Trityl Group as an Crystal Engineering Tool for Construction of

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Trityl group as crystal engineering tool for construction of inclusion compounds and for suppression of amide NH···O=C hydrogen bonds. Wioletta Bendzi#ska-Berus, Beata Warzajtis, Jadwiga Gajewy, Marcin Kwit, and Urszula Rychlewska Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b00105 • Publication Date (Web): 28 Mar 2017 Downloaded from http://pubs.acs.org on March 30, 2017

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Crystal Growth & Design

Trityl group as crystal engineering tool for construction of inclusion compounds and for suppression of amide NH···O=C hydrogen bonds. Wioletta Bendzińska-Berus, Beata Warżajtis, Jadwiga Gajewy, Marcin Kwit and Urszula Rychlewska* Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznań, Poland

The manuscript presents the results of the recent research on the ditrityl derivatives of chiral (R,R)-N,N'-cyclohexane-1,2-diyldiacetamide

as

a

continuation

of

our

studies

on

intramolecular chirality transfer. It has been demonstrated that the investigated molecules offer interesting solid state supramolecular applications: the bulky trityl substituent suppresses the amide···amide hydrogen-bond aggregation and shields the NH hydrogen donor group, thus acting as a supramolecular protection group, contributing to the enhanced solubility in common organic solvents. The molecules provide crystalline inclusion compounds in a predictable manner. Modification of the host structure such as N-methyl substitution, extension of the linkage group connecting the trityl moieties with the cyclohexane skeleton or racemization of the sample does not affect the formation of inclusions. X-Ray diffraction, combined with the electronic circular dichroism measurements supported by theoretical calculations, provide full information about structural dynamics of the chiral trityl derivatives in both, the solid state and solution.

*Urszula Rychlewska

Faculty of Chemistry, Adam Mickiewicz University, 61-614 Poznań, Poland phone +48 (61) 8291683, fax +48 (61) 8291555 [email protected]

ACS Paragon Plus Environment


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Trityl group as crystal engineering tool for construction of inclusion compounds and for suppression of amide NH···O=C hydrogen bonds. Wioletta Bendzińska-Berus, Beata Warżajtis, Jadwiga Gajewy, Marcin Kwit and Urszula Rychlewska* Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznań, Poland KEYWORDS: chirality transfer, conformation of trityl group, lattice inclusion, hydrogen bonding, supramolecular protection group

ABSTRACT: It has been found that ditrityl derivatives of (R,R)-N,N'-cyclohexane-1,2diyldiacetamide and their analogues invariably form crystals that possess inclusion properties. Enantiopurity of crystals is not a prerequisite for inclusion properties. The molecules form either two- or three-component inclusion compounds, in which hosts and guests are connected by hydrogen bonds specific for the included guest molecules but always involving the carbonyl groups of the host as acceptors. The association mode of the host molecules undergoes certain changes depending on the chemical modification of the host molecule, the type of included solvent molecule (protic/non-protic) and whether the crystals are two- or three-component. Despite the potential for hydrogen bonding of the amide groups, no direct hydrogen bonding between the amide units of the host was observed in any of the reported structures allowing to classify a trityl group as a protection group of the amide N-H


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functionality in crystal engineering. X-Ray diffraction combined with the electronic circular dichroism measurements supported by theoretical calculations, provide full information about structural dynamics of the chiral trityl derivatives in both, the solid state and solution.

INTRODUCTION The triphenylmethyl (trityl, Tr) group is a common protection group widely used in organic synthesis.1-3 Simple Tr derivatives often adopt three-bladed propeller conformations of C3 symmetry both in the solid state and in the solution. It has been shown that molecules with C3 symmetry are important synthons in the crystal engineering of supramolecular architectures.4,5 Moreover, compounds incorporating Tr motif constitute an emerging family of potent anticancer agents.6 In the solid state chemistry, the Tr group is known from its capacity in promoting crystallinity7,8 and an ability to build host lattices for accommodating guest molecules.9,10 Initiated by Toda, a pioneer in organic crystal engineering, there have been several reports concerning the wheel-and-axle compounds that contain a long, linear axis (the 'axle') that bears at both terminals Tr substituents, classified as the wheels, which form inclusion compounds with a variety of solvents.11-15 Hart, Ward and Goldberg and their co-workers investigated the development of host molecules among N,N'-ditritylureas.10,16-19 More recently Akazome and co-workers demonstrated the utilization of inclusion properties of N-trityl amino acid salts and N,N’-ditrityl amino amides in the process of enantioselective inclusion of racemic alcohol and amide guests. 20-22. In our previous work on chiral ditrityl amines and diols, aimed at the investigations of possible transmission of structural information from a permanent stereogenic center to a propeller shaped Tr group, we have noted a tendency of some of the N,N’-di(trityl)diamines to incorporate solvent molecules in their crystals to compensate for the close-packing frustration



