Molecular structure and selective theophylline complexation by conformational change of diethyl N,N′-(1,3-phenylene)dicarbamate

The diethyl N,N′-(1,3-phenylene)dicarbamate–theophylline (1–TEO) complex was obtained by mechanochemistry involving the conformational change of one of the ethyl carbamate groups of 1 from the endo conformation to the exo conformation to allow the formation of intermolecular interactions.


Introduction
Host-guest complexes are supramolecular species formed by two or more molecules or ions stabilized by noncovalent interactions (principally hydrogen bonds) involving molecular recognition between the functional groups of both.A host (or receptor) is a molecule with a cavity suitable for guest binding.The design of molecular receptors involves an understanding of the intermolecular interactions using building blocks with functional groups that allow the binding of specific guests (or substrates).The study of host-guest complexes in solution and the solid state has allowed its application in various fields, such as drug delivery systems (Wankar et al., 2020), molecular diagnostics (Yu & Chen, 2019), biomaterials (Webber et al., 2016), artificial molecular machines (Erbas-Cakmak et al., 2015), sensors (Kim et al., 2012) and biosensors (Lim et al., 2021).
Molecules with the amide group [R 0 -NH-(C O)-R] have been used in the design of molecular receptors due to their ability to act as a donor and acceptor of hydrogen bonds in the formation of supramolecular complexes.These amide receptors have been exploited in a cyclic and acyclic manner using functionalities such as carboxamides (Bondy & Loeb, 2003), ureas (dos Santos et al., 2008), oxalamates (Gonza ´lez- Gonza ´lez et al., 2014), amino acids (Kubik & Mungalpara, 2017) and carbamates (Saucedo-Balderas et al., 2015), which have been studied in the formation of supramolecular complexes with anions, polyphenols, amino acids and pharmaceutical ingredients (Siering et al., 2006).
The chemical structure of phenyl carbamates includes carbonyl (C O) and amino (N-H) groups, which can form inter-and intramolecular hydrogen-bond interactions.Also �-interactions can be formed by the phenyl ring (Matos ˇevic ´& Bosak, 2020).Supramolecular studies of phenyl carbamates (Shahwar et al., 2009;AaminaNaaz et al., 2017) are focused on the self-assembly of crystal structures, revealing that the N-H� � �O C hydrogen-bond interaction drives the supramolecular architecture in the solid state, leading to the formation of supramolecular chains in phenyl carbamate derivatives, and supramolecular columns in phenylenebiscarbamates (Garcı ´a-Ba ´ez et al., 2004;Lu et al., 2005a,b).
Theophylline (bronchodilator) and caffeine (nervous system stimulant) are pharmacologically active molecules (Boushey, 2012) that possess functional groups (C O and N-H in only TEO) capable of forming noncovalent interactions which have been applied in the development of molecular receptors for the molecular recognition of TEO and CAF due to its potential biomedical and industrial applications (Sahoo, 2015).
The formation of supramolecular complexes has allowed the identification and quantification of compounds of pharmaceutical interest.To evaluate the ability of diethyl N,N 0 -(1,3-phenylene)dicarbamate (1) as a receptor to form hostguest complexes, we report here the mechanochemical complexation of 1 with theophylline (TEO) and caffeine (CAF) (Scheme 1).The obtained 1-TEO complex was prepared by solvent-assisted grinding and was characterized by IR spectroscopy (IR), powder X-ray diffraction (PXRD) and solidstate 13 C nuclear magnetic resonance (NMR).The molecular structure was obtained by single-crystal X-ray diffraction.

compounds
1,3-Phenylenediamine, ethyl chloroformate, triethylamine, tetrahydrofuran (THF) anhydrous, dimethyl sulfoxide (DMSO) anhydrous and theophylline anhydrous were purchased from Aldrich.Chloroform, dichloromethane, methanol and acetonitrile of ACS grade were purchased from Quı ´mica Mayer.Caffeine was purchased from BASF.All the reagents were used as received.

