Experimental and theoretical studies of molecular complexes of theophylline with some phenylboronic acids

Abstract

Molecular complexes of the active pharmaceutical ingredient (API) theophylline, 1 with 4-halophenylboronic acids [4-chlorophenylboronic acid (a), 4-bromophenylboronic acid (b), 4-iodophenylboronic acid (c)], 4-hydroxyphenylboronic acid (d) and 1,4-phenylene-bis-boronic acid (e) have been reported. The complexes were characterized and analysed using the intensity data obtained by X-ray diffraction techniques. All the halo substituted boronic acid complexes are found to be isostructural (1.a, 1.b and 1.c) irrespective of the variations in size and electronegativity of halogen atoms while complexes with non-halogenated boronic acids, 1.d and 1.e, show distinctly different features between themselves as well as with that of 1.a–c, both in two and three-dimensional arrangements. Complexes 1.a–c are noted to be crystallized in the form of sheet structures, which are stacked in three dimensional arrangements, while channels and square grid networks are observed in 1.d and 1.e, respectively. Further the homomeric and heteromeric interactions which occur in the complexes have been analysed by a DFT-D3 method.

---

Introduction

In recent years boronic acids have received a lot of attention due to their wide range of applications – for example, as intermediates in various organic synthesis,^1–5 as sensors due to their ability to form reversible diol formation with glucose,^6–10 as reactants/substrates in the formation of boroxine networks,^11–14 etc. Also, boronic acids are well employed in medicinal chemistry as antibiotics,^15,16 for instance, in the treatment of tumors¹⁷ as well as inhibitors.^18–20 In recent times, boronic acids also have been used as building blocks in non-covalent synthesis for the synthesis of exotic supramolecular assemblies, as has appeared in the literature in the domains of both experimental as well as theoretical studies.^21–24

A noteworthy examples being molecular complexes of 1,4-phenylene-bis-boronic acid, 4-bromophenylboronic acid, 4-hydroxyphenylboronic acid, etc. which are resulted through the formation of preferentially by hetero-dimers formed by boronic acid with various aza-donor compounds.^25,26 Also, a recent report by some of us²⁷ indeed demonstrates the competitive nature of boronic acid functionality even in the presence of a strong hydrogen bonding donor group like hydroxyl (–OH) in the formation of exotic supramolecular assemblies with various aza donor compounds.

Another notable example that highlights the significance of boronic acids in supramolecular synthesis is the crystallization experiments performed on 4-carboxyphenylboronic acid, in which the boronic acid forms heterodimers with carboxylic acid group.^28–30 In fact, such experimental observations are corroborated with theoretical studies demonstrating that boronic acid heterodimers are energetically more favourable than their homodimers.^31–35

Realization of such a distinct self-assembled assemblies are attributed to the ability of –B(OH)₂ to yield syn–anti, syn–syn and anti–anti, and also ability to mimic strong hydrogen bond affinity functional groups like carboxylic acids (–COOH) and amides (–CONH₂).^26,28

Though boronic acids gained much interest as a co-crystal former in the development of myriad of supramolecular assemblies, theoretical studies performed on boronic acids mediated assemblies are very much limited.

In the parallel developments in the arena of supramolecular chemistry, in recent times, supramolecular synthesis is directed towards preparation of co-crystals with bio-active entities like Active Pharmaceutical Ingredients (APIs) as one of the components, to implant varied bioactivity for the APIs different from the native form. However, in such pharmaceutical co-crystals, boronic acids although possess effective bio properties have not been well explored except a few examples in recent years.³⁵

Thus, in this article, we present the experimental as well as theoretical studies of supramolecular assemblies of a pharmaceutically active bio-compound, theophylline, with some boronic acid as illustrated below in Chart 1. The theophylline is chosen as it is an effective drug used in the treatment of acute asthma,³⁶ apart from its use in tumour therapy^37,38 and as diuretic, but its effectiveness is hindered by its low stability, mainly due to the interconversion between its anhydrous and hydrate forms as a function of relative humidity (RH).

Chart 1

Thus, co-crystals of theophylline, 1 with some boronic acids – 4-chlorophenylboronic acid (a), 4-bromophenylboronic acid (b), 4-iodophenylboronic acid (c), 4-hydroxyphenylboronic acid (d) and 1,4-phenylene-bis-boronic acid (e) – have been prepared by solvent evaporation method of crystallization and characterized through X-ray diffraction techniques, keeping in view the propensity of these boronic acids in the formation of molecular complexes as exemplified by us in the literature.^26c,27 The energy of the heteromeric and homomeric interactions have been computed and compared using DFT calculations.