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caused by the presence of the bulky Tr groups.23 On the other side, similar studies carried out for a series of chiral triphenylacetamides revealed that these compounds yielded solvent free crystals. In this group of crystals, packing difficulties caused by the presence of bulky Tr group were overcome by the pseudocentrosymmetric type of packing, achieved by increasing the number of symmetry independent molecules, or by allowing for the presence of small unoccupied voids in the crystal lattice.24 Similarly, compounds having two tritylacetamide functionalities attached at 1,2-positions to the cyclopentane or to the dihydroethanoantracene rings, or to the flexible carbon chain frame, yielded solvent free crystals. This contrasted with the packing mode of the ditrityl derivatives of (R,R)-N,N'-cyclohexane-1,2-diyldiacetamide, which lead crystalline inclusion compounds.25 This behavior is examined more closely in the present work. Another issue that emerged from our previous studies was the phenomenon of blocking by the bulky Tr group of the N-H amide functionality in hydrogen bond formation. According to the general rules derived from systematic studies of crystal packing, crystallization of secondary amide derivatives is directed by N-H···O=C amide···amide hydrogen bonds, which typically lead to their low solubility in many organic solvents. When many functional groups in a molecule form strong and directional multiple interactions, crystallization may lead to generation of open networks containing structural voids, which are then occupied by included guests. With compounds having large Tr substituents attached to the hydrogen-bond forming functionalities, such as amine or amide, the situation seems to be the opposite. The bulky Tr group is able to reduce or inhibit the involvement of these groups in strong intermolecular interactions,22,26 so the assessment of the presence of particular structure directing interactions might not be unequivocal or straightforward. In this context the Tr group attached to acetamide fragment plays a role of a protection group in crystal engineering, i.e. the group that protects the amide fragment from getting involved in supramolecular N-H···O=C


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hydrogen bond or in any other hydrogen bond that involves N-H functionality. In such circumstances the inclusion phenomenon, if it occurs, is not caused by the presence of many strong and directional intermolecular interactions but results from the presence of the Tr group that produces large intermolecular spatial hindrance and at the same time disrupts the amide hydrogen bonding pattern. All these observations prompted us to further investigate the inclusion properties of ditrityl derivatives of (R,R)-N,N'-cyclohexane-1,2-diyldiacetamide and its analogues, and the loss of hydrogen bonding capability of the amide functionality caused by installation of the Tr groups. Our work is the first comprehensive study of the inclusion ability of chiral bistriphenylacetamides. These compounds have not been so far a subject of interest to the scientific community. In the present paper we demonstrate experimentally that both the cyclohexane frame and two ditrityl functionalities are required for guest inclusion to occur in this class of organic crystals and so far we have found no exception to this generalization, although this is rather rare for weakly interacting compounds. The novelty of our approach also relies on treating the triphenylacetamide moiety as a source of molecular helicity and on studies of chirality transfer from the stereogenic center to the triphenylacetamide reporter group. The phenomenon of chirality transmission to the trityl group is presently intensively studied by other groups on both molecular27 and supramolecular level.28

EXPERIMENTAL SECTION 1

H and

13

C NMR spectra were recorded on Varian VNMR-S 400 MHz instrument.

Chemical shifts (δ) are reported in ppm relative to SiMe4. Mass spectra were recorded on a AB Sciex TripleTOF® 5600+ System. IR spectra were recorded on a Thermo Scientific Nicolet iS50 FT-IR spectrometer and are reported as wave numbers ν in cm-1 with band intensities indicated as: s (strong), m (medium), w (weak). A Jasco P-2000 polarimeter was