Synthesis of diethyl N,N 0 -(1,3-phenylene)dicarbamate, 1
A mixture of 1,3-phenylenediamine (3.0 g, 27.7 mmol) and triethylamine (61.0 mmol, 8.5 ml) in tetrahydrofuran (THF, 250 ml) was placed in an ice bath.After 10 min of stirring, ethyl chloroformate (5.3 ml, 61.0 mmol) was added dropwise.The mixture was stirred for 24 h at room temperature and then filtered to obtain a THF solution which was evaporated to dryness.The obtained solid was solubilized in chloroform and filtered to separate the insoluble solid.The chloroform solution was evaporated to obtain a solid corresponding to compound 1.

Mechanochemical synthesis and crystallization
A mixture in a 1:1 molar ratio of 1 (0.30 g, 1.18 mmol) and TEO (0.21 g, 1.18 mmol) was placed in a porcelain mortar.Before starting the grinding with a pestle, 0.5 ml of dichloromethane was added and the mixture was ground for 3 min.At the end of the grinding time, the dichloromethane was evaporated and the ground powder was collected in the centre of the mortar.The cycle of adding 0.5 ml of dichloromethane and grinding for 3 min was repeated three more times until 12 min of grinding time was completed.After 12 min of grinding time, the obtained ground powder was stored in a glass vial.1-CAF ground powder was obtained by grinding 1 (0.30 g, 1.18 mmol) and CAF (0.22 g, 1.18 mmol) under the same conditions as described for the 1-TEO mixture.
Solutions of 1 and 1-TEO were prepared by dissolving the powder of 1 in DMSO and the ground powder of 1-TEO in a 1:1 methanol/acetonitrile mixture.Single crystals were obtained after evaporation of the solvent.
Solution 1 H and 13 C NMR spectra of 1 were recorded on a Bruker 400 Avance III spectrometer ( 1 H = 400 MHz and 13 C = 100 MHz) at room temperature (25 � C) using DMSO-d 6 as solvent and SiMe 4 as the internal reference (the NMR spectra of 1 are shown in Figs.S1 and S2 in the supporting information).Solid-state cross-polarization/magic angle spinning (CP/ MAS) 13 C spectra of 1, TEO and the polycrystalline ground powder of 1-TEO were recorded on a Bruker 400 Avance III ( 13 C = 100 MHz) instrument at 25 � C, using 4 mm bullet-type Kel-F zirconia rotors with a spinning rate of 8 kHz and an acquisition time of 32 ms.The recycle time of the pulse was 3 s.An adamantane signal was used as the external reference (� = 38.48ppm).Processing of the NMR spectra was performed with MestReNova software (Version 14.2.0-26256;Mestrelab Research, 2021).Elemental analysis of 1 was performed using a vario MICRO Cube CHN(S) analyzer (Fig. S3 in the supporting information).
The melting point (m.p.) of 1 was measured using an Electrothermal IA9300 apparatus and is uncorrected.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 1.The H atoms of the amine group (H-N) were located in a difference map and refined isotropically with U iso (H) = 1.2U eq (N) for H-N hydrogens.H atoms attached to C atoms were placed in geometrically idealized positions and refined as riding on their parent atoms, with C-H = 0.93-0.99A ˚and U iso (H) = 1.2U eq (C) for aromatic and methylene groups, and 1.5U eq (C) for methyl groups.

IR spectroscopy
The IR spectra of 1, TEO and CAF (Gonza ´lez-Gonza ´lez et al., 2017) were compared with the IR spectra of the polycrystalline ground powders (1-TEO and 1-CAF) and the single crystal of 1-TEO (the IR frequencies are listed in Table 2).The formation of the 1-TEO powder complex was evidenced by the shift of the N-H and C O stretching bands in the IR spectrum of the 1-TEO ground powder with respect to the starting compounds, suggesting the formation of intermolecular N-H� � �O C hydrogen bonds (Fig. 1).On the other hand, the IR spectrum of the 1-CAF ground powder did not show shifts with respect to the starting materials, suggesting that the formation of the 1-CAF complex was not favored under mechanochemical conditions.
The IR spectrum of the 1-TEO powder complex and the IR spectrum of the single crystal were similar, indicating a structural homogeneity between the powder and the single crystal.The IR spectrum of 1 showed a single N-H band at 3283 cm À 1 .After the formation of the complex, the N-H band was red-shifted and split (suggesting asymmetry in the molecule) into two bands with values of 3312 and 3293 cm À 1 [��(N-H) = 10 and 29 cm À 1 , respectively].The N-H band of TEO was also red-shifted as a consequence of the complex formation from 3120 to 3169 cm Concerning the carbonyl frequencies, compound 1 showed two bands at 1704 and 1688 cm À 1 , with ��(C O) = 12 and À 4 cm À 1 .Theophylline showed ��(C O) = À 5 and À 24 cm À 1 .
The grinding process reorders the hydrogen-bonding patterns of the compounds involved in the formation of the complex shifting the C O and N-H bands.Compound 1 is self-assembled by N-H� � �O C hydrogen bonds [C(4) homosynthon] in the free form (see Single-crystal X-ray diffraction, x3.4).After the formation of the 1-TEO complex, the N-H� � �O C hydrogen-bond (heterosynthon) pattern is maintained; this explains the smaller values of ��(N-H) and ��(C O) compared with the starting 1.On the other hand, in the free form of TEO, the molecules are interlinked by N-H� � �N(imidazole) hydrogen bonds and �-interactions (Larkin et al., 2014)

