configuration of secondary amines can be
studied with the use of NMR spectroscopy.[3] X-ray diffrac-
tion studies are mainly applicable to rigid amine molecules
in the solid state, such as Trçger base,[4] N-chiral 1-chloro-
2,2-diphenylaziridine[5] or a chiral oxaziridine.[6]
Chiroptical methods, which are sensitive to absolute con-
figuration, have been widely used to determine the perma-
nent point of chirality at a carbon atom by the mechanism
of chirality transmission, which induces dynamic helicity in
the aromatic chromophoric system attached.[7] However, chi-
roptical methods have only rarely been applied to chiral
amines,[8] since they usually lack a chromophore suitable for
electronic circular dichroism (ECD) studies. In the present
study, we show that in chiral N-tritylamines permanent chir-
ality of the carbon atom is efficiently transmitted to a nitro-
gen atom and to a trityl group, which plays the role of a dis-
tinct ECD chromophore. The calculated diastereoisomer
population and their Boltzmann averaged ECD spectra can
be compared with the experimental ones by a generally ac-
cepted verification protocol. This approach provides the dis-
tribution of amine molecules of RN and SN configuration
and allows us to demonstrate that dynamical configuration
change at the nitrogen atom is correlated with permanent
chirality at the carbon atom and dynamic helicity of the
trityl group.
spectra in the region of 1B transition around 192 nm (e=
0.6–0.8ꢀ105). These Cotton effects are of the exciton type
(Table 1) and are strong (except 1 and 2); this suggests a
well-defined preferred helicity of the trityl chromophore.
Table 1. Short-wavelength experimental ECD data for trityl amines 1–12
(cyclohexane solution).
De [nm]
1
2
3
4
5
6
7
8
3 (205)
À4 (207)
À36 (200)
8 (202)
4 (213)
23 (205)
6 (222)
21 (205)
23 (201)
23 (203)
21 (201)
23 (206)
À3 (190)
À7 (197)
16 (188)
À15 (188)
À17 (190)
À10 (190)
À42 (198)
À52 (188)
À33 (187)
À48 (188)
À27 (188)
À22 (189)
9
10
11
12
A number of N-tritylamines (1–12) prepared for this
study, display characteristic Cotton effects in their ECD
In order to determine the low-energy structures and their
populations we used molecular modeling with a Monte
Carlo search followed by a DFT structure optimization at
the B3LYP/6-31G
at the M06-2X/6-311+G
ACHTUNGTRENNUNG
´
´
[a] J. Sciebura, Prof. Dr. J. Gawronski
AHCTUNGTRENNUNG
Department of Chemistry, A. Mickiewicz University
chiral tritylamines (1–4). In fact, 1 represents the simplest
acyclic chiral structure possible, with increasing diversifica-
tion in 2–4. There are several structural variables that have
to be considered in the calculations: the conformation of the
alkyl group, the configuration of the nitrogen center and the
´
Grunwaldzka 6, 60780 Poznan (Poland)
Fax : (+48)061-8291505
E-mail: gawronsk@amu.edu.pl
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101699.
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Chem. Eur. J. 2011, 17, 13138 – 13141

COMMUNICATION
helicity of the trityl group. The
helicity of the trityl group can
be described by a set of dihe-
dral angles w1–w3 (in order of
descending absolute values),
which are defined by the near-
ence between populations of the conformers of both types
(invertomers) determines the dominant configuration of the
nitrogen atom. In molecules 1 and 2 it is the SN configura-
tion, although the differentiation is low, SN/RN, 66:34 and
58:41, respectively.
In the case of 3, a tert-butyl substituted N-tritylamine, a
surprising conformational effect was observed. The popula-
tion of M-type conformers was low (5%) and a dominant
(95%) PMM conformer induced RN configuration. This is
because the PMM conformer is less strained with respect to
the steric interactions between the trityl and the tert-butyl
groups (see below). On the other hand, compound 4,[13]
which has the same absolute configuration, showed a strong
preference for an enantiomorphic conformer MPP (72% in
the equilibrium) and hence for the SN configuration. It is
evident that in molecules 1–4 the trilyl group when placed
in a different spatial environment displays different confor-
mational equilibria.
Conformational equilibria can be verified by comparing
the experimental and calculated ECD spectra. For example,
in the case of 3 and 4, in which one type of conformer is
dominant, the experimental and calculated ECD spectra are
quite similar, and show the principal Cotton effects (around
200 nm) in the sequence +/À for the former and À/+ for
the latter, in the order of decreasing excitation energies.