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used for optical rotation measurements (at 20 °C). UV and CD spectra were measured with the use of Jasco J-810 spectropolarimeter. Flash column chromatography was performed on Merck Kieselgel type 60 (250-400 mesh). Merck Kieselgel type 60F254 analytical plates were employed for TLC. Melting points were measured on Büchi Melting Point B-545 and uncorrected. Ditrityl derivatives of (R,R)-N,N'-cyclohexane-1,2-diyldiacetamide (1-3, Chart 1) were synthesized according to known procedure and initially recrystallized from dichloromethane under ambient conditions.25 Acylation of (R,R)-1,2-diaminecyclohexane by trans-4,4,4triphenylcrotoyl chloride provides amide 4, which is quantitatively transformed to its analogue 5 through hydrogenation on palladium. The detailed experimental procedures and spectral characteristics of all new compounds are deposited as Supporting Information. To investigate the potency of solids 1–5 as hosts for crystalline inclusion formation, they were recrystallized from a variety of solvents ranging from polar protic via polar aprotic to nonpolar species and involving solvents of acyclic and cyclic nature. Both specification of the solvents and findings obtained from this study are summarized in Figure 1 and Tables S1-S3, and Tables S4-S6 included in the Supporting Information.


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Chart 1. Structures of compounds under study (a) and definition of torsion angles that

describe the molecular conformation (b).



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Figure 1. The host molecule and its analogues present in crystals at 130K. Dotted lined mark

local attractive 1,3-dipolar C=O/C-H interactions. Hydrogen atoms in aromatic systems have been omitted for clarity.


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Single Crystal X-ray Diffraction. Reflection intensities were measured at 130K on a

SuperNova diffractometer equipped with Cu microfocus source (λ=1.54178 Å) and 135 mm Atlas CCD detector. Diffraction data for 4·EtOH·H2O were measured at 130K on a Xcalibur kappa-geometry diffractometer equipped with monochromated Mo Kα radiation (λ=0.71073 Å). Data reduction and analysis for all investigated crystals were carried out with the CrysAlisPro program.29 In all experiments the sample temperature was controlled with an Oxford Instruments Cryosystem cold nitrogen-gas blower. The structures were solved in SHELXT and refined with SHELXL from the SHELX-2014 package.30-32 Crystals of 1·CH3CN appeared to be twinned. The twinning matrix (010, 100, 00-1) corresponds to a

rotation of 180° about the [110] direct lattice direction. Subsequent refinement indicated that the twin fraction of the second domain was 0.487(1). All heavy atoms were refined anisotropically, except for the heavily disordered dimethoxyethane (DME) molecule in 1·DME·H2O which was refined isotropically. In the crystal structure of 2·MeCN solvent

molecules were highly disordered and could not be properly modelled therefore their contributions were removed from the diffraction data using the SQUEEZE as implemented in PLATON.33 The estimated electron count is 81 in an accessible void volume of 674 Å3 and can indicate squeezing of 4 molecules of acetonitrile per unit cell (81/22≈4). Taking into account the number of solvent molecules which were squeezed we determined host to guest ratio as 1:1. The hydrogen atoms were placed at calculated positions and refined using the riding model, and their isotropic displacement parameters were assigned a value 20% higher than the isotropic equivalent for the atom to which they were attached. Methyl hydrogen atoms were positioned using SHELXL HFIX 137 instruction. The H-atoms in the disordered DME molecule have not been located. Where necessary, restraints for the 1,2- and 1,3distances as well as the ADP restraint (SIMU) and rigid-bond restraint (DELU) were applied. In cases, where the Flack parameter value34 was meaningless, the absolute structure of the



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investigated crystals was assumed from the known absolute configuration of the (R,R)-1,2diaminecyclohexane which was used as a starting material in the syntheses. Graphical images were produced in Mercury35 program. Crystal data and refinement parameters are listed in Table S1. Two of the structures presented here (1·CH2Cl2 and 2·CH2Cl2) confirm older data, but the results for 2·CH2Cl2 were obtained from a new data-set collected at 130K for the freshly made crystals. All other X-ray data are reported for the first time. TGA. Thermogravimetric analysis (TGA) was carried out using a TA Instruments

Discovery Series thermogravimetric analyzer. The sample was heated at a constant heating rate of 10 °C/min from room temperature to 450 or 500 °C. The furnace was purged with N2 gas flowing at a rate of 25 cm3 min-1. Registered mass losses are adequate to solvents content in the crystals (see the SI file, where the available TGA curves have been deposited as Figures S16-S19). The solvent content in the samples from TGA experiments was calculated directly from the percentage of the mass loss. Based on weighing accuracy for Discovery TGA, which is 0.1%, and using a type B evaluation of standard uncertainty for one measurement, we have determined the mass percent error of 0.2%. Calculation details were deposited as Supporting Information. RESULTS