Experimental

All the chemicals have been purchased from Sigma-Aldrich with >99% purity and have been used without further purification. The solvents employed for the crystallization studies were of spectroscopy grade of highest available quality. All the molecular complexes 1.a–e were obtained by dissolving theophylline, 1 and the respective boronic acid, as the case may be, in a 1 : 1 ratio, in either water or ethanol solvents depending upon the solubility of solutes and kept it aside by covering it with aluminium foil to attain supersaturation environment. In all the cases, good quality crystals suitable for X-ray diffraction studies were obtained within 48 hours.

Molecular complex, 1.b, however, did not yield single crystals and the obtained microcrystalline solid was used for characterization by powder X-ray diffraction.

In a typical experiment, 90 mg of 1 (0.5 mmol) and 78 mg of a (0.5 mmol) were dissolved in about 15 ml ethanol by gently boiling the solution and kept aside. Good quality crystals are obtained within 24 hours which are utilized for single crystal diffraction studies.

Single crystal X-ray diffraction studies

The crystals of suitable dimension and good quality were chosen under a Leica microscope, equipped with a polarizer and a CCD camera. A crystal was glued to a glass fibre using an acrylate adhesive and placed on a goniometer of the Bruker single crystal X-ray diffractometer equipped with CCD area detector and a graphite-monochromated Mo-K_α radiation (λ = 0.71073 Å). The X-ray intensity data were collected at room temperature and the process was smooth in all the cases, and no additional precautions are necessitated, as the crystals were quite stable. The intensity data were processed using Bruker's suite of programs (SAINT),³⁹ and absorption corrections were applied using SADABS.⁴⁰ The structure solution of all the compounds have been carried out by direct methods and refinements were performed by full matrix least squares on F² using the SHELXTL-PLUS⁴¹ suite of programs. All the non-hydrogen atoms were refined anisotropically, while the hydrogen atoms are placed in either calculated positions or obtained from Fourier maps, are refined isotropically. Complete structure solution and refinement parameters are listed in Table 1. All the intermolecular interactions as listed in Table 2 were computed using PLATON.⁴²

Table 1 Crystallographic data for the supramolecular assemblies, 1.a, 1.c, 1.d & 1.e

Parameters	1.a	1.c	1.d	1.e
Formula	C7H8N4O2:C6H6BClO2	C7H8N4O2:C6H6BIO2	C7H8N4O2:C6H7BO3	2(C7H8N4O2):C6H8B2O4 : H2O
Mr	336.54	427.99	318.10	542.09
Crystal shape	Plate	Plate	Block	Plate
Crystal colour	Colourless	Colourless	Colourless	Yellow
Crystal system	Triclinic	Triclinic	Monoclinic	Triclinic
Space group	P1̄	P1̄	P21/c	P1̄
T, K	293(2)	293(2)	293(2)	293(2)
λ(Mo-Kα)/Å	0.71073	0.71073	0.71073	0.71073
a/Å	7.510(1)	7.475(1)	12.858(3)	8.528(2)
b/Å	9.471(2)	9.623(2)	8.215(2)	8.711(2)
c/Å	11.878(2)	11.957(3)	14.199(3)	9.661(3)
α/°	85.63(3)	87.25(1)	90	109.74(1)
β/°	79.47(4)	80.94(1)	98.03(4)	94.47(1)
γ/°	68.96(3)	71.63(1)	90	104.78(1)
V/Å^3	775.1(3)	806.1(3)	1485.1(5)	642.5(3)
Z	2	2	4	1
Dc/g cm^−3	1.442	1.763	1.423	1.401
μ, mm^−1	0.271	2.011	0.110	0.108
2θ range [°]	50.06	50.08	50.52	50.06
Limiting indices	−8 ≤ h ≤ 8	−8 ≤ h ≤ 8	−15 ≤ h ≤ 15	−10 ≤ h ≤ 10
	−11 ≤ k ≤ 11	−11 ≤ k ≤ 11	−9 ≤ k ≤ 9	−10 ≤ k ≤ 10
	−14 ≤ l ≤ 14	−14 ≤ l ≤ 14	−17 ≤ l ≤ 17	−11 ≤ l ≤ 11
F(000)	348	420	664	282
Total reflections	7555	3923	7220	6198
Unique reflections	2723	2626	2698	2268
Reflection at I > 2σ(I)	2716	2379	2021	1815
No. of parameters	248	236	244	213
R1, I > 2σ(I)	0.075	0.059	0.046	0.080
wR2, I > 2σ(I)	0.184	0.152	0.139	0.183
GoF on F^2	1.161	1.116	1.048	1.220
CCDC no.	1440006	1440007	1440008	1440009

