Molecular and supramolecular helicity induction in trityl group-containing compounds: The case of chiral 3,3,3-triphenylpropionic acid derivatives

Article abstract of DOI:10.1016/j.tet.2019.06.040

The process of dynamic chirality transmission from permanent chirality element to stereodynamic triphenylmethyl group placed in the distance of 4 bonds, has been studied for series of optically active 3,3,3-triphenylpropionic acid derivatives. Structural

Full text of DOI:10.1016/j.tet.2019.06.040

Accepted Manuscript
Molecular and supramolecular helicity induction in trityl group-containing compounds:
The case of chiral 3,3,3-triphenylpropionic acid derivatives
Paweł Skowronek, Agnieszka Czapik, Zuzanna Rajska, Marcin Kwit
PII:
S0040-4020(19)30712-4
https://doi.org/10.1016/j.tet.2019.06.040
TET 30432
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 18 April 2019
Revised Date: 21 June 2019
Accepted Date: 24 June 2019
Please cite this article as: Skowronek Paweł, Czapik A, Rajska Z, Kwit M, Molecular and supramolecular
helicity induction in trityl group-containing compounds: The case of chiral 3,3,3-triphenylpropionic acid
derivatives, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.06.040.
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Molecular and supramolecular helicity induction in trityl group-containing
compounds: the case of chiral 3,3,3-triphenylpropionic acid derivatives
Paweł Skowronek,*a Agnieszka Czapik,a,b Zuzanna Rajskaa and Marcin Kwit*a,b
a) Department of Chemistry Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61 614
Poznań, Poland
b) Centre for Advanced Technologies Adam Mickiewicz University, Uniwersytetu Poznańskiego
10, 61 614 Poznań, Poland
e-mail: skowron@amu.edu.pl or marcin.kwit@amu.edu.pl
Keywords
amino acids, chirality, induced optical activity, propeller, structure, trityl group
Abstract
The process of dynamic chirality transmission from permanent chirality element to stereodynamic
triphenylmethyl group placed in the distance of 4 bonds, has been studied for series of optically
active 3,3,3-triphenylpropionic acid derivatives. Structural analysis, carried out with the use of
complementary methods and supported by theoretical calculations, enabled us to determine the
mechanism of chirality transmission. The observed chirality transfer phenomenon, demonstrated
unequivocally as raising of non-zero Cotton effects in the region of UV absorption of trityl group, is a
cascade process driven by weak intramolecular interactions. Despite the much larger inductor-
effector distance, the sensitivity in chirogenesis is comparable to other stereodynamic probes
reported so far. In the crystalline phase, the combination of trityl group with amino acid moiety
results in the formation of helical superstructures, where individual molecules are held together by
hydrogen bonding cascades. The proper combination of functionalities in the molecule skeleton
allows, to some extent, the control over the association process and authorizes determination of the
trityl group as the supramolecular synthon.
1. Introduction
Induction, control, detection and determination of chirality, together with interactions between
chiral objects, are the basis for the stereoselective synthesis, some analytical techniques and
chiroptical spectroscopy.[1-4] Chiral molecules resembling macroscopic mechanical devices, such as
bevel gears, ratchets and propellers, are still of growing interest to many research groups.[5-7] The
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intense studies on the propeller-like group of compounds have been initiated by Mislow and
Iwamura. Now, the results of these pioneering works have been recognized as important steps in
development of more sophisticated molecular machines fueled by external energy source.[8-11]
One of the most important representative of molecular propellers – the triphenylmethyl group (trityl,
Tr) is widely used in synthesis, mostly for protection of polar functionalities such as OH, NH, SH.[12]
Recently, Franzén and others have proven utility of stable trityl cations as catalysts in organic
synthesis.[13-17] Combination of amino acids and trityl group led to N-tritylamino acid derivatives
acting as cytostatics,[18-20] exchange-coupled biradicals,[21] and as stationary phases in ligand-
exchange chromatography.[22]
Structurally, the mother triphenylmethane molecule consists of three phenyl rings (blades)
connected to the central sp3-hybridized carbon atom (hub) residing on the propeller axis. The
triphenylmethane and its TrX congeners (where X is a spherically-symmetrical substituent), might
adopt two extreme, low-energy enantiomerical, C3-symmetrical conformations. Qualitatively, the
rings twist is conveniently determined by either P or M helicity. The other diastereoisomeric
conformations are characterized by different blade angle and by higher relative energy.[23]
Triphenylmethane and its simple derivatives form dynamic racemates with low enantiomerization
barrier estimated as ca. 5 kcal mol-1. The twist of the phenyl rings is preserved also in the
triphenylmethyl cation and the energy barrier between the enantiomeric structures of the P and M
helicity has been estimated as 9.1 kcal mol-1.[23-26]
The twisted phenyl rings in the trityl moiety form non-planar (chiral) system consisting of three
independent but interacting chromophores, which in principle, should led to the rise of non-zero
Cotton effects (CEs) in the electronic circular dichroism (ECD) spectra and in the region of ultraviolet
(UV) absorption of the chromophore. In the case of triphenylmethane, the mutual contributions of
enatiomeric P- and M-helical conformers cancel CEs to zero, hence, no ECD spectrum is observed.