Chemical formulas of the investigated host molecules are shown in Chart 1. Crystal and structure refinement data are listed in Table S1. All investigated compounds display lattice inclusion properties. The molecules form two- and three-component crystals mostly in a 1:1 or 1:1:1 H:G ratio, but polar molecules such as acetonitrile, DMSO, DME and ethanol provide higher host to guest ratio. All this information has been accumulated in Figure 1. Structural characterization of the host molecules

The host molecules as present in crystals of the investigated series are displayed in Figure 1. These include ditrityl derivative of (R,R)-N,N'-cyclohexane-1,2-diyldiacetamide (1) and its


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modifications that involve N-methylation (2), introduction of a double bond to the cyclohexane skeleton (3) and extension of the tritylacetamide chain by insertion of a pair of additional carbon atoms, connected to the Tr group by either double (4) or single (5) C-C bond. The crystal structure of 3 has been investigated in a form of a racemic compound (rac3), all other crystals were enantiomerically pure.

Like in our previous reports24,25 conformation of the bis(triphenylacetamides) has been described by a set of torsion angles α, β, γ, δ, ζ and ω, defined in Chart 1. The angles α (H-C*N-C(=O)) and β1 – β3 (O=C-C-Cipso) characterize the spatial arrangement of atoms around the amide groups. Conformation of the trityl group was described by a set of three twist angles γ1 – γ3 (C(=O)-C-Cipso-Cortho) lying in the range of -90 to 90°, with γ1 corresponding to the lowest and γ3 to the highest absolute value of γ. Qualitatively, conformation of each phenyl ring in a given trityl group has been defined by its helicity which can be either M (-90° < γ < 0°), P (0° < γ < 90°) or 0 (for γ angles deviating from zero by no more than ±7°). In amides 4 and 5 the torsion angle δ (O=C-C=C or O=C-C-C) characterizes orientation of the C=O group relative to the double or single C-C bond connected to the Tr group while angle ζ describes the conformation/configuration around the extra carbon-carbon bond. The ω torsion angle (N-C*C*-N) defines mutual orientation of the nitrogen atoms attached to the stereogenic centers, which is always minus synclinal (-sc) due to the uniform chirality of presented molecules, including the one which is a component of the racemic crystal of 3. The X-ray single crystal data that characterize the molecular structures of the investigated compounds 1-5 as present in crystals at 130K has been compared in Tables S2 and S3 with the analogous values calculated for the lowest energy conformers obtained at the B3LYP/6-311G(2d,2p) level (vide infra). In crystals, the conformation of the host molecules associated with the α torsion angle is nearly uniformly synperiplanar (sp), approaching the synclinal (sc) orientation only in two out of 17 cases. The antiparallel or close to antiparallel orientation of C=O and C-H dipoles



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allows existence of attractive 1,3-dipolar C-H/O=C interactions that stabilize this sp conformation as well as the s-cis conformation of the conjugated system of double bonds in 4 and the analogous system of bonds in 5. (Figure 1). Conformation defined by a set of β angles depends on the nature of the amide (secondary 1 vs tertiary 2). In 1 and its analogues 3-5 the carbonyl group is oriented sc with respect to two phenyl rings of the trityl moiety and antiperiplanar (ap) with respect to the third, so the set of three β angles describes a combination (in random order) of sc/sc/ap orientations. In 2, having methyl groups attached to the nitrogen atoms, the carbonyl group is oriented sp (β3 value close to 0°) with respect to one of the three phenyl rings of the trityl moiety, and the remaining two β angles assume values indicative of the anticlinal (ac) conformation leading to a ac/ac/sp combination. The Tr unit approximates to a distorted C3 symmetry. The propeller has the all-positive helicity (PPP) in all but one (1·DMSO) host molecules of 1 and 4. Due to the space group symmetry requirements, the inclusion crystals formed by 1 and 4 are built of host molecules that are both homochiral and homohelical. Although the molecule 2 has the same absolute configuration at the stereogenic centers as the molecule 1, in crystals it contains Tr groups in a distorted 0MM form. Having the same absolute configuration as 1 and 2, the molecule of 5 displays all-minus helicity (MMM), but again its inclusion crystals contain solely the molecules that are homochiral and homohelical. Only in the crystals of rac-3·CH2Cl2 there is an approximate object to mirror-image relationship between trityl groups within the same molecule. A substantial change in the symmetry of the Tr group from approximate C3 to Cs (compare the values of the γ angles), is observed in the crystal structure of 1·DMSO. Most likely, the conformational change of the Tr group is being forced by the included solvent molecule containing very strong hydrogen-bond acceptor – the sulfoxide group – that acts as mediator in joining together two amide units present in one molecule (Figure 2) (for a description of crystal packing see below).


