Trityl-containing alcohols—an efficient chirality transmission process from inductor to the stereodynamic propeller and their solid-state structural diversity

Article abstract of DOI:10.3390/molecules25030707

The cascade process of a dynamic chirality transmission from the permanent chirality center to the stereodynamic triphenylmethyl group has been studied for series of optically active trityl derivatives. The structural analysis, carried out with the use of complementary methods, enabled us to determine the mechanism of chirality transfer. The process of chirality transmission involves a set of weak but complementary electrostatic interactions. The induction of helicity in a trityl propeller is revealed by rising non-zero cotton effects in the area of trityl UV-absorption. The presence of an additional stereogenic center in close proximity to the trityl-containing stereogenic center significantly affects the sign and, to a lesser extent, magnitude of the respective cotton effects. Despite the bulkiness of the trityl, in the crystalline phase, the molecules under study strictly fill the space. In the crystal, molecules form aggregates stabilized by OH???O hydrogen bonds. However, the presence of two trityl groups precludes formation of OH???O hydrogen bonding. Additionally, the trityl group seems to be responsible for the formation of the solid solutions by e.g., racemates of trans- and cis-2-tritylcyclohexanol. Therefore, the trityl group acts as a supramolecular protective group, which in turn can be used in the crystal engineering.

Full text of DOI:10.3390/molecules25030707

molecules
Article
Trityl-Containing Alcohols—An Efficient Chirality
Transmission Process from Inductor to the
Stereodynamic Propeller and their Solid-State
Structural Diversity
Sylwia Górczyn´ska 1,2, Aleksandra Brzdonkiewicz 1, Maciej Jelecki 1,2, Agnieszka Czapik 1,2
,
Bartosz Stasiak 1 and Marcin Kwit 1,2,
*
1
Department of Chemistry Adam Mickiewicz University, Uniwersytetu Poznan´skiego 8, 61614 Poznan´,
Poland; sylwia.gorczynska@amu.edu.pl (S.G.); ola.brzdonkiewicz@gmail.com (A.B.);
maciej.jelecki@gmail.com (M.J.); agnieszka.czapik@amu.edu.pl (A.C.); bartosz.stasiak@amu.edu.pl (B.S.)
Centre for Advanced Technologies Adam Mickiewicz University, Uniwersytetu Poznan´skiego 10,
61614 Poznan´, Poland
2
*
Correspondence: marcin.kwit@amu.edu.pl
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 15 January 2020; Accepted: 4 February 2020; Published: 6 February 2020
Abstract: The cascade process of a dynamic chirality transmission from the permanent chirality
center to the stereodynamic triphenylmethyl group has been studied for series of optically active
trityl derivatives. The structural analysis, carried out with the use of complementary methods,
enabled us to determine the mechanism of chirality transfer. The process of chirality transmission
involves a set of weak but complementary electrostatic interactions. The induction of helicity in a
trityl propeller is revealed by rising non-zero cotton effects in the area of trityl UV-absorption. The
presence of an additional stereogenic center in close proximity to the trityl-containing stereogenic
center significantly affects the sign and, to a lesser extent, magnitude of the respective cotton effects.
Despite the bulkiness of the trityl, in the crystalline phase, the molecules under study strictly fill the
space. In the crystal, molecules form aggregates stabilized by OH•••O hydrogen bonds. However,
the presence of two trityl groups precludes formation of OH•••O hydrogen bonding. Additionally,
the trityl group seems to be responsible for the formation of the solid solutions by e.g., racemates of
trans- and cis-2-tritylcyclohexanol. Therefore, the trityl group acts as a supramolecular protective
group, which in turn can be used in the crystal engineering.
Keywords: chirality transmission; induced circular dichroism; stereoselective synthesis; trityl
1. Introduction
The triphenylmethyl group (trityl, Tr) and its congeners are frequently used in synthetic organic
chemistry for protecting alcohols, thiols, and amines [1]. Steric requirements make trityl particularly
useful in carbohydrate chemistry, where a selective protection of primary alcohol(s) functionality
is needed.
Very recently, the trityl-containing compounds have attracted attention in medicinal and, especially,
in material chemistry [2]. N-Tritylated amino acids and the other molecules containing a trityl fragment,
have been tested as promising therapeutic agents against many civilization diseases. The triarylmethane
motifs are often found in the structure of functional materials, probes, and dyes. Akazome has proven
that N-tritylated amino acids have the ability to form inclusion compounds and therefore an aptitude
for enantiodiscrimination [3]. The steric properties of the trityl moiety have been recognized as
Molecules 2020, 25, 707; doi:10.3390/molecules25030707
www.mdpi.com/journal/molecules