However, the connection of trityl group to the non-spherically symmetrical and chiral substituent
disturbs the local symmetry of the trityl chromophore and has led to the generation of non-zero CEs
of the characteristic pattern. Such induction of chirality (helicity) has been previously observed for O-
trityl alcohols, N-trityl amines, sulfides and selenides, triphenylacetic acid derivatives and related
compounds.[27-32] Thus, the observed chirality transfer from permanent chirality element to the
dynamically chiral chromophore allows to classify trityl as stereodynamic chirality probe.[33]
The so far proposed models of optical activity connect the signs of observed CEs (and helicity of the
triphenylmethane chromophore) with the steric power of substituents flanking stereogenic center,
which is not always directly related to the absolute configuration of the chirality element.[27-32] In
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particular, the induction of optical activity in O-trityl alcohol and N-trityl amines results from the
direct gearing between trityl and inductor fragment ("a bevel gear" mechanism). Interestingly, a
similar chirality transfer from chiral alcohols to the O-triphenylsilyl group has been recently
reported.[34] More subtle interactions involving C–H/C=O(amide) dipoles together with C-H···π and
O···H-C electrostatic attractive interactions are responsible for the chirality transfer in mono and
bis(triphenylacetamides).[30,31]
Recently, we and others have shown that trityl moiety might play an important role in the crystal
engineering as a supramolecular protecting group that precludes formation of hydrogen bonded
aggregates in the crystalline phase. Even in the enantiomerically pure crystals, the symmetry
independent part of the unit cell contain the molecules characterized by opposite helicity of the trityl
fragments, which exhibit tendency to form aggregates made from pairs of pseudocentrosymmetric
dimers.[35]
On the other hand, the poor shape complementarity of some trityl derivatives led to the low-density
crystals, in which empty voids are formed, that may or may not be occupied by the guest molecules.
Akazome has proven possibility of chiral recognition by crystals of tritylated amino acid
derivatives.[36,37]
Feeling that the problem of the interplay between permanent chirality element and stereodynamic
trityl reporters is still at the initial stage of research, we decided to expand the studies on the
derivatives, where the process of chirality transmission precedes among larger inductor-reporter
distance. We chose the 3,3,3-triphenylpropionic acid as a reporter system, that will be modified by
transformation into chiral esters and amides including amino acid derivatives. In these cases, the
distance between the inductor and the reporter (i.e. 4 bonds) is larger than in previously reported O-
tritylethers and N-tritylamines (2 bonds distance) and triphenylacetic acid derivatives (3 bond
distance). We are hoping that the detailed mechanism of the generation of optical activity in selected
derivatives will be established by ECD spectroscopy supported by theoretical calculations at the DFT
level. The effectiveness of the chirality transfer from permanent chirality element to the
stereodynamic trityl probe is proportional to the magnitude of induced CE’s. However, the
convenient way to compare sensitivity in chirogenesis between different molecular or
supramolecular systems, is to compare their dissymmetry factors g, that are defined as Δε/ε ratio at
a given wavelength.[3]
Elongation of the carbon chain in 3,3,3-triphenylpropionic acid can significantly affect the way of
molecular packing of its chiral derivatives in the crystal. Especially, due to liberation of secondary
amide supramolecular synthon from a protective umbrella of trityl fragment, the molecular
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association can be governed by hydrogen bonding cascades. The response of the trityl fragment to
the association and, therefore, the possibility to form dense or low-density crystals capable of
inclusion, is also worth mentioning. The latter problem is crucial to the rational planning of new
chiral materials of defined (i.e. sorption) properties.
2. Results and discussion
2.1. Synthesis.
The starting 3,3,3-triphenylpropionic acid has been obtained according to the procedure of
Hellerman,[38] by first melting triphenylmethanol with malonic acid and subsequent treatment of
melted alloy with sodium hydroxide to separate unreacted triphenylmethanol and then with an
excess of hydrochloric acid (Scheme 1a). The methyl esters of selected amino acids were prepared
according to the known procedures.[39] The representative series of chiral 3,3,3-triphenylpropionic
acid esters 1, amides 2 and N-(3,3,3-triphenylpropionyl)amino acid derivatives 3-4, have been
conveniently obtained from alcohol, amine, amino acid ester or from free amino acid and 3,3,3-
triphenylpropionyl chloride. Yields of the reactions were varied from good to moderate and the
products were easily purified either by crystallization or by flash column chromatography. Exemplary
synthetic procedures were shown in the Experimental section; the remaining results including full
spectroscopic characteristics of the new compounds were deposited as supplementary material.
Scheme 1. a) General procedure for synthesis of the optically active derivatives of 3,3,3-triphenylpropionic acid
1-4. b) Definition of dihedral angles that characterize the molecular conformation.
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2.2. ECD spectra and mechanism of chirality transmission in 3,3,3-triphenylpropionic acid
derivatives 1-4.