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Figure 2. DMSO solvent molecules penetrate deeply into the host molecules and by doing so

enforce conformational change of the Tr groups. Some hydrogen atoms have been omitted for clarity.

Chirooptical properties of molecules 4 and 5 and the mechanism of the intramolecular chirality transfer

The observed influence of the included gest molecules on the conformation of the host indicates that, in the solid state, the expected transfer of chirality from the permanent stereogenic center (inductor) to the flexible Tr group (reporter)24 can be affected by crystal packing and/or by the presence of a specific guest molecule. Thus, the X-ray data alone may not give the right answer to the question about the mechanism and the sense of induced chirality (helicity) within the triphenylmethyl unit. However, our recent literature reports clearly demonstrate that the chirality transfer phenomenon from the stereogenic center to the conformationally flexible trityl moiety can be conveniently detected and interpreted by simultaneous use of experimental electronic circular dichroism (ECD) method supported by



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theoretical calculations.23-25,36-38 Since the chirality transfer within 1, 2 and (R,R)-3 was studied in details previously and this manuscript deals mainly with inclusion properties of 1-5, we shall only briefly discuss the chiroptical/structural properties of amides 4 and 5 in solution (remaining details are deposited in SI). Due to significant elongation of the distance between inductor and reporter in 4 and 5, we expected very small chiroptical response of the Tr groups to chiral environment. Surprisingly, the ECD spectra measured for 4 and 5 in non-polar cyclohexane show intense Cotton effects (CE's) within the 250–185 nm range, typical for Tr chromophore (Figure 3). Measured for 4 and 5 the CE's amplitudes are comparable with those measured for optically pure 1-3 in which the reporter Tr units are attached directly to the C=O groups.

The

sequence

of

the

CE's

is

opposite

for

the

two

derivatives

i.e.

positive/negative/positive for 4 and negative/positive/negative for 5, which suggests opposite helicities of the reporter units in the two amides. This indeed takes place in crystals of 4·EtOH·H2O and 5·EtOH·H2O but might not necessarily mirror the preferences of these

molecules in solution. In order to compare the solid state and ‘in silico’ conformations of the two molecules and to explain such unexpectedly effective chirality transfer we performed extensive DFT calculations on structure and chiroptical properties of amides 4 and 5 (see SI for details).


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Figure 3. Experimental (solid black lines) and calculated ∆E-(solid blue lines) and ∆∆G-

Boltzmann averaged (dashed blue lines) ECD spectra of amides 4 and 5. The calculated ECD spectra were wavelength corrected to match experimental UV absorption bands.

The relative ∆E and ∆∆G° energies calculated at the B3LYP/6-311G(2d,2p) level and percentage populations of individual conformers for 4 and 5 were collected in Table 1, whereas structural parameters that characterize these structures were collected in Table S3. Data from Table 1 suggested dominant population of conformer no. 11 for 4 and no. 16 for 5 in conformational equilibriums (note, conformers are numbered according to their appearance during conformational search). These conformers have dominant contribution to calculated ECD spectra, therefore further discussion was limited only to these two representative structures. Figure 4 illustrates the lowest energy conformers of 4 and 5 with indicated