Furthermore, a comparison of chiroptical properties of trityl
amines 4 and 5 showed that N-methylation apparently does
not significantly affect the conformational equilibria and
chiroptical properties (Figure 1).
Calculations showed that there is an additional correlation
available between absolute configuration at the nitrogen
atom and the ECD spectra: positive sign of the characteris-
tic, longest-wavelength Cotton effect (ca. 240 nm) correlates
with the SN configuration, negative sign is associated with
RN configuration. However, in the experimental ECD spec-
tra of trityl amines this correlation might not be evident due
to a more complex pattern of Cotton effects present at
above 220 nm.
Tritylamines 6, 7 showed strong Cotton effects, similar to
those of 4, as expected for molecules of the same R absolute
configuration. Derivatives of amino acids of S absolute con-
figuration, 8–11, still followed the same pattern of CD spec-
tra. These cases indicate that substituents R are L while the
COOMe group is M.
À
est Cipso Cortho bonds in the two
phenyl rings, connected by an
imaginary bond between the
two Cipso atoms[10]
.
There are eight possible types of trityl group conformers,
defined by the signs of dihedral angles w1–w3, P or M. Ho-
mohelical conformers of C3 symmetry, MMM or PPP, are
not available in chiral molecules of C1 symmetry, as noted
previously.[10] Available conformers of C1 symmetry, MPM/
PMP, MMP/PPM and MPP/PMM (pairwise enantiomorph-
ic), have typical absolute values of dihedral angles w1 =56–
698 and w2 =50–608. In conformers MPM/PMP and MPP/
PMM, w3 is less than 108 while in MMP/PPM it is in the
range 348–388.[11,12] These conformers are distributed un-
evenly in molecules 1–4 (Table 2).
Table 2. Conformer distribution, their angles w and configuration at the
nitrogen calculated for N-trityl amines 1–4.
Conformer DE
type
%
w1
w2
w3
Configuration
at N
[kcalmolÀ1
]
1
2
MPM
MPP
PMP
PMM
MMP
0.0 and 0.38
1.32
0.31
52 À68
58
58
À2
S
S
R
R
S
4
20
14
À68
2
3
68 À59
0.52
68 À57
À1
0.82 and 2.47 10 À58 À56
34
MPM
MPP
PMP
PMM
MMP
other
0.0
55 À69
57
58
À4
7
3
S
S
R
R
S
2.64
0.21
1.63
2.04
1
38
3
À67
68 À58
67 À57
À7
2
À57 À53
38
1
3
4
MPP
PMM
MMP
2.24
0.0
1.97
2
95
3
À68
57
5
À6
34
S
R
S
68 À56
À58 À56
MPP
PMM
PPM
0.0
0.59
2.89
72 À67
60
6
S
R
R
27
1
66 À59 À10
61
50 À36
Diastereoisomeric structures of tritylamine 1 can be ob-
À
In molecules 1 and 2 the most abundant conformers
tained by nitrogen inversion and by chiral carbon nitrogen
belong to types MPM/PMP, PMM and MMP. Absolute con-
figuration induced at the nitrogen atom is strictly related to
the induced helicity of the trityl group, MPM and MPP
induce SN configuration while PMP and PMM are related to
RN configuration. The other two conformers, MPP and
PPM, are of low abundance (Table 2), however, they still
conform to the above-mentioned correlation; the former in-
duces SN configuration and the latter RN configuration.
Thus, conformers with the largest dihedral angle (w1) nega-
tive (M) have SN configuration, positive (P) dihedral angle
w1 is associated with RN absolute configuration. The differ-
bond rotation (Scheme 1). The calculated nitrogen configu-
ration inversion barriers are low, less than 4 kcalmolÀ1,
while the rotation barriers vary, depending on steric repul-
sion in the eclipsed transition conformations. Within avail-
able conformers of 1 the highest rotation barrier (13.2 kcal
molÀ1) was calculated for MPM/MPP equilibrium in which
there is eclipsing of R/L and Tr/M substituents in the transi-
tion structure. Note that the PMM type conformer of the
À
trityl group is found in the two C N bond rotamers with
either anti or gauche conformation of the n-butyl substitu-
ent. The equilibria shown in Scheme 1 do not involve the
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13139

´
´
J. Gawronski and J. Sciebura
À
Scheme 1. Relative free energies, barriers to Cl N bond rotation and to
configuration inversion on the nitrogen (kcalmolÀ1) for 1 (L=Et, M=
Me). All conformers have the n-butyl chain in a +sc conformation,
except PMM*, which is ap.