Having obtained the optically active derivatives 1-4, we were able to study the possibility of chirality
transmission from stereogenic center to the stereodynamic trityl chromophore. For convenient
sensing of the induced optical activity in the trityl chromophore, we used the ECD spectroscopy as
the method of choice. Additionally, in our studies, we have taken an opportunity of hydrophobicity of
these compounds, since the solubility in the non-polar hydrocarbons will facilitate further theoretical
analysis. This approach allows us to direct comparison of experimental ECD results with theoretical
ones obtained for molecules calculated in vacuo.[40] In particular, we will focus on derivatives
characterized by the presence of aliphatic inductor moieties, since for these derivatives the observed
CEs should originate from induced chirality in the chromophore. Both, the –COOR ester group and –
CONHR amide group alone are recognized as weak UV active chromphores. The π-π* transition in
ester and amide chromophore is separated from the strong 1B band (195-210 nm) in phenyl rings by
distance as well as by energy difference, which makes transitions coupling weak and does not led to
generation of intense Cotton effects. It implies that the influence of ester and amide chromophores
on the prospective UV and ECD effects might be treated as negligible.[3,41]
In general, for all compounds under study, we observed generation of optical activity in the
stereodynamic probe, which is revealed by raising non-zero CEs in the spectral region of trityl
absorption (see Table 1 and Figure 1). Taking into account the significantly larger distance between
inductor and effector (reporter), the measured induced CEs, although lower than for previously
reported derivatives, might by recognized as those of unexpectedly high magnitudes. The natural
correlation between the pattern of the spectrum and absolute stereochemistry of the given
compound is straightforward in the majority of the cases. For instance, the sign of Cotton effects
appearing at about 204 nm seems to be ruled by absolute configuration at stereogenic center. For
ester derivatives 1a and 1b, aliphatic amides 2a-2d and amino acid derivatives 3a-3d and 4b-4f, a
negative sign of this particular CE and positive of the higher-energy CE (if visible) corresponds to S
configuration and vice versa. In the remaining cases, the correlations are not obvious due to the
presence of additional chirality elements or chromophoric groups such as phenyl ring.
The amplitude of the observed CEs can be related to the steric bulk of substituents at stereogenic
center, as it is particularly seen for amides 2a-2c. The increase of the number of methyl group
attached to the carbon atom directly translates to the magnitude of the Cotton effect, i.e. for amide
2c the observed CE at around 204 nm is over three times as big as that measured for 2a. The
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experimental results suggest that for aliphatic amides the steric power of substituents in the dynamic
induction of chirality rises as follows: Me < Et ≈ Cy < i-Pr < bornyl < tert-Bu.
The presence of an additional aromatic chromophore in inductor skeleton makes the ECD spectrum
more difficult to the unequivocal interpretation. In the case of 2f, the presence of phenyl ring
increases the intensity of the UV absorption maximum, whereas in the ECD spectrum, it manifests
itself as a negative Cotton effect around 215 nm, not well-separated from the main Cotton effect
appearing at around 200 nm. It has been known that the model N-pivaloyl amide of (S)-1-
phenylethylamine is characterized by one negative CE appearing at 197 nm, in the same region
where negative CE is observed for 2f.[30] This suggests a dominant role of over induced CE to the net
ECD spectrum of 2f in the lower-energy region, whereas the short-wavelength CE is rather
dominated by induced CE within trityl chromophore.
Table 1. Absolute configurations (AC) at stereogenic centers, ECD (Δε) and UV (ε) data and dissymmetry factors
g (Δε/ε × 10-4) for 3,3,3-trifenylpropionic acid derivatives 1-4 measured in cyclohexane solution (see also Table
S_1 for remaining data).
Cmpd. AC Δε (nm)
ε (nm)
g
Cm AC Δε (nm)
ε (nm)
g
pd.
1a
1b
1c
1d
R
S
+5.0 (203)
77900
(197)
0.64
0.02
2f
S
S
S
S
-7.8 (215); -14.8 105000 -1.41
(202); +20.8 (188) (189)
-2.9 (204); +0.2 (196); 78300
-1.6 (188) (198)
3a
4.8 (225); -28.9 92500
(204); 18.4 (190) (194)
-3.12
-2.53
-1.44
R
S
+2.4 (227); -6.5 (197) 75800
(196)
-0.76 3b
-0.32 3c
4.1 (226); -20.9 82500
(203); 12.4 (187) (194)
+1.0 (228); -0.14 71000
(218); +2.8 (204); -2.3 (196)
(196); +4.3 (187)
5.4 (224); -12.2 84400
(203); 1.9 (186) (195)
1e
2a
2b
2c
2d
2e
S
S
R
S
R
S
-11 (209)sh; -16.6 124000 -1.34 3d
(198) (189)
S
S
S
S
S
S
6.8 (225); -15.9 82400
(205); 11.4 (185)a (195)
-1.93
-4.1 (205); +4.9 (194) 80540
(192)
0.61
4a
n .a.b
n .a.b
+10.3 (206); -8.7 76720
-1.14 4b
3.7 (226); -10.8 77900
(200); 3.7 (187) (195)
-1.38
1.50
(192)
(194)
-17.6 (206); +12.5 81350
(192) (193)
1.54
4c
2.2 (226); -11.6 77300
(203); 4.2 (187)
(195)
+5.7 (204); -4.2 (193) 73300
(192)
-0.57 4d
n. a.b
n .a.b
-5.0 (223); +10.1 76900
1.31
4e
2.8 (226); -13.7 79100
(204); 8.9 (187) (194)
1.73
(193)
(193)
[a] The end of measurement range. [b] Data not available due to the poor solubility in cyclohexane.
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The same trend as it is seen for amides 2a-2c is observed for derivatives 4b-4e. The increase of
molecular complexity of the aliphatic substituent attached to the stereogenic manifests itself in
increasing the amplitude of the corresponding Cotton effects.
Surprisingly, a reverse relationship has been found for amino acid derivatives 3a-3d. The
characteristic feature for these compounds is step-wise decreasing of the magnitude of the CE
appearing at around 205 nm associated with gradual increase of the alkyl backbone size. This might
suggest that the increase of the aliphatic substituent size balances the steric bulk of carbomethoxy
COOMe group. In the case of 3a-3d and 4b-4e, the first positive long-wavelength CE at around 230
nm is clearly distinguishable. Note, for some compounds, due to the measurement condition
restriction (instrument sensitivity and solvent absorption), a maximum of the short-wavelength
Cotton effect was not reached and positive values presented in Table 1 show rather a tendency of
the CD curve and not the maximum achieved.