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attractive interactions responsible for chirality transfer. Quite surprisingly, comparison of the lowest energy structures for 4 and 5 with their solid state counterparts revealed substantial conformational differences between the more rigid molecules of 4 and close similarities between the more flexible molecules of 5. Conformation described by the α angles is sc for both low energy conformers of 4 and 5, but the sets of β angles in the two structures are different (Table S3). This is in contrast with the situation observed in crystals of 4 and 5, where this molecular fragment displays similar conformation, closely resembling the lowest energy conformer of 5. The α,β-unsaturated fragment in conformer no 11 of 4 appears in less energetically favored s-cis conformation, both in the crystal and in the calculated structures. Similar situation is found for 5, in which the hyperconjugated O=C-C-C fragment contains the C=O bond oriented antiperiplanar with respect to one of the two C-H bonds and in bisecting position with respect to the C-C and the other C-H bond.39 For both amides, the carbon chains adopt the ap conformation. The conformational properties of the sub-molecular fragments are mainly controlled by the formation of cascades of 1,3-dipolar C-H/O=C and CH···π interactions within molecules. These attractive interactions cause carbon-chain stiffened and are responsible for effective chirality transfer from the permanent point stereogenic center to the flexible trityl unit. The conformation of carbon chain influences also the helicity of the trityl unit. For the lowest-energy conformers of 4 and 5 the two trityl groups in one molecule adopt the quasi-enantiomeric helicities, PPP and MMM in the case of conformer no. 11 of 4 and 0PP/0MM for conformer no. 16 of 5. Observed in ECD spectra of 4 and 5 the reversal of CE's sequence is apparently due to the zeroing of one of the γ angles in the reporter unit in the lowest-energy structure of 5. Similar effect was previously observed for chiral secondary and tertiary triphenylacetamides.24 Comparison of experimental ECD spectra with those calculated for 4 and 5 showed their almost perfect match thereby confirming the abovementioned structural studies. Note, that deconvolution of the ECD spectra for 4 ultimately


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confirmed the overwhelming contribution of the trityl chromophores to the calculated rotatory strengths (see SI for details).

Table 1. Total energies (in Hartree), relative energies (∆E, ∆∆G° in kcal mol-1) and

percentage populations calculated for individual conformers of amides 4 and 5 at the B3LYP/6-311G(2d,2p) level.

Amide[a]

Energy

4 (conf. 1)

∆E

Pop.

∆∆G°

Pop.

-2193.515921 1.93

3

2.67

4 (conf. 11)

-2193.518997 0.00

73

0.00

51

4 (conf. 20)

-2193.517971 0.64

24

0.03

49

5 (conf. 7)

-2195.97049

2.62

1.72

2

5 (conf. 12)

-2195.97082

2.41

0.99

8

5 (conf. 16)

-2195.97466

0.00

82

0.00

41

5 (conf. 22)

-2195.97323

0.90

18

0.39

21

5 (conf. 43)

-2195.96963

3.16

0.64

14

5 (conf. 55)

-2195.96984

3.03

1.28

5

5 (conf. 64)

-2195.96962

3.17

1.47

3

5 (conf. 93)

-2195.96973

3.1

1.17

6

[a] – conformers are numbered according to their appearance during conformational search



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Figure 4. Calculated structures of the lowest-energy conformers of amides 4 (a) and 5 (b).

Dashed lines indicate possible attractive interactions. Geometrical parameters describing these interactions are listed in Table S3. Some hydrogen atoms were omitted for clarity.

To sum-up this section we can say that in the crystal the conformational response of Tr groups to chiral environment formed by stereogenic centers within the cyclohexane skeleton is strongly affected by the presence of guest molecules, which form relatively strong hydrogen bonds with the carbonyl oxygens of the host, whereas in isolated molecule, in the non-polar environment, the chirality transmission is not disturbed and precedes solely through cascades of C-H/O=C and CH···π interactions. ECD studies supported by theoretical calculations together with X-ray diffraction study provide full information about structural dynamics of the chiral trityl derivatives of various kinds in both, the solid state and in solution. Types of host aggregates and host:host interactions (Table S5)

No intermolecular N-H···O=C hydrogen bond between host molecules is formed, which should be attributed to the great spatial hindrance of the Tr groups. Packing of the host molecules is frustrated by the six phenyl groups belonging to the two trityl functionalities that are attached to the rigid cyclohexane frame. By creating a space around themselves that


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prevents an approach of the neighboring molecules, the two trityl groups act as supramolecular protection groups with respect to the neighboring N-H amide functionalities, precluding their participation in the formation of the classical hydrogen bonds between the host molecules (Figure 5). As a consequence, the host molecules associate mainly via C-H···π interactions and less commonly via C-H···O interactions, which involve, respectively, from 65.2 to 73.7% and from 16.2 to 23.4% of the molecular surface of the host, as calculated using Crystal Explorer program.40-43 The relatively infrequent involvement of carbonyl oxygens in host:host interactions steams from their widespread engagement in host:guest (H:G) recognition (vide infra). In majority of cases, packing of the host molecules of 1 can be described as layered (Figure 6). The molecules in the neighboring layers are shifted with respect to the reference layer as a result of a single translation in crystals of triclinic symmetry (1·Me2CO, 1·MeCN) or a twofold screw axis operating in between the neighboring layers (1·H2O, 1·MeOH·H2O, 1·EtOH·H2O, 1·i-PrOH·H2O, 1·CHCl3, 1·CH2Cl2). A pair of the two-fold screw axis