Powder X-ray diffraction
The powder X-ray diffraction patterns of the polycrystalline powder of 1, solid TEO and CAF, and the polycrystalline powder of 1-TEO and 1-CAF were obtained.The solid form of TEO and CAF were identified as form II (Liu et al., 2013;Mazel et al., 2011) of each compound from the experimental powder diffraction pattern.The recorded powder pattern of 1 was similar to that simulated with Mercury (Macrae et al., 2020) (Fig. S4), indicating structural homogeneity between the polycrystalline powder and the single crystal.The formation of the polycrystalline complex was evidenced because the PXRD crystallography in latin america Figure 1 The IR spectra of (a) 1, (b) TEO, (c) the polycrystalline powder of 1-TEO after 12 min of grinding, (d) a single crystal of 1-TEO, (e) CAF and (f) the ground powder of 1-CAF.

Figure 2
Hydrogen-bond patterns in free TEO.
diffraction pattern of the 1-TEO polycrystalline ground powder was different compared with those of the starting materials (Fig. 3), showing new diffraction peaks at 2� = 7.7, 14.8, 16.7 and 23.4 � , and was similar to that simulated with Mercury (Macrae et al., 2020).The absence of the signals at 2� = 19.6 and 12.5 � of starting 1 and TEO, respectively, in the powder pattern of 1-TEO indicates the complete transformation of 1 and TEO to form the complex (Fig. 3).The PXRD pattern of 1-CAF showed a combined pattern of 1 and CAF as a physical mixture [Fig.3(f)] thus showing that the 1-CAF complex was not formed.

Solid-state 13 C NMR
The solid-state 13 C NMR spectra of 1, TEO and the 1-TEO powder complex were recorded (Fig. 4) and the 13 C NMR assignments are listed in Table 3.Most of the signals in the 13 C NMR spectrum of the 1-TEO complex appeared shifted with respect to the starting compounds as a result of the change in the chemical environment due to the rearrangement of the hydrogen-bond patterns.The C O signals were shifted from 155.9 to 154.5 ppm in 1 and from 150.9 to 151.9 ppm in TEO, indicating the formation of C O� � �H-N hydrogen bonds between 1 and TEO.It worthy of mention that in the solidstate 13 C NMR spectrum of 1, only half of the signals were observed, indicating the presence of a C 2 symmetry axis, which is consistent with the endo-endo conformation of 1, as confirmed by single-crystal diffraction.Meanwhile, in the solid-state 13 C NMR spectrum of the 1-TEO complex, the signals of C10 and C11 from the ethyl group, and also the aromatic C4 and C6 signals, appeared split (Table 3), suggesting two crystallographically different ethyl groups originated from the adoption of the exo-endo conformation after the formation of the 1-TEO complex.
The 1-TEO complex crystallized in the triclinic space group P1, the discrete unit consist of one molecule of 1 and one molecule of TEO [Fig.7 (a

Conformational change of 1 and selective binding of TEO
The molecular structure of starting 1 adopts the endo-endo conformation, showing a single N-H band in the IR spectrum and half of the signals in the solid-state 13 C NMR spectrum.The formation of the 1-TEO complex by mechanochemical grinding involves the conformational change of 1 from the endo-endo conformation to the exo-endo conformation (showing two N-H bands in the IR spectrum and the split of the ethyl signals in the solid-state 13 C NMR spectrum of 1-TEO), while the grinding of 1 and CAF under the same conditions used to obtain 1-TEO did not result in the formation of the 1-CAF complex.
In the endo-endo conformation, a potential carbonylcarbonyl repulsive effect avoids the complex formation by adopting a 'locked' state (Fig. 9).The formation of the 1-TEO complex implies that grinding provides the energy necessary