Figure 1. Exemplary ECD spectra of chiral triphenylpropionic acid derivatives 1a, 1c, 2a, 2c, 3a and 3c,
experimental, measured in cyclohexane (solid black lines) and calculated at the TD-CAM-B3LYP/6-311++G(d,p)
level and ΔΔG-based Boltzmann averaged (dashed blue lines). Calculated ECD spectra were wavelength
corrected to match experimental UV maxima.
Theoretical studies, carried out for selected 3,3,3-trifenylpropionic acid derivatives 1a, 1c, 2a, 2c, 3a
and 3c, have shed light on the structure and mechanism of chirality transmission (for calculation
details see ESI).[42] The structure of each individual conformer of 1a, 1c, 2a, 2c, 3a and 3c can be
conveniently described by a set of angles α – φ (defined in Scheme 1b) and juxtaposed in Table S_3
in Supplementary Info. The angle α (X-C(=O)-C(H2)-C) characterizes the conformation of the reporter
carbon chain, which is directly related to the inductor-effector distance. The angles β1 – β3 ((O=C)-
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C(H2)-C-Cipso) and γ1 – γ3 (C(H2)-C-Cipso-Cortho) describe the conformation of phenyl groups. The first set
describes the orientation the phenyl rings with respect to the alkyl chain whereas the second
characterizes the helicity of the Tr fragment. The angles γ1 – γ3 define helicity of the blades: M (-90° <
γ < 0°), P (0° < γ < 90°) or 0 (for γ angles deviating from zero by less than 5°). The angles δ and φ,
respectively, describe mutual relationship between inductor and effector skeletons and
conformation of an inductor.
Despite the expected larger conformational freedom of 3,3,3-trifenylpropionic acid derivatives, the
number of low-energy conformers (see Table S_2) is comparable to that established previously for
more rigid chiral triphenylacetic acid amides.[30] The structures of ΔΔG-based lowest energy
conformers of 1a, 1c, 2a, 2c, 3a and 3c have been shown in Figure 2 (the remaining structures of low-
energy conformers are deposited in ESI).
Figure 2. Structures of ΔΔG-based the lowest energy conformers of 1a, 1c, 2a, 2c, 3a and 3c, calculated at the
B3LYP/6-311++G(d,p) level. In the square brackets percentage population of given conformer and helicity of
the trityl moiety are provided. Dashed lines indicate possible attractive interactions that control conformation
of the trityl groups. Distances are in angstroms.
Conformation of the reporter chain, defined by the α angles, varied from ±anticlinal (ac) to +synclinal
(sc). The latter are especially visible for amide derivatives 2a and 2c. To minimize the torsion strains,
the phenyl rings are placed consequently ±antiperiplanar (ap) and ±sc, as analysis of β angle
conformations revealed. Similar conformation of trityl group is observed for triphenylethane and
other trityl derivatives substituted by achiral substituent of spherical symmetry. The low-energy
conformers of 1a, 1c, 2a, 2c, 3a and 3c are characterized by MMM or PPP helicity of phenyl rings,
where conformation of two of three phenyl rings are ±sc and the third one is ±synperiplanar (sp).
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Further flattening of the third γ angle (up to 0 helicity) is associated with an increase in energy of the
given conformer. With no exceptions, the δ angles adopt sp conformation. This is due to the
attractive C=O···H-C* dipole-dipole interactions, which strongly stabilize the structure and determine
orientation of the substituents at the stereogenic center in space. Statistically, the angle φ adopts
±ap and ±sc conformation in the case of ester derivative 1a, and ±sc or ±ac conformation in amino
acid derivatives 3a and 3c.
However, even the most detailed description of the angles does not give the view on the chirality
transfer mechanism. The carried out theoretical analysis indicates the subtle electrostatic C=O···H-
Cortho interactions as the decisive factor for the efficiency of the chirality transfer. The calculated
C=O···H-Cortho distances ranging from 2.150 Å to 2.794 Å, and the shorter ones are characteristic for
conformers with lower relative energies. The C=O···H-Cortho interactions control sp conformation of
one of the phenyl rings from the trityl moiety. Conformation of the remaining phenyl groups is
controlled mostly by the Cortho-H···Cipso interactions and, to less extend, by sterical interactions with
substituents attached to the stereogenic center. In the case of the lowest energy conformers of
secondary amides 2a and 2c, the attractive N-H···π interactions seem not to be less important than
the C=O···H-Cortho interactions for controlling the molecular conformation. In these particular cases,
the third propeller blades are forced to adjust their conformation to the remaining two.
Confrontation of the structural data with calculated ECD spectra for each low-energy conformer of
1a, 1c, 2a, 2c, 3a and 3c clearly indicate that MMM helicity of the propeller is associated with
positive-negative-positive (+/-/+) sequence of CEs, whereas for PPP helicity a reversed order -/+/- of
CEs is established by theoretical calculations.