---

Table 2 Hydrogen bond distances, [Å] and angles [°] observed in 1.a, 1.c, 1.d & 1.e^a

D–H⋯A	1.a			1.c			1.d			1.e
a Three columns for each structure represent H⋯A, D⋯A distances and ∠D–H⋯A angles, respectively, for a typical hydrogen bond, being represented as D–H⋯A.
O–H⋯O	2.11	2.81	150	2.11	2.79	167	1.85	2.74	153	2.06	2.86	162
							1.91	2.71	172
N–H⋯O	1.94	2.78	170	2.02	2.80	156	1.90	2.79	174	1.86	2.74	166
O–H⋯N	1.92	2.85	167	2.15	2.90	173	2.02	2.80	152	2.06	2.81	169
C–H⋯O	2.47	3.32	156	2.35	3.28	159	2.41	3.19	139	2.63	3.27	125
	2.53	3.33	149	2.54	3.33	151	2.57	3.52	170
C–H⋯X	2.84	3.67	144	3.11	3.92	144

---

Powder diffraction studies

X-ray powder diffraction (XPRD) data were collected on a PANalytical diffractometer with Cu-K_α radiation (λ = 1.54060 Å). X-ray generator set up at 40 kV and 30 mA was used to collect intensity data with a step size of 0.017° (2θ) in a continuous scanning mode. Diffraction patterns were collected in the 2θ range of 5–50° at room temperature.

DFT methodology

Theoretical calculations using DFT methods, implemented in NWChem,⁴³ have been performed on all the complexes to compute the strength of the hydrogen bonding. The association energy of hydrogen bonded dimers have been calculated by subtracting energy of isolated molecules from the total energy of hydrogen bonded molecular motif, by using DFT-D3 method by Grimme⁴⁴ with B3LYP⁴⁵ functional. The initial coordinates are taken from the single crystal diffraction data. Observed conformations have been used without further optimization. We have used 6-31G(3df,3pd) basis set for complexes 1.a, 1.c and 1.d while 6-311G** for 1.b complex and results obtained with these basis sets have been presented in similar studies.⁴⁶

Results and discussion

The co-crystals 1.a and 1.c–e, as specified in Chart 1, thus, obtained as described in preceding section, were characterized by single crystal X-ray diffraction method. All the complexes are found to be anhydrous, except 1.e, and the resultant asymmetric units are shown in Fig. 1 in the form of ORTEP. The structural features of each assembly is discussed in following section along with correlations and diversity among the structures.

Fig. 1 ORTEP Of molecular contents in the crystal structures of (a) 1.a, (b) 1.c, (c) 1.d and (d) 1.e.

An important characteristic feature to be emphasized that in all the assemblies, respective boronic acids adopt syn–anti conformation, which was noted as stable amongst others, as reported in the literature.^26,28 Further, structural analyses of all the complexes reveal that boronic acid functionality exclusively participate in heteromeric interaction with theophylline molecule, while theophylline forms both homomeric and heteromeric interactions, except in the complex 1.d where it forms only heteromeric interaction with the corresponding boronic acid moiety.

Structural description of complex, 1.a

Co-crystallisation of theophylline 1, with 4-chlorophenylboronic acid (a) from an ethanol solution gave plate-like colourless crystals 1.a, suitable for X-ray diffraction studies. Structural analysis reveals that in the molecular complex 1.a, the co-former are present in a 1 : 1 molecular ratio, in a triclinic space group. Contents of an asymmetric unit are shown in Fig. 1(a), while pertinent crystallographic parameters are listed in Table 1.

From the molecular structure, it is apparent that –B(OH)₂ moiety of boronic acid is in syn–anti conformation. Further, packing analysis of the molecules in the crystal lattice reveals that theophylline and molecules of a are held together through O–H⋯N (H⋯N, 1.92 Å) and N–H⋯O hydrogen bonds (H⋯O, 2.53 Å) yielding binary units. Such adjacent dimers are further self-assembled through the formation of O–H⋯O hydrogen bonds (H⋯O, 2.11 Å) yielding a tetrameric network, as shown in Fig. 2(a).

Fig. 2 (a) A two dimensional sheet structure in the complex 1.a (b) stacked layer arrangement observed in 1.a.