Molecules 2020, 25, 707
2 of 15
responsible for precluding the formation of intermolecular hydrogen bonds between secondary chiral
triphenylacetic acid amides and between secondary chiral ureas and thioureas [4,5].
The structural and electronic properties of the trityl moiety offer the possibility to use
trityl-containing compounds in catalysis and in stereoselective synthesis. For example, the presence of
trityl in cinchona alkaloid-based catalysts reverses the diastereoselectivity of asymmetric cycloadditions
between aldehydes and enolizable anhydrides with respect to that usually observed. The stability of
trityl cations allowed for their efficient use as Lewis acids in catalytic versions of Diels-Alder and aldol
reactions [6–9].
Apart from usability in synthesis, the trityl, and related groups of the general Ar3X type, represents
a unique example of a molecular fragment whose structural dynamics and mode of action resemble that
of the macroscopic propeller. The stereochemistry of such molecular propellers has been extensively
explored in the past, independently, by Mislow and Iwamura [10,11]. In the parent triphenylmethane
(TrH) and its derivatives of the TrY type (where Y is a spherical substituent), the twisted phenyl rings
connected to the central sp3-hybridized carbon atom adopt a chiral, C3–symmetrical conformation,
characterized by ring twists of either P or M helicity. However, due to the low enantiomerization
barrier, triphenylmethane and its TrY derivatives exist as non-separable dynamic racemates, hence no
optical activity is observed in the region of UV absorption of the trityl chromophore.
On the other hand, the recently demonstrated ability of trityl to adapt to disturbances in the
local symmetry of the chromophore’s chiral environment, has led to new applications of molecular
propellers in dynamic stereochemistry [12]. The observed chirality transfer from the permanent
chirality element to the stereodynamic probe has been observed by us and others for O-trityl alcohols,
N-trityl amines, sulfides and selenides, triphenylacetic acid derivatives, and related compounds [13–20].
The phenomenon is revealed by the appearance of non-zero cotton effects (CEs) in electronic circular
dichroism (ECD) spectra and in the region of the trityl UV absorption (usually between 220 nm and
180 nm). However, despite some similarities in the ECD spectra patterns, the mechanism of the
chirality transmission is rather specific for a given class of compounds. For the prototypical example
of O-trityl alcohols, the transfer of structural information proceeds through “a bevel gear” mechanism,
which assumes direct steric interaction between the permanently chiral part of the system (the inductor)
and the stereodynamic trityl unit (the reporter part). The direct gearing between trityl and inductor
fragment is possible by the bent structure of the whole molecule. In all other cases, the chirality transfer
is driven by more subtle (mostly electrostatic) interactions. As expected, the structural information
transfer is more efficient for inductors characterized by high structural diversity, i.e., the substituents
flanking the stereogenic center significantly differ in size and/or electronic properties.
In general, the chiroptical spectroscopy, mainly electronic and vibrational circular dichroism
spectroscopy (ECD and VCD, respectively) is the method of choice for investigating structure and
structural dynamics of chiral molecules in solution. Among the chiroptical methods, ECD spectroscopy,
supported by theoretical DFT calculations, seems to be the most suitable for testing the dynamic
chirality induction process in the trityl chromophore [21]. This combination of experimental and
theoretical approaches enables an accurate perception of the structure of the molecular entity and the
mechanism of the optical activity induction. Due to the wider availability of commercial spectrometers,
VCD spectroscopy emerges now as a complementary source of structural information for compounds
lacking the appropriate UV-Vis active chromophore.
Very recently, Monde, Abbate, Polavarapu, and others expanded the exciton chirality concept,
fundamental for ECD spectroscopy, to vibrational circular dichroism (the vibrational circular dichroism
exciton chirality (VCDEC) rule) [22,23]. In brief, the interactions through space between electronic
transition moments associated with particular stretching vibrations for a given chromophoric system
(mainly C=O, C=C and C=N) may lead to bisignate VCD couplets of the sequence of the cotton effects
signs that reflect chirality in the interacting system [24].
In contrast, the X-ray crystallography provides the answer to the questions regarding the
role of particular molecular fragments in the formation of the crystals [25]. As a result, these

Molecules 2020, 25, 707
3 of 15
complementary methods allow for establishing the “supramolecular behavior” of the molecule and its
individual fragments.
In this study, we put the emphasis on the chirality transfer in derivatives in which the chromophoric
group is directly attached to the stereogenic center, the inductor being characterized by a low structural
diversity and/or an additional chirality element being present in the close proximity. In the first
case, the trityl group will constitute the inherent part of the molecule and it does not have to be
artificially attached. In other cases, the direct chirality transfer from the stereogenic center to the
propeller, could be disturbed by the presence of an additional stereogenic center within close proximity
and further by the possibility of trityl–trityl interactions. The combination of two chiral molecules
with a fragment of oxalic acid may enforce non-planar conformation of the linker. The interaction
between electronic transition moments associated with C=O stretches will induce dynamic optical
activity in vibrational circular dichroism and lead to bisignate exciton-type Cotton effects in the region
1700–1800 cm−1
.
In this work, we will demonstrate the usefulness of the experimental/theoretical approach to
determine the absolute stereochemistry of compounds being the products of asymmetric synthesis.
Also, to date, the influence of the small, permanently chiral part of the molecule on the
conformational preference of trityls in the solid state has not been the subject of interests. Therefore,
we will expand our study on the behavior of trityls to its association modes in the crystalline phase
and to possible crystalline forms differing in densities and capable of hosting inclusions.
2. Results and Discussion
2.1. Synthesis
In these studies, we have focused on derivatives 1–12 (Scheme 1) which, in principle, may be
conveniently obtained by addition of a carbon nucleophile to a suitable electrophile and then further
functionalized. However, the initially tested stereoselective addition of aliphatic C-nucleophiles to the
triphenylacetaldehyde did not yield alcohols 1a
stability of trityl anion obtained through a direct reaction between triphenylmethane and n-buthyllithium.
We have selected compounds 11, and 12 as the basic structures, which might be obtained through the
addition/substitution of the trityl anion to the respective electrophile (see Scheme 1).
–1e. Thus, we have taken advantage of a facile generation and
1, 3,
Scheme 1. The general synthetic routes that provide optically active derivatives
1,
3–
5, and meso-12
and structures of the other compounds under study. In the case of
diastereoisomeric form was shown.
3, 8, and 9, only one enantiomeric or