The correctness of the theoretical analysis has been confirmed by the direct comparison of
experimental and theoretical ECD spectra of the model compounds 1a, 1c, 2a, 2c, 3a and 3c (see
Figure 1). The agreement between experimental and theoretical results is very good, with the
exception of amide 3a, representing indeed a very complex system. In line with expectations, the
ΔΔG-based and Boltzmann averaged theoretical ECD spectra of 1a, 1c, 2a, 2c and 3c are dominated
by the lowest-energy and, therefore, the most abundant conformer. The ECD spectrum calculated for
the ΔΔG-based lowest energy conformer of 3a, characterized by PPP helicity of the chromophore,
remains in disagreement with the experiment. However, the calculated and Boltzmann averaged ECD
spectrum of 3a is influenced by higher energy conformers (mainly by the second lowest-energy
conformer no 39) characterized by MMM helicity of Tr moiety (see Figure 3). As the population of
these structures is underestimated, the averaged theoretical ECD spectrum of 3a remains in fair
agreement with the experimental one.
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It is worth emphasizing that within the series of model compounds 1a, 1c, 2a, 2c, 3a and 3c, the
structure of the chiral inducer and the presence of chromophores different than Tr ones, have small
or even negligible contribution to the overall ECD spectrum (see Figure 3b).
Figure 3. a) Structure of low-energy conformer no 39 of amide 3a, calculated at the B3LYP/6-311++G(d,p) level.
b) Exemplary “depuzzled” ECD spectra calculated for ΔΔG-based low-energy conformers of 1a, 2a and 3a (solid
black lines), their trityl parts only (solid blue lines) and their non-aromatic parts only (solid red lines).
Wavelengths were not corrected.
2.3. Molecular and supramolecular structures of chiral amides of 3,3,3-triphenylpropionic acid as
revealed by X-ray crystallography
The reported here crystal structures of chiral 3,3,3-triphenylpropionic acid derivatives 2a-2c, 3a-3c
and 4a were analyzed taking into account their molecular and supramolecular structures. Due to the
formally larger distance between the inductor and the effector, we are expecting lesser influence of
hydrophobic trityl group on the structure of possible associates than it has been found for respective
triphenylacetic acid derivatives. In addition to the most common secondary amide supramolecular
synthon, the presence of free carboxylic group might lead to formation of various supramolecular
assemblies. Therefore, from the compounds under study, the 3,3,3-triphenylpropionic acid
derivatives of amino acids are of the special attention. The summary of crystallographic data is given
in Table S_4 and selected X-ray structural data are juxtaposed in the Table S_5 in ESI. The molecular
structure of compounds 2a-2c, 3a-3c and 4a in crystals are presented in Figure S_44-S_50.
The general and characteristic feature of all compounds under study is their large structural diversity
in the solid state. The molecules in the crystalline phase adopt extended conformation of the effector
fragment (the α angles are ap). In the crystal structures of compounds 2a-2c and 3a-3c, amide groups
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are involved in the N-H···O=C hydrogen bonds cascade to form a structural 1D motif (for hydrogen
bonds geometry see Table S_6). Due to the large volume of the trityl group it is impossible to create
a flat structure and observed molecular ribbon is twisted with trityl groups arranged helically on the
shore (Figure 4a). The ribbon structure in the crystals is stabilized by additional intermolecular weak
C-H···O=C interactions.
In the crystal structure of compounds 2a and 2b, the asymmetric units consist of two independent
molecules. The differences in molecular conformation are observed mainly for trityl groups, which
are close to the mirror images (for compound 2a see Figure 4 b, for compound 2b see Figure S_45,
ESI). Conformation of molecule is stabilized by intramolecular Cortho-H···O=C hydrogen bonds (2.34 Å
and 2.79 Å for 2a, 2.35 Å and 2.81 Å for 2b) and structure of twisted ribbon is assisted by
intermolecular Cortho-H···O=C interactions.
Figure 4. a) The twisted-ribbon 1D motif in the crystal structure of 2a. b) The comparison between the
conformation of symmetrically independent molecules A and B. The O and N atoms are shown as balls, C-
bound hydrogen atoms have been omitted for clarity. Symmetrically independent molecules are indicated with
different colors.
In the crystal of amide 2c (Figure 5a), the asymmetric unit consist of four symmetrically independent
molecules A, B, C, D. In the crystalline phase, they are linked via N-H···O=C hydrogen bonds to form
two independent 1D motifs with a sequence ...ABABA... and ...CDCDC... respectively. The molecules A
and B (or C and D), forming one column, are pseudo-symmetric. For the corresponding molecules A
and C (or B and D) forming the symmetrically independent columns, the pseudo-symmetry applies
only to trityl groups (see Figure 5b). In contrast to the previous ones, the trityl groups are not
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arranged helically around the column, but they are placed on one side of the column (see Figure 5a).
The three-dimensional structure is stabilized by C-H··· π interactions between adjacent columns.
Figure 5. a) Molecular packing in the crystal structure of amide 2c, view along x axis. b) The comparison
between the conformations of symmetrically independent molecules A, B, C and D. The O and N atoms are
shown as balls, hydrogen bonds are shown as dashed line and C-bound hydrogen atoms have been omitted for
clarity. Symmetrically independent molecules are indicated with different colors.
In the crystals of N-(3,3,3-triphenylpropionyl)alanine and N-(3,3,3-triphenylpropionyl)valine methyl
esters (3a and 3b, respectively), two independent molecules were found. The conformation of these
independent molecules, do not differ significantly from each other. The twisting angles of phenyl
groups (γ1 – γ3) are of similar value in both cases (-77.3(2), -31.7(2), 20.0(2) and -70.9(2), 11.1(2),-
37.6(2) for 3a and -76.9(2), 18.3(2), -32.7(2) and -67.9 (2), 17.2 (2), -37.5 (2) for 3b). Such MPM
arrangement of γ1 – γ3 angles has not been found for the calculated in vacuo low-energy conformers
of 2a.