and oxygen atoms connected to the trityl group. The present
study shows, in addition, that the steric effect of substituents
in trityl amines can be different from that determined for
trityl ethers.[10] This implies that the steric effect of substitu-
ents is not a universal parameter. It is strongly dependent
on the molecular system (“molecular balance”) used for
sensing steric interactions. For example, classical conforma-
tional energies of substituents in the cyclohexane ring
(A values) place the tert-butyl group at the far end of the
scale,[14] making it an anchor for the equatorial position. In
3, the tert-butyl group is formally seen as less sterically de-
manding (M) than the methyl group (L). In the system used
here, the tert-butyl group is attached directly to the nitrogen
atom and the source of such a controversy is found in re-
duced steric interactions between one of the methyl groups
of the tert-butyl group and ortho hydrogen atoms of the two
phenyl groups in conformer PMM compared to conformer
MPP (Figure 2).
Figure 1. Experimental (c) ECD spectra of 3–5 in cyclohexane solu-
tion and calculated (a) ECD spectra of 3 and 4 (M06-2X/6-311+G-
ACHTUNGTRENNUNG(2d,p) method).
very low populated conformer PPM, however, this confor-
mer is found as a minor contributor to the equilibrium mix-
ture of conformers of 4.
One can compare the structures and ECD spectra of the
corresponding trityl amines and trityl ethers. For 1 and its
trityl ether analogue,[10] the calculated distribution of con-
formers was qualitatively similar, with MPM type dominat-
ing. While calculated ECD spectra for individual conformers
in the short-wavelength region were also qualitatively simi-
lar, the experimental ECD spectra of 1, 7 and 10 and their
oxygen counterparts showed only limited similarity (see the
Supporting Information) due to a different conformer distri-
bution and different electronic properties of the nitrogen
Figure 2. Comparison of calculated structures of PMM and MPP con-
formers of 3. Some short interatom distances are shown.
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Chem. Eur. J. 2011, 17, 13138 – 13141

Double Chirality Transmission in Trityl Amines
COMMUNICATION
As the outcome of our study, we propose that in trityl
amines with a chiral a-carbon atom a double chirality trans-
mission operates, and induces preferred dynamic helicity of
the trityl group and consequently preferred dynamic config-
uration of the nitrogen atom. For an assumed R configura-
tion at the a-carbon atom (N>L>M) the preferred trityl
helicity is MPM or MPP and the absolute configuration of
the nitrogen atom is S. This induces a characteristic set of
short wavelength Cotton effects in the ECD spectra, a posi-
tive Cotton effect at longer wavelength (ca. 200 nm) and a
negative one at a shorter wavelength (ca. 190 nm; Figure 3).
Judging from the results of calculations and ECD meas-
Keywords: amine configuration
dichroism · density functional calculations · trityl amines
·
chirality
·
circular
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Figure 3. A model of induction of trityl helicity, nitrogen configuration
and ECD spectra in trityl amines.
similar but less satisfactory results, in terms of relative excitation en-
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´
[10] J. Sciebura, P. Skowronek, J. Gawronski, Angew. Chem. 2009, 121,
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through 1 and 2 (ca. 60%) to 4 (ca. 70%) and it is apparent-
ly similarly high in the remaining molecules 5–12. These re-
sults also suggest that the steric/electronic power of substitu-
ents in the induction of chirality at the neighboring atoms
might not be the same as that found for other, well-estab-
lished systems. For example, here the methyl group appears
to be more important than the tert-butyl group. These find-
ings can stimulate further research in both molecular and
supramolecular systems equipped with chiroptical sensors.
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[11] The values of w1–w3 for molecules in the solid state, calculated from
available X-ray data, are of similar pattern, for 4: 69, À59, 1 (PMP),
for N-trityl-exo-isobornylamine: À62, 61, 4 (MPP), for N-trityl-tert-
butylamine: 78, À49, 7 (PMP; see ref. [15]) and for benzyl ester ana-
logue of (S)-9: 64, À62, À15 (PMM; see ref. [16]).
[12] Note that achiral conformers of the trityl group of Cs symmetry are
characterized by dihedral angles w1 =Àw2 and w3 =0.
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Acknowledgements
All calculations were performed in the Poznan Supercomputing and Net-
working Center, Poland.
Received: June 3, 2011
Published online: October 18, 2011
Chem. Eur. J. 2011, 17, 13138 – 13141
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13141