Molecules 2020, 25, 707
4 of 15
With the exception of 11, the applied synthetic method did not allow us to obtain the desired
compounds in the optically pure form. In the case of 1a 1e, we were forced to extend the synthetic
procedure to the step of oxidation of racemic alcohols and asymmetric Corey–Bakshi–Shibata (CBS)
reduction of the resulting ketones 2a 2e, which, in turn, provided the enantiomerically enriched
1a 1e 26 28]. The obtained enantiomeric excesses of 1a 1e did not exceed 85%, but were sufficient to
–
–
–
[
–
–
allow us to proceed with the study.
The racemic trans-2-tritylcyclohexanol (rac–
opening the epoxide ring with a trityl anion. The optically active
has been obtained from the racemate via oxalate
3
) was obtained from cyclohexene oxide through
, in both enantiomeric forms,
and by employing the procedure previously
described by Hazmi et al [29]. The reactions provided both diasteroisomers of , differing in the
3
8
8
absolute configurations of the trans-2-tritylcyclohexanol moiety, denoted here as 8a ((1S,2R)) and 8b
((1R,2S)), respectively.
Oxidation of racemic and optically enriched (1S,2R)–
the racemate and as the optically active form ((R)- , ee = 80%). The ketone rac- or (R)-
diastereoselectively reduced to the cis-2-tritylcyclohexanol (rac- or (1R,2R)- , if the enantiomerically
enriched was used), with the use of LS-Selectride. To complete the reduction reaction, a prolongated
3
by PCC led to the ketone
4
, respectively, as
5
5 may be further
6
6
5
heating was required, and (1R,2R)-5 was obtained with moderate yield (60%) and enantioselectivity
(ee = 49%).
To enhance the steric bulkiness at the neighboring stereogenic center, and to show the influence of
an external chiral unit on the possible chirality transfer, the optically pure was acylated with various
acid chlorides. While simple acetylation of with acetyl chloride proceeded smoothly and gave acetate
, the initial attempt at synthesis of the diester 9, which consists of two trans-2-tritylcyclohexanol units
linked by the oxalyl acid moiety, failed. As the only product, we have obtained the monoester , having
one free carboxyl group. It is worth noting that the ESI-MS mass spectrum of does not show peaks
3
3
6
7
7
that might be ascribed to structure of isolated 7. Instead, we observed a sodiated dimeric structure
of the general formula [2 × 7 + Na]+. Surprisingly, the replacement of methylene chloride by freshly
distilled THF and by performing the reaction at elevated temperature within 20 h led to the diester
9
with a yield of 41% after column chromatography. Despite the fact that the starting
3 was not optically
pure (ee = 45%), the reaction was stereoselective and provided only chiral products. For the purpose of
this study, we obtained both enantiomers 9 and ent-9. For no obvious reason, ent-9, which consists of
two units characterized by the 1R,2S absolute configuration of each trans-2-tritylcyclohexanol moiety,
crystallized better than 9 and provided crystals of a sufficient quality for X-ray structure determination.
The oxirane 11 was obtained according the procedure published by Zhang and coworkers [30].
In principle, oxirane 11 was to be the starting point for the further synthesis of an achiral stereodynamic
reporter system consisting of two trityl fragments and an anchoring group enabling covalent or
non-covalent binding of an inducer molecule. However, while the opening of the oxirane by the trityl
anion led to an achiral meso-12 with good yield, the further modification of the hydroxyl group turned
out not to be possible, probably due to the steric congestion around the OH group.
2.2. Structure and Induced Circular Dichroism of 1, 3–11
The complementary use of experimental CD measurements and DFT calculations allows a study
of the structure/chiroptical properties and mechanism of chirality transmission within the selected
compounds. To achieve this goal, ECD spectra measurements are required in order to compare them
to the results of DFT calculations, carried out at a sufficiently high level of theory (calculation details
can be found in Supplementary Information). In this study, we have decided to discuss experimental
and theoretical results together to preserve the logical stream.
The ECD data for
in non-polar cyclohexane for 1a
under study can be described by providing the sets of torsion angles strictly determining the structure
of the particular species. The angle (X-C(=O)-C(H2)-C) characterizes the conformation of the carbon
1–
11 are juxtaposed in Table 1, whereas the exemplary ECD spectra measured
, 3–5,
9, and 11 are shown in Figure 1. The structure of the compounds
α

Molecules 2020, 25, 707
5 of 15
chain. The angles β1
–
β3 ((O=C)-C(H2)-C-Cipso) describes the conformation of the phenyl groups in
the relation to the inductor carbon chain. The sign, and to the same extent, the magnitude of observed
CE’s depends on the helicity of the trityl group. The angles γ1 γ3 (C-C-Cipso-Cortho) values may be
used quantitatively for a precise description of the trityl helicity. However, for the needs of this work,
it seems more convenient to use a qualitive descriptor, namely helicity of the blades: M (
90◦ < < 0◦),
P (0◦ < < 90◦) or 0 (for angles deviating from zero by less than |5◦|). Since, for the majority of the
–
−
γ
γ
γ
cases, the chiroptical properties are dominated by the most abundant conformer, we have limited our
structural discussion to the ∆∆G-based the lowest energy species only. The structures of the lowest
energy conformers of selected compounds 1a, 3–6, 9, and 11 are shown in Figure 2, whereas Table 2
collects the essential information extracted from the theoretical results (the remaining data can be
found in Supplementary Information).
Table 1. Electronic circular dichroism (ECD) (∆ε) and UV (ε) data for derivatives 1, 3–11 measured in
cyclohexane solution.
Compd.
ECD [∆ε (nm)]
UV [ε (nm)]
1a
1b
1c
1d
1e
3
−9.0 (228); 2.9 (215); −0.1 (208); 47.0 (197); −41.8 (185)
−8.0 (229); 1.9 (214); 50.4 (197); −41.8 (186)
−6.3 (232); 45.6 (200); −52.8 (185)a
70,500 (194)
67,500 (194)
67,800 (194)
69,700 (194)
67,400 (194)
−5.0 (229); 2.6 (217); −9.1 (207); 43.4 (196); −31.1 (186)
−6.2 (233); 52.5 (201); −62.3 (186)
2.4 (241); −20.2 (207); 14.0 (185)a
8,000 (236); 73,300 (193)
1,200 (265); 74,500 (190)
70,600 (194)
4
5
1.4 (296); −0.8 (265); 6.0 (235); −25.7 (205); 47.5 (185)a
−5.9 (235); 41.4 (205); −28.0 (185)a
6
1.0 (240); −8.5 (222); −14.7 (204); 20.9 (185)a
−2.9 (238); −3.7 (220); 4.3 (207); −2.9 (197); 8.5 (185)a
−2.5 (238); 3.2 (220); 11.4 (207); −6.5 (191)
−14.6 (235); 83.3 (207); −92.4 (192)
8,400 (236); 76,100 (193)
7b
8
59,700 (193)
5,500 (248); 83,600 (193)
147,000 (192)
20,000 (238); 135,000 (193)
77,900 (197)
9
10
11
+5.0 (238); −24.0 (204); 45.0 (185)a
−7.0 (226); 32.3 (200); −24.0 (185)a
[a] end of measuring range; [b] partially insoluble in cyclohexane.
Figure 1. Exemplary ECD spectra of 1a
lines) and calculated at the TD-CAM-B3LYP/6-311++G(d,p) level for geometries optimized at the
B3LYP/6-311++G(d,p) level (dashed blue lines). With the exception of , the calculated ECD spectra
, 3–5, 9, and 11 measured in cyclohexane (solid black
3
were Boltzmann-averaged based on ∆∆G values. Wavelengths were corrected to match experimental
UV maxima.