The conformation of the trityl group is ordered mainly by intermolecular interactions. However,
some intramolecular interactions were found as well. In the case of 3b, the C-H···π intramolecular
attractive interactions are postulated. In the crystal state, the molecules of 3b differ mainly in the
position of isopropyl group in the valine backbone. In one of the independent molecules, the
methine hydrogen atom of the i-Pr group is almost perpendicular to the plane of phenyl ring and it is
directed towards the center of the ring (the distance to the center of the phenyl ring is 2.63 Å, the
distance to the plane of the phenyl ring is 2.56 Å). For the second molecule, where methine hydrogen
is in the opposite direction, a similar interaction with hydrogen atom from the one i-Pr methyl group
can be proposed. In this particular case, the arrangement is not perfect (the distance to center of the
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phenyl ring is 2.59 Å, the distance to the plane of the phenyl ring is 2.56 Å) and C-H bond is not
perpendicular to the plane of the aromatic ring. As a result, a significant distortion (by 30°) of γ
angles from the optimal value (around ±40°) established for simple triphenylmethane has been
noticed.
In the case of 3a, the C-H···π interactions between hydrogen atom from methyl group of alanine
backbone (which is equivalent to methine hydrogen atoms in 3b) and π-electron clouds are weaker.
Similar type of supramolecular architecture has been found in the crystals of 3c. In this case, in the
asymmetric unit 5, independent structures were found. These molecules differ mainly in
conformation of the trityl group. While one of the γ angles is always negative, the remaining phenyl
rings adopted various M and P conformations.
In the crystal of N-(3,3,3-triphenylpropionyl)alanine (4a) two independent molecules are observed.
The characteristic feature of these molecules is their pseudo-symmetry. Trityl groups in these
conformers are almost mirror images (deviation of the γ angles is less than 10°) and exhibit either
PPP or MMM helicity. A dominant force in determination of trityl groups conformation are weak
intramolecular C-H···O and intermolecular C-H···π interactions.
Crystal structure of 4a is determined by strong O-H···O hydrogen bonds cascades between
neighboring molecules and linking hydrogen atom from carboxylic group with oxygen from the amide
group of the second molecule. In contrast to the methyl esters of amino acids, the hydrogen atom
from NH amide group in 4a is not involved in hydrogen bonding. This is due to the shielding effect of
the trityl group, particularly seen in this case (Figure 6).
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Figure 6. a) Molecular packing in the crystal structure of 4a (view along x axis). b) The comparison between the
conformation of symmetrically independent molecules A and B. The O and N atoms are shown as balls,
hydrogen bonds are shown as a dashed line and C-bound hydrogen atoms have been omitted for clarity.
Symmetrically independent molecules are shown with the use of different colors.
3. Conclusions
In this work, we have intended to show a complementary approach to the problem of chiral 3,3,3-
triphenylpropionic acid derivatives. We have shown a possibility of chirality transfer from permanent
chirality element to the stereodynamic probes in compounds, where the inductor and effector parts
are separated by four bonds. Due to the cascade of weak but complementary interactions, the trityl
group adopts helical conformation, which is related to the appearance of non-zero Cotton effects in
the region of trityl absorption. The sign of Cotton effect appeared at about 205 nm was found
dependent on absolute configuration of stereogenic center on the carbon atom in α position to the
linker atom. The calculated low-energy conformers of 1a, 1c, 2a, 2c, 3a and 3c are characterized by
PPP or MMM helicities. Therefore, we can generally determine that in the case of 3,3,3-
triphenylpropionic acid derivatives, the chiral substituents generate homohelicity of the trityl group.
Taking into considerations the larger distance between inductor and reporter group, we may
conclude that sensitivity to chiral environment is high. In general, the estimated dissymmetry factors
Δε/ε, which can be a measure of the sensitivity in chirogenesis, are not much smaller than those
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estimated for other optically active derivatives containing trityl group (see ESI, Table S_8). For
example, estimated dissymmetry factors for 2a and for N-triphenylacetyl-2-amino butane are almost
the same (0.61×10-4 and 0.62×10-4, respectively). On the other hand, the dissymmetry factor
estimated for O-tritylmenthol is the highest within all trityl derivatives, which have been taken into
consideration so far, and equals to 11.21×10-4, whereas estimated for triphenylsilyl ether of menthol
and for 1c equal to 1.35×10-4 and 0.76×10-4, respectively. While for O-trityl alcohols and for N-trityl
amines the sterical interactions are the major factors responsible for chirality transfer, for N-
triphenylacetamides the sterical interactions are supported by electrostatic interactions. In the case
of chiral 3,3,3-triphenylpropionic acid derivatives the large distance between inductor and reporter is
balanced by the ordering effect of the carbonyl group from triphenylpropionic acid moiety. This in
turn reveals in the lower conformational freedom of the 3,3,3-triphenylpropionic acid derivatives in
comparison to other trityl-containing and optically active compounds.
The incorporation of the trityl group allowed, to some extent, for the control over the
supramolecular assembly of amide derivatives of 3,3,3-triphenylpropionic acid. Observed in the
asymmetric part of the unit cell multiplication of the molecules, characterized by different
conformation of trityl group, is often accomplished with pseudo-centrosymmetric type of packing.