Further, the juxtaposed tetrameric ensembles are arranged in the form of tapes by homomeric interactions formed between adjacent theophylline molecules with the aid of cyclic and centrosymmetric N–H⋯O hydrogen bonds (H⋯O, 1.94 Å). Within the two-dimensional arrangement, the tapes are connected to each other by heteromeric interactions formed between co-formers by C–H⋯Cl hydrogen bonds (H⋯Cl, 2.84 Å), as represented in Fig. 2(a). Complete characteristics of hydrogen bonds are given in Table 2.

In three-dimensional arrangement, such sheets are further stacked as is shown in Fig. 2(b). To continue the exploration with other halo derivatives, co-crystallization of 1 and 4-bromophenylboronic acid, b is carried out.

Structure evolution of molecular complex, 1.b

Co-crystallization of 1 and b from any of the solvents did not yield good quality single crystals suitable for X-ray diffraction studies to determine molecular structure of the complex and further to analyse recognition and self-assembly process. However, the microcrystalline solid obtained shows high crystallinity as the powder X-ray diffraction patterns show well resolved peaks, with a characteristic peak of high intense at 26.5°, as shown in Fig. 3(a). Further, the pattern has distinctly different peaks than in the patterns of the co-formers, as shown in Fig. 3(b) and (c), respectively, in their native forms. In particular, the characteristic peaks corresponding to either of the co-formers, for instance, at 2θ 7, 11.5, 14.5 and 8.5, 18, 24 in Fig. 3(b) and (c) are not present in Fig. 3(a), thus suggesting formation of a molecular complex, 1.b.

Fig. 3 Powder X-ray diffraction patterns of (a) complex, 1.b, (b) theophylline, 1, (c) 4-bromophenylboronic acid, b, (d) co-crystals of 1.a, (e) simulated patterns of 1.a and (f) co-crystals of 1.c.

Interestingly, upon comparison of the patterns of the microcrystalline solid of 1.b with that of the X-ray powder patterns of the 1.a, as represented in Fig. 3(d), both of them are noted to be similar in all aspects, especially the coincided signature peaks at 26.5°. Such correlated patterns may be resultant of iso-structurality of the solids, hence it may be considered that replacement of –Cl by –Br showed no structural deviations between 1.a and 1.b. In fact, it is well known from the literature that in many instances, compounds of halogen series are iso-structural.^26b,c Thus, 1.b may be regarded to have the same structural packing features as that of 1.a which were derived experimentally from single crystal X-ray diffraction studies. Furthermore, to ensure that crystalline phases are of the same from both single and microcrystalline solids, simulated patterns of 1.a (Fig. 3(e)) are compared with that of the experimental patterns and noted that both are identical.

Establishing structural correlation between 1.a and 1.b, further experimentation was followed up by preparing co-crystals of 1 with 4-iodophenylboronic acid, c.

Supramolecular assembly in molecular complex, 1.c

Structure determination of molecular complex, 1.c, reveals that the crystal lattice is similar to that of the molecular complex 1.a, with closely related unit cell parameters (1.a, a = 7.510, b = 9.471, c = 11.878 Å, α = 85.63, β = 79.47, γ = 68.96°; 1.c, a = 7.475, b = 9.623, c = 11.957 Å, α = 87.25, β = 80.94, γ = 71.63°). Furthermore, the space group (triclinic, P1̄) is also found to be as same as that of 1.a. Complete structure parameters are listed in Table 1. Thus, asymmetric unit of complex 1.c also contains one molecule of each reactant, as shown in Fig. 1(b). The packing of the molecules in the crystal lattice are shown in Fig. 4, which are very much similar to that were shown in Fig. 2 for the complex 1.a. The iso-structurality is also established by the matching of PXRD patterns of 1.c with that of 1.a and 1.b. Such observations further, support the literature survey on the iso-structural features among the halogenated structures, although halogens differ with each other by various factors like, electronegativity, size, etc.

Fig. 4 (a) Two dimensional sheet structure in complex 1.c; (b) layer structure of complex 1.c in three dimensions.

It is apparent from the structural analysis of 1.a–c, that both –B(OH)₂ and halo groups show structure directing features of the observed assemblies. Since only halogen groups have been used in conjunction to –B(OH)₂ in 1.a–c, the study has also been extended to non-halogenated functional groups like –OH, to explore its impact on the process of molecular recognition of such boronic acids towards theophylline, 1. Thus, co-crystallisation experiments of 1, carried out with 4-hydroxyphenylboronic acid (d) from an ethanol solution, gave a molecular complex, 1.d.