Molecules 2020, 25, 707
6 of 15
Figure 2. The structures of the lowest energy conformers of 1a, 3–6, 9, and 11 calculated at the
B3LYP/6-311++G(d,p) or B3LYP/6-311G(d,p) (compound ) level of theory. The dashed lines indicate
9
possible attractive interactions (the remaining structures are deposited as Supplementary Information).
Table 2. The ∆∆G-based percentage populations (Pop.) and helicities of trityl chromophore calculated
for the lowest energy conformers of 1a–1e, 3–9, and 11 at the B3LYP/6-311++G(d,p) level of theory.
Compound a
Pop.
Helicity
1a (conf. 72)
1b (conf. 27)
1c (conf. 9)
1d (conf. 25)
1e (conf. 14)
3 (conf. 1)
4 (conf. 1)
5 (conf. 22)
6 (conf. 1)
55
54
45
42
85
46
100
97
100
42
78
PPP
PPP
PP0
PPP
PP0
MPM
MM0
PPM
MPM
PPM
PPM
PPM
PP0
7 (conf. 13)
8 (conf. 5)
9 (conf. 13) b
11 (conf. 1)
100
50
[a] The conformers are numbered according to their appearance during conformational search; [b] calculations were
carried out at the B3LYP/6-311G(d,p) level.
The data listed in Table 1 clearly indicates large chiroptical response of the trityl chromophore in the
presence of chirality element in its neighborhood. The measured ECD spectra are characterized by the
presence of at least three well-defined absorption bands typical of trityl chromophore. The low-energy
absorption band appearing at around 220 nm, is preceded by two bands with much higher intensity,
which appear around 200 and 185 nm. In the case of the monoester
fragment makes the ECD spectrum more complex.
7, the presence of an oxalyl acid

Molecules 2020, 25, 707
7 of 15
Generally, the –COOR ester group is recognized as the weak UV active chromphore of the π-π*
transition separated from the strong 1B band (195–210 nm) in phenyl rings. However, in the case of
7, we are dealing not only with the presence of two different directly connected groups (COOH and
COOR), but also with the possibility to form various associates [17].
As expected, the direct connection between the chirality element and the stereodynamic part of the
molecule for 1a
1a 1e, the amplitudes (A) that are estimated for the higher-energy CEs reach values between 94 to
195. In fact, these A values are the highest for all the monotrityl derivatives studied so far. The signal
patterns observed in all the spectra are identical: Negative/positive/negative ( /+/ ), which suggests
the same absolute configuration at the stereogenic centers. To confirm this hypothesis, for all of
the alcohols 1a 1e, DFT calculations (B3LYP/6-311++G(d,p)) were carried out [31]. Note that the
–1e leads to the CEs of the highest intensity within the whole series. In tritylcarbinols
–
−
−
–
choice of a calculation method was based on our previous studies. We have previously shown that
the use of hybrid functionals, B3LYP for geometry and CAM-B3LYP for excited states calculations
and for compounds containing trityl groups, gives results closest to the experimental ones [17,18].
Hence, we have decided to use these functionals in conjunction with the enhanced 6-311++G(d,p)
basis set (or 6-311G(d,p) for larger systems) for calculations. The empirical correction for dispersion
interactions does not improve the quality of the results obtained. In other words, the trityl–trityl
interactions are usually overestimated, which ultimately leads to large discrepancies between the
experiment and calculations [20].
The use of B3LYP hybrid functional is not recommended for excited state calculations, which is in
accordance with our observations [17,18,20,32]. We received comparable results (let us say—of the same
quality) to those obtained with the use of CAM-B3LYP functional, when the Thrular’s M06–2X hybrid
functional was employed. In this work, only the results obtained with the use of TD-CAM-B3LYP
hybrid functional were discussed.
In the simplest case of 1a, only two thermally accessible conformers have been found. However,
the number of thermally accessible conformers increases in alcohols with longer or more flexible alkyl
backbones. Despite the structure of the alkyl substituent flanking the stereogenic center, two general
factors can be distinguished as responsible for inducing helicity and, thus, the optical activity in the
trityl chromophore. The first of them are attractive interactions between an oxygen atom from the
hydroxyl group and a hydrogen atom in ortho position from one of the phenyl rings. The proton from
the hydroxyl group is directed towards the plane of the second phenyl group. The O-H···π interactions
together with C-H···π interactions stabilize the conformation of this particular phenyl ring. The third
phenyl ring adjusts its conformation to the conformation of the remaining two.
The
−
/+/
−
signal pattern of CEs, observed for 1a–1e, are due to the predominance of PPP or PP0
helical conformers in conformational equilibria. This experimental/theoretical analysis provides an
additional reward—the absolute configuration, determined for 1a–1e, at the stereogenic centers is
uniformly S for all of these compounds.
(1S,2R)-trans-2-Tritylcyclohexanol (
and intermediate ketone (R)-2-tritylcyclohexanone (
influence of a neighboring group (hydroxyl group or carbonyl oxygen atom) on trityl conformation.
The lowest-energy conformations of and
3), its diastereoisomer (1R,2R)-cis-2-Tritylcyclohexanol (
5),
4
) constitute interesting examples showing the
3
4
are stabilized mostly by Cortho-H···O or O-H···π attractive
interactions and to a lesser extent by Cortho-H···π and steric interactions between axial proton(s)
attached to C1 and C3 carbon atoms in cyclohexane ring. The importance of Cortho-H···O interactions is
particularly seen for the lowest-energy conformer of
4
. The calculated (Cortho-)H···O(=C) distance is
2.210 Å. The case of
5
is different. The axial position of hydroxyl group prevents direct Cortho-H···
O
interactions. Therefore, the primordial factor that determines the conformation of
5 seems to be
O-H···π interactions.
As mentioned previously, the process of optical induction in the trityl chromophore is cascading.
The electrostatic Cortho-H···O (if applicable) interactions constitute the primary factor that fixes the
conformation of the phenyl rings that faces the axial protons at C1 and C3 and enforces a (+)-synclinal