related layers forms a bilayer with cyclohexane rings directed outwards and Tr groups directed inwards (Figure 6). Structural voids are created in between such bilayers related either by a single translation along the c-direction or a two-fold symmetry axis (1·DME·H2O). In binary inclusion compounds, the voids usually take a form of cavities (Figure 7a), while in ternary inclusion compounds they transform into undulated channels (Figure 7b). In general, channels are occupied by chain alcohol molecules while water molecules are attached to them by hydrogen-bonds at places where the channels protrude, but in the two-component crystals of 1·CHCl3 the bulky solvent molecules are situated in 1D channels, rather than cavities (Figure 7). It is interesting to note that the walls of the channels are lined with hydrogen atoms, whereas the cavities also comprise oxygen atoms at the walls. In majority of cases the ternary crystals of 1 are isostructural (Table S1) but the lack of



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isostructurality of crystals of 1·H2O and 1·DME·H2O does not diminish the layer-packing. The appearance of the channels leads to significant separation of the neighboring bilayers, which in the absence of one of the two types of the guest molecules are brought much closer together (Figure 6). This is reflected in changes of the c lattice parameter in monoclinic crystals from 21.7871(5) Å (1·i-PrOH·H2O) to 18.9673(2) Å in 1·H2O.

Figure 5. Space-filling representation of 1 to show the complete entombment of the N-H

amide functionality.


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Figure 6. Layer packing of the host molecules (layers distinguished by colors) and relative

orientation of bilayers in channel (a) or cavity (b) – (d) forming crystals of 1·MeOH·H2O, 1·EtOH·H2O, 1·i-PrOH·H2O, 1·CHCl3 (a), 1·CH2Cl2 (b), 1·H2O (c) and 1·DME·H2O (d).

Channels are marked by arrows. Hydrogen atoms have been omitted.


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Figure 7. Packing of the host molecules in the crystals of 1·CH2Cl2 and 1·CHCl3

exemplifying formation of either cavities (a) or channels (b) filled by the respective solvent molecules. View along the a lattice directions.

Modifications of the host molecule 1, i.e. N-methylation (2) or flattening of the cyclohexane ring combined with the loss of the crystal’s chirality (rac-3), as well as extension of the triphenylacetamide fragment by the two-carbon chain (4 and 5) introduce certain modifications to the mode of association of the host molecules, but the inclusion ability of these sets of crystals is still valid.

Chemical characteristics of the guest molecules and types of H:G interactions (Table S6)

The guest molecules usually form hydrogen bonds with the host molecules by acting as donors to the carbonyl oxygens or as acceptors of hydrogen bonds mainly from the host C-H groups and rarely from the N-H groups. Both cavities and channels accept only polar solvents (both protic and non-protic); crystallization from n-hexane and cyclohexane yielded always hydrated crystals. Attempts to include larger molecules as guests, e.g. longer-chain alcohol molecules (n-butanol, sec-butanol), diethyl ether, dimethylformamide, or chiral molecules have so far been unsuccessful. In the three-component crystals, solvent molecules are hydrogen-bonded to each other as well as to the host molecules (Figure 8), while in twocomponent crystals hydrogen bonding takes place only between the host and the guest molecules. The rare involvement of the N–H group takes place in 1·Me2CO, 1·DMSO and in H2O+EtOH inclusion compounds of 4 and 5. Where only one of the two N-H groups is involved in hydrogen bonding, no drastic changes in the molecular conformation of the host are observed but the engagement of both N-H groups in hydrogen bonds induces noticeable


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changes in the shape of the Tr groups, which either lose the propeller shape (1·DMSO) (Figure 2) or change the helicity from the commonly observed in the investigated crystals PPP/PPP combination to a much less frequent MMM/0MM form thus diminishing the percentage of the unit cell volume occupied by the solvent molecules to only 5.3% in 5·EtOH·H2O. This can be achieved because of an increased flexibility of the host molecule,

which, compared to the parent molecule 1, has a prolonged aliphatic chain and altered helicity of the Tr chromophores. It follows from the above that an obstruction of the N-H functionality by the neighboring Tr group can partially be released by chemical modification of the host molecule or upon incorporation into the crystal lattice of an ‘aggressive’ type of solvent. Acetonitrile molecules well accommodate in crystal cavities and, due to their small size, possess an ability to form inclusion compounds of higher than 1.0 host:guest ratio without causing any drastic changes in the molecular conformation of the host. Inclusion of acetonitrile molecules gives two different cavities of different sizes existing both in one crystal (Figure 9).