Figure 8
The observed synthons in TEO cocrystals.
for the rotation of one of the ethyl carbamate groups to adopt the exo-endo conformation of the 'unlocked' state (Fig. 9) [conformational change after complexation from the exo to the endo conformation (Gonza ´lez-Gonza ´lez et al., 2014), and from the endo to the exo conformation (Gonza ´lez-Gonza ´lez et al., 2015) is also observed in the formation of molecular complexes of diethyl N,N 0 -1,3-phenylenedioxalamates with 1,3-benzenediols], allowing the formation of intermolecular hydrogen bonds between 1 and TEO.On the other hand, the IR spectrum and the PXRD pattern of the 1-CAF ground mixture indicated that the 1-CAF complex was not formed and receptor 1 remains in the 'locked' state (endo-endo conformation).
To obtain information about the possible mechanism of the conformational change of 1 to form the 1-TEO complex and the preference of receptor 1 to link TEO over CAF, firstly, the mechanochemical grinding of 1 (in the endo-endo form), under the same conditions to obtain the 1-TEO complex (12 min of grinding time adding dichloromethane), was performed.The IR spectrum of 1 after 12 min of grinding time remained unchanged (Fig. S6 in the supporting information), indicating that the mechanochemical energy of the grinding is not able to drive the conformational change of free 1.A second strategy was to perform the mechanochemical grinding of 1 and TEO without solvent to retard the formation of the complex, and compare the IR spectra of the obtained ground powder with the IR spectrum of the physical mixture and with the IR spectrum of the 1-TEO single crystal (Fig. 10).The IR spectrum of the physical mixture showed the N-H bands at 3283 cm À 1 for 1 and at 3119 cm À 1 for TEO; meanwhile, the C O bands were observed at 1704 and 1688 cm À 1 for 1, and at 1665 for TEO.After 3 min of 'dry' grinding, the obtained IR spectrum showed two N-H bands: a shoulder band at 3314 cm À 1 (N-Ha) and the principal N-H band of 1 at 3287 cm À 1 (N-Hb).The presence of two N-H bands of 1 (as in the IR spectrum of the 1-TEO single crystal) indicates the asymmetry of the molecule by the conformational change of one of the ethyl carbamate fragments, adopting the exo-endo conformation.The carbonyl region showed three bands: (i) a band at 1704 cm À 1 (C Oa) belonging to 1; (ii) a band at 1667 cm À 1 (C Ob) for TEO; and (iii) a band at 1640 cm À 1 (C Oc) which is present in the 1-TEO complex.Here, the C Ob band is slightly more intense than C Oc, indicating that after 3 min of grinding, part of TEO remains free, and the complex has started to be formed.The IR spectra obtained after 6, 9, 12 and 15 min of 'dry' grinding showed the following: the intensity of the N-Ha band increased as a signal of the formation of the complex and the N-Hb band was red shifted; the intensity of the C Oa band remained unchanged.As the 1-TEO complex was formed, the intensity of the C Ob band of TEO at 1668 cm À 1 decreased; meanwhile, the intensity of the C Oc band increased.This indicates that the presence of TEO and the mechanochemical grinding induces the rotation of the ethyl carbamate group of 1 and 'unlocks' the endo-endo conformation to allow the formation of intermolecular interactions between 1 and TEO to form the complex (Fig. 9).The formation of the (TEO)-N-H� � �O C(1) hydrogen-bond interaction acts as the 'key' that unlocks the endo-endo conformation and then the ethyl carbamate group rotates (to the 'unlocked' state) to allow the formation of the rest of the intermolecular interactions and form the diamide-pseudoamide R 2 2 (13) synthon in the exoendo conformation (Fig. 9).On the other hand, CAF is unable to form the N-H� � �O C 'key' hydrogen bond because it possesses an N-CH 3 group instead of the N-H group in TEO, avoiding the formation of the 1-CAF complex in the same way as 1-TEO (almost coplanar with respect to the plane of the benzene ring).It is important to mention that in the urea-CAF cocrystal and the host-guest complexes of CAF with triphenylene ketal triurea-based receptors, CAF acts as a hydrogen-bond acceptor, forming N-H� � �O� � �H-N and N-H� � �N� � �H-N hydrogen bonds where the urea group is positioned perpendicular with respect to the plane of the CAF molecule, unlike the 1-TEO complex where 1 and TEO are coplanar (MacFhionnghaile et al., 2020;Fiammengo et al., 2003;Schopohl et al., 2005).