Molecules 2020, 25, 707
8 of 15
((+)-sc) conformation of associated angle
β
. Then a second ring is positioned in such a way as to
allow O-H···π interactions with the hydroxyl proton, and Cortho-H···π interactions with the first phenyl
ring. Finally, the third ring adjusts its conformation to the first two in a way to maximize Cortho-H···π
interactions. The opposite absolute configuration reached by the change in the position of hydroxyl
group from equatorial to axial is reflected in the change of CE sequence. For
which appears in the region of trityl absorption is +/ /+, whereas for it is reversed (
sequences correspond to the preferred helicities of the trityl group, namely MPM and PPM for the
most abundant conformers of and , respectively. It is worth mentioning that the presence of the
3
and 4, the CE sequence
−
5
−
/+/ ). These
−
3
5
trityl, which acts as a protective umbrella, is responsible for the non-reactivity of the axial hydroxyl
group, particularly in reactions requiring OH activation prior nucleophilic substitution.
Having compared the ECD spectra of
equatorial hydroxyl group does not have any significant effect on the amplitude and the sequence of the
respective CEs. In both cases, the same +/ /+ sequence is observed. However, the mechanism of optical
activity induction, deducted from our theoretical results, is slightly different from that established for
the free alcohol. In the case of
3 and 6, we may conclude that the acetylation of the
−
6
, the Cortho-H···O attractive interactions lose their importance in favor of
sterical interactions between the acetyl group and the adjacent phenyl ring of trityl.
Due to the unrestricted rotation around the C-C bond in the linker, the adipinic acid derivative
10 is characterized by a great conformational flexibility. While the shape of the ECD spectrum of 10
resembles that of acetate
6 and of the free alcohol 3, the magnitudes of its CE doubles. This is not
surprising, given that the observed effects are a linear combination of contributions from individual
(non-interacting) trityl chromophores.
Compounds
7
–
9
represent systems whose common denominator is the presence of an oxalyl
/+/ sequence of CE
moiety. Despite structural differences, these compounds display the same
observed in the region of the trityl UV absorption. This is apparently due to the dominant influence of
−
−
conformers of PPM helicity of the trityl group(s) on the overall ECD spectra.
Among oxalates
bis((1S,2R)-2-tritylcyclohexyl) oxalate (
conformer of
is stabilized by a set of weak Cortho-H···O interactions that involve all C=O and
C-O oxygen atoms present in the linker. Moreover, the Cortho-H···O=C interactions involve the phenyl
group characterized by the (+)-sc conformation of the angle and a more distant oxygen atom,
while Cortho-H···O-C interactions take place between the phenyl group of ( )-sc conformation for
the angle and with a closer oxygen atom. The third phenyl group of (+)-antiperiplanar ((+)-ap)
conformation for the angle adjusts its position in a way to minimize steric repulsion while allowing
7–
9,
the most interesting one is represented by the symmetrical
9). Conformation of the C2-symmetrical, lowest-energy
9
β
−
β
β
some Cortho-H···π interactions.
The Cortho-H···O interactions not only stabilize the conformation of the trityl groups, but also
cause a bending of the oxalate linker. In the lowest-energy conformer of 9, both COOR fragments
are arranged almost perpendicularly (
energy conformer number 26 retains the (
angle gives a chance for observation of non-zero CE in the region of C=O stretches in the VCD spectrum
of . In fact, the VCD spectrum of measured in CCl4, shows a bisignate couplet in the region of C=O
φ
= 91.4◦, where
)-ap orientation (
φ
is the O=C-C=O angle), whereas the higher
−
φ
=
−
162.9◦). The non-planarity of the
φ
9
9
absorption (1700–1800 cm−1, see Figure 3) that may be ascribed to through-space interactions of two
C=O chromophores. However, the negative sign of this couplet remains inconsistent with the twist
of the neighboring vicinal C=O bonds. Similarly, the DFT calculations gave results that are opposite
to the experimental ones, regardless of the calculation method used. A possible explanation for this
discrepancy could follow from the underestimation of structures characterized by (+)-sp or (+)-synclinal
((+)-sc) conformations of the O=C-C=O angle. Despite these disappointing results, this particular
compound is an interesting example of shortcomings in the experimental/theoretical approach to
structural studies with the use of VCD spectroscopy. Further studies on this and related compounds
will be undertaken in the near future.

Molecules 2020, 25, 707
9 of 15
Figure 3. IR (upper panel) and vibrational circular dichroism (VCD) (lower panel) spectra of 9,
measured in CCl4 (solid black lines) and calculated (blue dashed lines) for geometries optimized at
the IEFPCM (CCl4)/B3LYP/6-311G(d,p) level. The calculated VCD spectra were Boltzmann-averaged
based on ∆∆G values and were not scaled. Only the region of C=O absorption (1850–1650 cm−1) is
shown. The experimental, measured in the region between 850 and 2000 cm−1 and calculated IR and
VCD spectra are available in Supplementary Information.
The oxirane 11 represents a somewhat different system, in which the trityl group is connected
indirectly to the stereogenic center. In this particular case, the reporter part of the molecule should be
sensitive enough to distinguish distant substituents of the stereogenic center. Among the thermally
accessible conformers, two of them, number 1 and number 73, dominate in conformational equilibrium
and are characterized by PP0 and PPP helicities of the trityl fragment, respectively. The ECD spectra,
calculated for these conformers, exhibit the same
the experimental ECD spectrum. The structure of the trityl moiety in low-energy conformers of 11
−
/+/ sequence of CE, in perfect agreement with
−
,
is stabilized mostly by Cortho-H···π interactions and to a lesser extent by electrostatic repulsion between
the oxygen atom and the π-electron cloud of the phenyl ring facing the oxirane moiety.
2.3. X-ray Diffraction Study
Taking advantage of the ability of some compounds to form crystal phases, we have extended our
work to the solid phases of the trityl-containing molecules. In particular, we were interested in the
possibilities to form inclusion compounds, which in turn may lead to enantiodiscrimination. The crystal
structure of compounds rac-
means of the X-ray diffraction method (detailed information is included in Supplementary Information).
The derivatives obtained, with the exception of compound rac- , crystallize without solvent. Some
structural gaps are observed in the crystals of the rac- , (R)-4, and , however the accessible volume
is too small to include the solvent molecules. Nevertheless, in crystals of rac- , rac- 11, and 12,
3, rac-4, (R)-4, rac-5, rac-7, 8, 9, 11, and 12 has been determined and studied by
7
4
9
3
5, 8,
the molecules strictly fill the space, and despite the tests carried out, inclusion crystals containing at
least solvent molecules have not been obtained.
Interestingly, the two types of crystals of compound rac-
) were obtained in one crystallization, even though the structure of the molecule is the
same. Furthermore, the structural analysis showed that the polymorph rac-3- is a solid solution of
3 (orthorhombic (rac-3-α) and monoclinic
(rac-3-β
β