This is apparently due to the maximization of packing in the crystal lattice, where the conformational
liability of trityl allows for its easy adaptation to the environment, with a small increase in the energy
of an individual molecule. We expected that energetic effects associated with formation of
intermolecular O-H···O hydrogen bonding would prevail over the effects associated with the strains
resulting from steric congestion. Hence, the studied chiral 3,3,3-triphenylpropionic acid amides are
characterized by very low ability to form microporous crystals.
On the other hand, the presence in the same molecule of two supramolecular synthons significantly
different in sterical requirements and hydrophobicity led to helical superstructures previously never
observed for N-acylamino acid derivatives or for trityl-containing compounds. In our opinion, such
results constitute a convenient starting point for rational design of molecules capable of forming
functional superstructures under controlled manner. Further studies are in progress in our
laboratory.
4. Experimental section
4.1. General Information.
Unless otherwise noted, all reactions were carried out in air atmosphere. Tetrahydrofuran (THF) was
dried by distillation over potassium; dichloromethane was dried by distillation over calcium hydride.
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Deuterated chloroform (CDCl3), solvents and other chemicals, were purchased from commercial
suppliers and used as received without further purification.
1H and 13C{H} NMR spectra were recorded on Bruker Ascend 600 MHz or Bruker Ultrashield 300 MHz
spectrometer at room temperature. Chemical shifts are reported in parts per million (ppm). Spectra
are referenced using an internal reference (TMS or CDCl3 residual solvent peak). Data are described
as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet,
br = broad) and integration. Thin-layer chromatography (TLC) was carried out using Sigma-Aldrich
precoated TLC plates (60 Å medium pore diameter with fluorescent indicator 254 nm). Melting points
were measured on the BUCHI B-545. High resolution mass spectra (HRMS) were measured on the
Bruker Impact HD. Optical rotations were recorded on the Jasco P-2000 polarimeter at 20 °C. ECD
and UV spectra were measured using the Jasco J-810 spectropolarimeter at room temperature in
cyclohexane and acetonitrile solution and with the use of quartz cell of the optical lengths varied
from 0.05 cm to 0.1 cm. The concentration of the solutions ranged from 1.2 to 2.5×10-4 mol L-1.
Background spectra of the pure solvents were recorded from 400 to 185 nm with a scan speed 100
nm min-1.
For the calculation details, see Electronic Supplementary Information.
4.2. X-ray diffraction experiment details.
A monocrystals suitable for X-ray structural analysis were obtained by slow evaporation of
chloroform (crystals of compounds 2a-2c), hexane : ethyl acetate 1:1 mixture (for compounds 3a-3c)
or diethyl ether : chloroform 1:1 mixture (for compound 4a). The diffraction data were collected at
130 K with an Oxford Diffraction SuperNova diffractometer using Co Kα radiation (λꢀ=ꢀ 1.54184 Å).
The intensity data were collected and processed using CrysAlis PRO software. The structures were
solved by direct methods and refined by full-matrix least-squares method on F2. The carbon-bound
hydrogen atoms were refined as riding on their carriers and their displacement parameters were set
equal to 1.5Ueq(C) for the methyl groups and 1.2Ueq(C) for the remaining H atoms. The hydrogen
atoms of OH and NH groups were located in electron-density difference maps. In the final cycles of
refinement they were included in calculated position and treated as riding atoms, their displacement
parameters were set equal to 1.5Ueq(N/O).
4.3. Representative synthetic procedures and spectral data for 1-4
3,3,3-Triphenylpropionic acid was synthesized from malonic acid and triphenylmethanol according
to the procedure of Hellerman.[38] Amino acid esters hydrochlorides were prepared according to
well-known general methods.[39]
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3,3,3-Triphenylpropionic acid chloride:[43] 3g (10 mmol) of 3,3,3-triphenylpropionic acid was
dissolved in 25 mL of chloroform containing a drop of DMF. To this solution, a 2.38g (20 mmol) of
thionyl chloride was added drop wise. The solution was stirred overnight under reflux. After
evaporation of all volatiles, 10 mL of toluene was added and the slurry was evaporated again. The
crude product was obtained as a slightly yellowish solid, which was used for next reaction without
purification.
General methods for preparation of esters 1a-1e. Representative procedure for ester 1a: 0.5 mmol
of 3,3,3-triphenylpropionic acid chloride was dissolved in 5 mL of dry dichloromethane. To this
solution 50 mg (0.069 mL, 0.5 mmol) of Et3N was added, followed by 37 mg (46 μL, 0.5 mmol) of R-(-
)-2-butanol in 5 mL of CH2Cl2. The mixture was stirred for 3h and the solvent was evaporated. Crude
product was redissolved in dichoromethane, washed with 2M HCl, 5% NaHCO3, water, brine and
dried over Na2SO4. After evaporation to dryness, the residue colorless oil was purified by column
chromatography on silica gel and using CH2Cl2 as eluent to give 116 mg (65%) of pure 1a as an oil.
[α]D = -3.1 (c = 1, CHCl3); ESI-MS 381.1832 [M+Na]+, calc. for C25H26NaO2 381.1830; 1H NMR (600 MHz,
CDCl3) δ 7.30–7.20 (m, 15H), 4.61 (d, J = 6.2 Hz, 1H), 3.76 (d, 2H), 1.45–1.23 (m, 2H), 0.93 (d, 3H), 0.75
13
(t, 3H); C NMR (151 MHz, CDCl3) δ 170.64, 146.73, 129.30, 127.76, 126.17, 72.26, 55.70, 46.80,
28.45, 18.88, 9.54; IR (ATR) cm-1: 3052, 3032, 2934, 2871, 1728, 1595, 1494, 1444, 1347, 1200, 1152,
756, 697.