Figure 8. Comparison of the arrangement of water and ethanol molecules in the three-

component crystals of 1 (a), 4 (b) and 5 (c) and types of hydrogen-bonded supramolecular



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aggregates. Note the involvement of N-H groups in hydrogen bonds to guest molecules in crystals of 4 and 5 containing host molecules with the elongated carbon chain. In 5 intramolecular amide···amide interactions are realized via mediating water molecules. Some hydrogen atoms have been omitted for clarity.

Figure 9. Two types of cavities filled by the same type of guest molecules in the crystal

structure of 1·MeCN.

CONCLUSIONS

The reported crystal structures combine several elements, all of which play a vital role in generating the inclusion properties. (a) The two trityl groups present in a single host molecule encourage crystal assembly using dispersion and aryl edge-to-face (EF) interactions, which involve, respectively, from 65.2 to 73.7% and from 16.2 to 23.4% of the molecular surface of the host. (b) The central cyclohexane (or cyclohexene) ring links two Tr-amide wings and creates a U-shaped molecule with approximate C2-symmetry. Each individual molecule is handed and the bulk sample is handed (with the exception of rac-3·CH2Cl2). The linking cycle is rigid but the side chains permit a certain degree of conformational twisting so the host can adapt and accommodate guest molecules of differing sizes and shapes. For this reason, the molecular


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conformation in crystal differs from the one adopted by the energetically most favorable isolated molecules 4 and 5. (c) The amide substituents are crucial in switching the trityl helicity from PPP to 0MM but this may also occur as a result of an increased flexibility of the side chain. Also strong hydrogen-bond acceptors as guests are able to modify the helicity of the Tr group. (d) Two types of recognition element are independently involved in guest binding. The first is a hydrogen bond accepting carbonyl groups of the host, which interact with several binding sites inside the cage associated with the set of CH groups and water or alcohol molecules as H-bond donors. The second, far less frequently used recognition element is the amide N–H group, which acts as a donor to these solvent molecules that contain strong hydrogen bond acceptor, i.e. carbonyl or sulfoxide oxygen or, very rarely (only one case), the hydroxyl oxygen. (e) In the absence of strong hydrogen-bond accepting guest molecules, the Tr group significantly restricts the role played by the N–H groups in hydrogen bonding and by doing so it acts as a supramolecular N–H protection group. (f) Guest molecules significantly affect transfer of chirality from the stereogenic centers to the Tr units, which is normally achieved by a cascade of C-H/O=C and CH···π interactions within an individual molecule. (g) The substances obtained are new inclusion forming host compounds featuring cavities and channels of diverse diameters.



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Supporting Information

The Supporting Information is available free of charge on the ACS Publications website at DOI: xxx. Accession Codes

CCDC 1528524-1528538 contain the supplementary crystallographic data for this paper. These data are provided free of charge by The Cambridge Crystallographic Data Centre. Corresponding Author

*[email protected] Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ACKNOWLEDGMENT

Authors are thankful to A. Janiak, Department of Chemistry, Adam Mickiewicz University for performing TGA experiment of 1·H2O, 1·Me2CO, 1·DMSO, 1·DME·H2O. This work was supported by research grant from National Science Center (NCN) Poland, UMO-2016/21/B/ST5/00100. All calculations were performed in Poznan Supercomputing and Networking Center (grant no 217). ORCID ID Urszula Rychlewska 0000-0002-6835-1734; Marcin Kwit 0000-0002-7830-4560; Jadwiga Gajewy 0000-0003-0638-9646



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For Table of Contents Use Only:

Trityl group as crystal engineering tool for construction of inclusion compounds and for suppression of amide NH···O=C hydrogen bonds. Wioletta Bendzińska-Berus, Beata Warżajtis, Jadwiga Gajewy, Marcin Kwit and Urszula Rychlewska* Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznań, Poland.

Originally designed for intramolecular chirality transfer, ditrityl derivatives of (R,R)-N,N'cyclohexane-1,2-diyldiacetamide offer interesting solid state supramolecular applications: the molecules can be utilized for construction of inclusion compounds and for suppression of amide aggregation by hydrogen bonds thus enhancing their solubility.


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Trityl Group as an Crystal Engineering Tool for Construction of

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