Molecules 2020, 25, 707
10 of 15
enantiomers (Figure 4b), and the ratio of refined occupancy factors for oxygen atoms is 0.71: 0.29.
In both orthorhombic and monoclinic crystals, the basic structural unit is a pair of (1S,2R) or (1R,2S)
molecules interacting through the O-H···O hydrogen bond. The helicity of the trityl group for all
molecules observed in the crystal phase, both in
α and β forms, is MPM, which corresponds to the
conformation of the calculated low-energy structure. A hydrogen atom of the OH group that is not
involved in this hydrogen bond, is further involved in the O-H···π interaction, which stabilizes the
structure of the molecule. In the rac-3-α crystals, pairs of hydrogen bonded molecules form columns
stabilized by C-H···π interactions (Figure 4a). However, similar columns are observed in the beta
form structure where the molecules from adjacent columns interact with each other through O-H···
O
hydrogen bonds (Figure 4b). The three-dimensional structure is stabilized by weak interactions
involving π-electron systems.
Figure 4. The molecular structure of asymmetric unit and supramolecular column in crystal structure
of compound rac-
3: (a) polymorph α,( b) polymorph β. The oxygen atoms are presented as balls and
hydrogen bonds are shown as dashed lines.
Crystals of (R)-4, where the compound crystallizes with two molecules in the asymmetric unit cell
(helicity MPM and PMP) where one of them is disordered (the ratio of refined occupancy factors for
oxygen atoms is 0.88: 0.12) turned out to be an unusual case. For the disordered molecule, the position
of the cyclohexane ring is undefined, and it mimics the phenyl ring.
Molecular disorder is also observed in the crystals of rac-
5 (Figure 5). The compound crystallizes
in the triclinic system (symmetry P ), with two molecules in the asymmetric unit cell where both of
1
them are disordered—the cyclohexyl ring mimics the phenyl ring in the crystal structure. In addition,
the enantiomer molecules can occupy the same positions in the crystal, and the cis-2-tritylcyclohexanol
crystallizes as a solid solution of enantiomers, as in the case of 3-β. The helicity of the trityl group for
all molecules observed in crystal is MPM (or PMP), which corresponds to the conformation calculated
for the low-energy structure. The hydrogen atoms of the OH groups do not form strong intermolecular

Molecules 2020, 25, 707
11 of 15
hydrogen bonds, as they participate in intramolecular O-H···π interactions stabilizing the structure
of the molecule. The formation of solid solutions by compounds containing a bulky trityl group
has previously been observed once and may be due to supramolecular protective properties of the
substituent [33].
Figure 5.
(a) Molecular structure of compound rac-5, (b) molecular is represented by the superposition
of different conformation in different colors.
The common feature of compounds
The conformation of this fragment is described by angle
for the monoester
, 127.8(2)◦ for 8, and 32.1 (4)◦ for the diester
monoester is stabilized by intramolecular interaction of the phenyl ring and the almost parallel oxalyl
7
,
8, and
9
is the presence of an oxalyl fragment in the molecule.
(defined as O=C-C=O), which is
152.6(2)◦
. The molecular structure of
φ
−
7
−
9
7
part (Figure 6). The free carboxyl group forms the bifurcate O-H···O hydrogen bonds and participates in
the formation of the supramolecular tape observed in the crystal structure. As mentioned, the ability to
form inclusions was confirmed only for the compound
the solvent (chloroform). The stacking-like arrangement of phenyl ring and oxalyl part is not preserved
in the structure of the diester , where the presence of a second trans-2-tritylcyclohexanol unit forces a
change in molecules geometry.
7 and the crystals obtained contain molecules of
9
Figure 6. Molecular structure of (a) compound
7, (b) compound 9, and (c) supramolecular chain via
hydrogen bonds in structure
shown as balls.
7 (hydrogen bonds showed as a dashed line). The oxygen atoms are
In the crystal structure of compound 11, the asymmetric unit cell consists of one molecule with
MMM helicity of trityl group (PP0 for calculated the low-energy structure). The oxygen atom is
involved in C-H···O hydrogen bond and molecules form a ladder-like structural motif (Figure 7). These

Molecules 2020, 25, 707
12 of 15
C-H···O interactions stabilize the structure of the molecule as well. The whole three-dimensional crystal
structure is stabilized by weak interactions involving aromatic systems.
Figure 7. (a) Molecular structure of compound 11 and (b) intermolecular interaction in crystal structure.
The oxygen atoms are shown as balls. The hydrogen bonds are shown as dashed line.
Compound 12 crystallizes with two molecules in the asymmetric unit cell. Interestingly, OH
groups do not form strong hydrogen bonds. Cortho-H···O interactions are observed between the
molecules, while the OH groups are involved in O-H···π interactions. The OH group has a great
potential for hydrogen bonding and constitute a reliable feature in planning the crystal structure.
As shown, the presence of a trityl group in close proximity to the hydroxyl group limits its availability
for forming hydrogen bonds. This observation confirms that the trityl group can act as a protective
group in crystal engineering.
3. Materials and Methods
Detailed experimental procedures, details regarding X-ray diffraction studies, and theoretical
calculations are given in Supplementary Information.
4. Conclusions
In this work, we have proposed a complementary approach to the problem of chiral derivatives,
in which the sterodynamic part of the molecule is directly connected to the stereogenic center or is
one CH2 group removed. Despite high conformational freedom of some derivatives, we have shown
the possibility of chirality transfer from the permanent chirality element to the stereodynamic trityl
group, through the set of relatively weak but complementary electrostatic interactions. The presence of
OH and/or C=O in the molecule is a factor that organizes and stabilizes the conformation. As a result,
the trityl group adopts helical conformation, which is revealed by the appearance of non-zero CE in
the region of trityl absorption. In the cases of more complex derivatives that contain more than one
chirality element, their respective CE signs sequences appear between 220 and 185 nm are not a simple
function of the absolute configuration at the stereogenic center. In these cases, the shapes of ECD
spectra were found to depend on the configuration of the additional stereogenic center, not directly
connected with the trityl group.
Due to the presence of two chiral fragments, the oxalyl linker in diester
conformation. Such a geometry allows, in principle, the observation of exciton-type CE’s in the region of
C=O stretches in VCD spectrum of . The bisignate couplet in the region of C=O absorption, observed
in the VCD spectrum of , may be ascribed to through-space interactions of 2 C=O chromophores.
9, adopts non-planar
9
9
However, further studies on this and related compounds will be carried out in the near future.
The presence of the trityl group allowed, to some extent, for the control over the supramolecular
assembly of alcohol derivatives. The molecules in the crystal form various aggregates stabilized by