Conclusions
The ability of receptor 1 to form host-guest complexes with TEO and CAF by mechanochemistry was evaluated, resulting only in the formation of the 1-TEO complex involving a conformational change of 1, in which one of the ethyl carbamate groups changes from the endo conformation to the exo conformation to allow the formation of noncovalent interactions between 1 and TEO.An IR spectroscopy study revealed that the (TEO)N-H� � �O C(1) hydrogen bond triggers the rotation of the ethyl carbamate group from the endo conformation to the exo conformation.The formation of the 1-CAF complex was not possible because CAF possesses an N-CH 3 group instead of the N-H group in TEO, thus avoiding the formation of the N-H� � �O C hydrogen bond.The formation of 1-TEO was evidenced by the shift of the N-H and C O frequencies in the 1-TEO powder complex, and by the shifts in the solid-state 13 C NMR signals compared with the IR and 13 C NMR spectra of the starting materials, suggesting the formation of N-H� � �O C hydrogen bonds.The formation of the new polycrystalline phase was confirmed because the powder X-ray diffraction pattern of 1-TEO was different from those of the starting 1 and TEO.Single-crystal X-ray diffraction analysis showed that 1 adopts the endo-endo conformation in the solid state and is self-assembled by N-H� � �O C hydrogen bonds; meanwhile, the molecular structure of the 1-TEO complex showed a 1:1 stoichiometric ratio, where 1 and TEO are interlinked by N-H� � �O C hydrogen bonds and C-H� � �O interactions, and 1 adopts the exo-endo conformation, exhibiting the diamide-pseudomide

Special details
Geometry.All esds (except the esd in the dihedral angle between two l.s.planes) are estimated using the full covariance matrix.The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry.An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s.planes.
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å

Special details
Geometry.All esds (except the esd in the dihedral angle between two l.s.planes) are estimated using the full covariance matrix.The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry.An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s.planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å
(Fig. 2).The rearrangement of these hydrogen-bond patterns to form a new hydrogen-bond pattern results in greater ��(N-H) and ��(C O) values of TEO with respect to the ��(N-H) and ��(C O) values of 1.

Figure 5 (
Figure 5 (a) Possible conformations of the carbamate group and (b) possible conformations of 1.

Figure 6 (
Figure 6 (a) The molecular structure of 1, with displacement ellipsoids drawn at the 30% probability level, showing the intermolecular interactions.(b) The supramolecular arrangement of 1 formed by N-H� � �O C hydrogen bonds.Dashed lines represent hydrogen bonds.Some parts of the molecules have been omitted for clarity.Dashed lines represent hydrogen bonds.
Figure 7 (a) The asymmetric unit, with displacement ellipsoids at the 30% probability level, of 1-TEO, showing the atom numbering.(b) The supramolecular sheet of 1-TEO formed by the N27-H27� � �O2C iv and C8C-H8C� � �O8 v interactions.(c) �-� and C-H� � �� interactions found in 1-TEO.Some parts of the molecules have been omitted for clarity.Dashed lines represent hydrogen bonds or noncovalent interactions.

Figure 9
Figure 9Conformational change of 1 in the formation of the 1-TEO complex and the lack of conformational change of 1 in the 1-CAF ground mixture.

Table 1
Agilent, 2013)etails.Experiments were carried out with Mo K� radiation using a Agilent Xcalibur Atlas Gemini diffractometer.The absorption correction was analytical (CrysAlis PRO;Agilent, 2013).H atoms were treated by a mixture of independent and constrained refinement.
Notes: (*) under spectral resolution; (**) the apparent shift of the band is due the change of the curvedness of the C O band in the IR spectra.Values in brackets belong to the IR frequencies of TEO or CAF.