General methods for preparation of amides 2a-2g. Representative procedure for amide 2a: 1 mmol
of 3,3,3-triphenylpropionic acid chloride was dissolved in 10 mL of dichloromethane. To this solution
101 mg (0.139 mL, 1 mmol) of Et3N was added followed by 73 mg (100 μL, 1 mmol) of S-(-)-2-
aminobutane in 5 mL of dichloromethane. The mixture was stirred for 3 h and then the solvent was
evaporated. The crude product was redissolved in dichoromethane, washed with 2M HCl, 5%
NaHCO3, water, brine and dried over Na2SO4. After evaporation, the residue was purified by column
chromatography on silica gel using 5% MeOH in CH2Cl2 as eluent to give 142 mg (40%) of 2a as white
crystals. M.p. = 173-174°C; [α]D = +6.95 (c = 1, CHCl3); ESI-MS 358.2163 [M+H]+, calc. for C25H28NO
358.2171; 1H NMR (300 MHz, CDCl3) δ 7.48–6.98 (m, 15H), 4.57 (d, 1H), 3.7–3.5 (m, 3H CH2 and CH),
13
1.08–1.00 (m, 2H), 0.70 (d, 3H), 0.62 (t, 3H); C NMR (75 MHz, CDCl3) δ 169.76, 146.37, 129.33,
128.12, 126.50, 56.10, 49.12, 46.25, 29.07, 19.61, 10.07; IR (ATR) cm-1: 3252, 3085, 3057, 2966, 2925,
2850, 1636, 1561, 1492, 1446, 1372, 753, 695.
General methods of preparation of 3,3,3-triphenylpropionic acid derivatives of aminoacids esters
3a-3d.[44] Representative procedure for 3a. To a solution of 0.14 g (1 mmol) of L-alanine methyl
ester hydrochloride and 1.5 mL of Et3N in 15 mL of CH2Cl2 was added a solution of 0.35g (1.1 mmol)
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of 3,3,3,-triphenylpropionic chloride in 2 mL of CH2Cl2 with stirring at room temperature. The solution
was stirred for 20 h and than evaporated to dryness. The crude solid was dissolved in 15 mL of CH2Cl2
and washed with 15 mL of saturated ammonium chloride solution, 10 mL of water, 10 mL of brine,
dried over Na2SO4 and filtered. The crude product was purified by column chromatography on silica
gel using 1% MeOH in CH2Cl2 or hexane:ethyl acetate (2:1) for others. The pure product was
dissolved in hexane with a small amount of CH2Cl2. Crystallization provided 0.02 g of pure crystals of
4a (5%). Mp = 170-172 °C; ESI-MS 388.1929 [M+H]+ calc. for C25H26NO3 388.1913; 1H NMR (300 MHz,
CDCl3) δ 0.95–0.98, (d 3H), 3.47 (d, 2H), 3.63 (s, 3H), 3.72 (d, 1H), 4.27 (m, 1H), 5.35 (d, 1H), 7.29 (m,
13
15H), C NMR (101 MHz, CDCl3) δ 17.80, 47.84, 48.57, 52.23, 56.5, 126.46, 128,08, 129.25, 146.26,
169.88, 173.02; IR (ATR) cm-1: 3265, 3084, 1745, 1640, 1557, 1213, 1158, 744, 612.
General methods of preparation for 3,3,3-triphenylpropionic acid derivatives of amino acids 4a-4e.
Representative procedure for 4a: 445 mg (5 mmol) of L-alanine was dissolved in 20 mL of water
containing NaOH (0.4 g, 10 mmol) and THF (5 mL). Then 3,3,3-triphenylpropionic acid chloride (1.05
g, 3.27 mmol) was added and the whole mixture was stirred for 2 h. The solution was gently acidified
with hydrochloric acid and the forming precipitate and the remaining solution was extracted several
times with ethyl acetate. Organic phase was separated and dried over Na2SO4. After removal of
solvent, the crude product was purified by column chromatography on silica gel and with the use of
hexane:ethyl acetate (2:1) as eluent, yielding 268 mg (22%) of the pure 4a as white solid. M.p. = 187-
188 °C; [α]D -120.5 (c = 1, CHCl3); ESI-MS 374.1763 [M+H]+, calc. for C24H24NO3 374.1756; 1H NMR (300
MHz, DMSO-d6) δ 0.94 (d. 3H), 3.43–3.48 (d. 2H), 3.77-3.90 (m. 1H), 7.21 (m. 15H), 7.84 (d. 1H), 12.36
13
(s. 1H); C NMR (75 MHz, DMSO-d6) δ 17.49, 46.48, 4.56, 56.26, 126.19, 127.87, 129.67, 147.65,
169.77, 174.44; IR (ATR) cm-1: 3303, 3057, 2962, 1745, 1643, 1537, 1203, 1147.
Declarations of interest
The authors declare no competing financial interest.
Acknowledgments
This work was supported by a research grant from National Science Center (NCN) Poland, Grant
UMO-2016/21/B/ST5/00100. All calculations were performed in Poznan Supercomputing and
Networking Center (grant no 406).
Appendix A. Supplementary data
1
13
Calculations details; Tables S_1-S_7, Figures S_1-S_50; copies of H and C NMR spectra;
copies of ECD spectra; Cartesian coordinates for all calculated low-energy structures.
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CCDC 1908897-1908903 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by email
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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