Molecules 2020, 25, 707
13 of 15
O-H···O hydrogen bonding. On the other hand, the presence of two trityl groups in the neighborhood
of OH hydroxyl group preclude formation of OH···O hydrogen bonding. Therefore, in this case, the
trityl group acts as a supramolecular protective group. Additionally, the presence of the “protecting
umbrella” is a decisive factor that is responsible for the formation of solid solutions by racemates of
trans- and cis-2-tritylcyclohexanol. Strictly speaking, the packing of the molecules in the crystal is
determined by the trityl, not by the absolute configuration of the chirality element. The protective
function of the trityl group can, in turn, be used in crystal engineering.
Supplementary Materials: The following are available online at http://www.mdpi.com/1420-3049/25/3/707/s1,
1
Experimental details, Calculation details, X-ray diffraction study details, copies of H and 13C NMR spectra,
Figures S1-S102; Tables S1-S4. CCDC 1977921-1977930 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 emailing
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.
Author Contributions: Conceptualization, M.K and A.C.; methodology, M.K. and A.C.; formal analysis, M.K.;
investigation, S.G., A.B., M.J., A.C., B.S., and M.K.; resources, S.G., A.B., M.J., and B.S..; writing—original draft
preparation, A.C. and M.K.; writing—review and editing, A.C. and M.K.; visualization, A.C. and M.K; supervision,
A.C. and M.K.; project administration, M.K.; funding acquisition, M.K. All authors have read and agreed to the
published version of the manuscript.
Funding: This work was supported by a research grant from National Science Center (NCN) Poland, Grant
UMO-2016/21/B/ST5/00100, and by grant no. POWR.03.02.00-00-I026/16 co-financed by the European Union
through the European Social Fund under the Operational Program Knowledge Education Development (S.G.). All
calculations were performed in Poznan Supercomputing and Networking Center.
Acknowledgments: The authors express their gratitude to Daniel Łowicki for the performance of chiral HPLC
analyses and to Marcin Konopka for assistance at the start of this project.
Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the
study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to
publish the results.
References
1.
2.
3.
Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis; Wiley: New York, NY, USA, 2006;
pp. 152–156.
MacGillivray, L.R. Comprehensive Supramolecular Chemistry II. In Supramolecular Engineering: Designing
the Solid State; Atwood, J.L., Gokel, G.W., Barbour, L.J., Eds.; Elsevier: Amsterdam, The Netherlands, 2017.
Akazome, M. Chiral Recognition by Inclusion Crystals of Amino-Acid Derivatives Having Trityl Groups.
In Advances in Organic Crystal Chemistry; Springer Science and Business Media LLC: Berlin, Germany, 2015;
Volume 23, pp. 463–482.
4.
Bendzin´ska-Berus, W.; Warz˙ajtis, B.; Gajewy, J.; Kwit, M.; Rychlewska, U. Trityl Group as an Crystal
Engineering Tool for Construction of Inclusion Compounds and for Suppression of Amide NH···O=Hydrogen
Bonds. Cryst. Growth Des. 2017, 17, 2560–2568. [CrossRef]
5.
6.
Prusinowska, N.; Czapik, A.; Wojciechowska, M.; Kwit, M. Dynamic optical activity induction in the
N-alkyl-N’-trityl ureas and thioureas. Org. Biomol. Chem. 2019, 17, 7782–7793. [CrossRef]
Khazaei, A.; Zolfigol, M.A.; Moosavi-Zare, A.R.; Zare, A.; Parhami, A.; Khalafi-Nezhad, A. Trityl chloride as
an efficient organic catalyst for the synthesis of 1-amidoalkyl-2-naphtols in neutral media at room temperature.
Appl. Catal. A: Gen. 2010, 386, 179–187. [CrossRef]
7.
8.
Khazaei, A.; Zolfigol, M.A.; Moosavi-Zare, A.R.; Abi, F.; Zare, A.; Kaveh, H.; Khakyzadeh, V.;
Kazem-Rostami, M.; Parhami, A.; Torabi-Monfared, H. Discovery of an in situ carbocationic system
using trityl chloride as a homogeneous organocatalyst for the solvent-free condensation of β-naphthol
with aldehydes and amides/thioamides/alkyl carbamates in neutral media. Tetrahedron 2013, 69, 212–218.
[CrossRef]
Khazaei, A.; Zolfigol, M.A.; Moosavi-Zare, A.R.; Zare, A.; Khojasteh, M.; Asgari, Z.; Khakyzadeh, V.;
Khalafi-Nezhad, A. Organocatalyst trityl chloride efficiently promoted the solvent-free synthesis of
12-aryl-8,9,10,12-tetrahydrobenzo[a]-xanthen-11-ones by in situ formation of carbocationic system in neutral
media. Catal. Commun. 2012, 20, 54–57. [CrossRef]

Molecules 2020, 25, 707
14 of 15
9.
Bah, J.; Franz
é
n, J. Carbocations as Lewis Acid Catalysts in Diels–Alder and Michael Addition Reactions.
Chem. Eur. J. 2014, 20, 1066–1172. [CrossRef]
10. Mislow, K. Stereochemical consequences of correlated rotation in molecular propellers. Accounts Chem. Res.
1976, 9, 26–33. [CrossRef]
11. Iwamura, H.; Mislow, K. Stereochemical consequences of dynamic gearing. Accounts Chem. Res. 1988, 21,
175–182. [CrossRef]
12. Wolf, C. Dynamic Stereochemistry of Chiral Compounds: Principles and Applications; Royal Society of Chemistry:
Cambridge, UK, 2008.
´
13. Sciebura, J.; Skowronek, P.; Gawron´ski, J. Trityl ethers: molecular bevel gears reporting chirality through
circular dichroism spectra. Angew. Chem. Int. Ed. 2009, 48, 7069–7072. [CrossRef]
´
14. Sciebura, J.; Gawron´ski, J. Double Chirality Transmission in Trityl Amines: Sensing Molecular Dynamic
Stereochemistry by Circular Dichroism and DFT Calculations. Chem. Eur. J. 2011, 17, 13138–13141.
´
15. Sciebura, J.; Janiak, A.; Stasiowska, A.; Grajewski, J.; Gawronska, K.; Rychlewska, U.; Gawronski, J.
Intramolecular Interactions of Trityl Groups. Chem Phys. Chem 2014, 15, 1653–1659. [CrossRef]
´
16. Skowronek, P.; Scianowski, J.; Pacuła, A.J.; Gawron´ski, J. Chirality transfer through sulfur or selenium to
chiral propellers. RSC Adv. 2015, 5, 69441–69444. [CrossRef]
17. Skowronek, P.; 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
75, 4497–4505. [CrossRef]
,
18. Bendzin´ska-Berus, W.; Jelecki, M.; Kwit, M.; Rychlewska, U. Transfer of chirality in N-triphenylacetylamino
acids and chiral derivatives of N-triphenylacetyl Gly–Gly dipeptide and control of their assembly with steric
constraints. Cryst. Eng. Comm. 2019, 21, 3420–3430. [CrossRef]
19. Prusinowska, N.; Bendzin´ska-Berus, W.; Jelecki, M.; Rychlewska, U.; Kwit, M. Triphenylacetic acid amides:
Molecular propellers with induced chirality. Eur. J. Org. Chem. 2015, 4, 738–749. [CrossRef]
20. Prusinowska, N.; Bendzin´ska-Berus, W.; Szymkowiak, J.; Gajewy, J.; Jelecki, M.; Rychlewska, U.; Warz˙ajtis, B.;
Kwit, M. Double helicity induction in chiral bis(triphenylacetamides). RSC Adv. 2015, 5, 83448–83458.
[CrossRef]
21. Berova, N.; Polavarapu, P.L.; Nakanishi, K.; Woody, R.W. Comprehensive Chiroptical Spectroscopy (Applications
in Stereochemical Analysis of Synthetic Compounds, Natural Products, and Biomolecules); Wiley: Hoboken, NJ,
USA, 2012.
22. Taniguchi, T.; Monde, K. The exciton chirality method in vibrational circular dichroism. J. Am. Chem. Soc.
2012, 134, 3695–3698. [CrossRef]
23. Abbate, S.; Mazzeo, G.; Meneghini, S.; Longhi, G.; Boiadjiev, S.E.; Lightner, D.A. Bicamphor: A Prototypic
Molecular System to Investigate Vibrational Excitons. J. Phys. Chem. A 2015, 119, 4261–4267. [CrossRef]
24. Szymkowiak, J.; Kwit, M. Electronic and vibrational exciton coupling in oxidized trianglimines. Chirality
2018, 30, 117–130. [CrossRef]
25. Desiraju, G.R. Crystal Engineering: The Design of Organic Solids; Elsevier: Amsterdam, The Netherlands, 1989.
26. Prelog, V.; Philbin, E.; Watanabe, E.; Wilhelm, M. Untersuchungen über asymmetrische Synthesen VIII.
Optisch aktive Hilfsalkohole mit einem asymmetrischen Kohlenstoff-Atom. Helvetica Chim. Acta 1956, 39,
1086–1095. [CrossRef]
27. Corey, E.; Cheng, X.-M.; Cimprich, K.A.; Sarshar, S. Remarkably effective and simple syntheses of
enantiomerically pure secondary carbinols from achiral ketones. Tetrahedron Lett. 1991, 32, 6835–6838.
[CrossRef]
28. Corey, E.J.; Helal, C.J. Reduction of Carbonyl Compounds with Chiral Oxazaborolidine Catalysts: A New
Paradigm for Enantioselective Catalysis and a Powerful New Synthetic Method. Angew. Chem. Int. Ed. 1998
,
37, 1986–2012. [CrossRef]
29. Al Hazmi, A.M.; Sheikh, N.S.; Bataille, C.J.; Al-Hadedi, A.A.; Watkin, S.V.; Luker, T.J.; Camp, N.P.;
Brown, R.C.D. Trans-2-Tritylcyclohexanol as a Chiral Auxiliary in Permanganate-Mediated Oxidative
Cyclization of 2-Methylenehept-5-enoates: Application to the Synthesis of trans-(+)-Linalool Oxide. Org. Lett.
2014, 16, 5104–5107. [CrossRef]
30. Zhang, A.; Yang, L.; Yang, N.; Liu, Y. The synthesis of chiral amino diol tridentate ligands and their
enantioselective induction during the addition of diethylzinc to aldehydes. Tetrahedron Asymm. 2014, 25,
289–297. [CrossRef]

Molecules 2020, 25, 707
15 of 15
31. Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.;
Mennucci, B.; Petersson, G.A.; et al. Gaussian 09, Revision, A.1; Gaussian, Inc.: Wallingford, CT, USA, 2009.
32. Pescitelli, G.; Bruhn, T. Good Computational Practice in the Assignment of Absolute Configurations by
TDDFT Calculations of ECD Spectra. Chirality 2016, 28, 466–474. [CrossRef]
33. Czapik, A.; Jelecki, M.; Kwit, M. Chiral Cocrystal Solid Solutions, Molecular Complexes, and Salts of
N-Triphenylacetyl-l-Tyrosine and Diamines. Int. J. Mol. Sci. 2019, 20, 5004. [CrossRef]
Sample Availability: Samples of the compounds 1-11 are available from the authors.
©
2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).