Packing of molecules in molecular complex, 1.d

Structure determination of 1.d reveals that it is an anhydrous molecular complex, in a 1 : 1 ratio of co-formers, with the asymmetric unit is as shown Fig. 1(c). It is apparent that in 1.d also, the boronic acid moiety adopts the syn–anti conformation, as found in the complexes 1.a and 1.c. Analysis of recognition features discloses that the co-formers are held together in the form of binary units by holding each other through a pair-wise hydrogen bonds O–H⋯O and N–H⋯O, with the corresponding H⋯O distances being 1.85 and 1.90 Å, respectively. A typical interaction is shown in Fig. 5(a). Although in the molecular complexes 1.a and 1.c also, the co-formers comprise of binary units, it is interesting to note that in 1.d, the pattern of interaction between the co-formers is vividly different (O–H⋯N/N–H⋯O vs. O–H⋯O/N–H⋯O). The dimers are further connected to each other through O–H⋯O hydrogen bonds, that are being established by –OH group, with an H⋯O distance of 1.91 Å (see Fig. 5(a)) leading to the formation of tetrameric linear chains. The four-component ensembles, indeed, progress along a direction yielding infinite chains due to the periodicity. Thus, in the complex 1.d, unlike 1.a and 1.c, homomeric dimers are not observed even between the molecules of 1. The chains are arranged in the crystal lattice in the form of crossed chains, by establishing a O–H⋯N (H⋯N, 2.02 Å) hydrogen bond between the entangled chains. Such packing arrangement yields a square-grid network as is shown in Fig. 5(b).

Fig. 5 (a) Molecular recognition between 1 and d and arrangement of linear tetrameric units. (b) Square-grid network observed in the crystal lattice of 1.d.

Structural description of complex, 1.e

Structure determination avowed that the molecular complex, 1.e, crystallises in a triclinic P1̄ space group. Unlike the complexes 1.a–d, discussed above, complex 1.e is a hydrate structure comprises of theophylline and molecules of e in a 2 : 1 ratio along with a water molecule. The asymmetric unit is delineated in Fig. 1(e) and the crystal data is presented in Table 1. The three-dimensional packing of molecules is quite alluring and different from other complex. The molecules are packed in the crystal lattice, in the form of stacked layers, as shown in Fig. 6(a).

Fig. 6 (a) Stacking of layers observed in the molecular complex 1.e. (b) Two dimensional structural arrangement in 1.e. (c) Channel structure of complex 1.e in three dimensions.

In a typical sheet, however the adjacent molecules of 1 and e establish a recognition through the formation of a pair-wise hydrogen bonds, O–H⋯N/C–H⋯O, with the corresponding H⋯N and H⋯O distances being 2.06 and 2.63 Å, respectively. It is interesting to note that the recognition pattern is entirely different than observed in 1.a–d. The dimers, thus, obtained are held together by a O–H⋯O (H⋯O, 2.06 Å) hydrogen bonding, realizing a quartet ensemble, somewhat similar to such units observed in complex, 1.a–c. However, in 1.e, the quartet ensembles are evolved with a void space of dimension ∼7 × 6 Ų, suitable to fit water molecules as shown Fig. 6(b). Such quartet ensembles embedded with water molecules are further connected to each other through homomeric interactions, in the form of centrosymmetric N–H⋯O (H⋯O, 1.86 Å) hydrogen bonds formed between theophylline molecules, (see Fig. 6(b)), yielding a planar layer structure. Ultimately, in the crystal lattice, the arrangement is stabilized by stacking of the layers (Fig. 6(a)). Since the stacking is through translational symmetry, the channels within the sheets are positioned such that voids are aligned channels. Within the channels, the water molecules are held each other as well as with boronic acids in the host network, by different types of O–H⋯O hydrogen bonds.

Density functional modeling

The formation of a co-crystal depends upon the lattice energy which is partly directed by favourable energy minimization through intermolecular interactions, for example, hydrogen bonds, present between the adjacent molecules, in the form of homomers and heteromers. Hence the estimation of binding energy for all such feasible and possible recognition patterns is appropriate even to emphasize the formation of a specific type of pattern over the other. Such an exercise has been carried out using DFT-D3 method with B3LYP functional. Energies have been estimated and their values are presented in Table 3.

Table 3 Binding energy of different recognition patterns observed in the molecular complexes 1.a, 1.c, 1.d and 1.e

Complex	Homomers	Energy (kcal mol^−1)	Heteromers	Energy (kcal mol^−1)
		B3LYP		B3LYP
1.a		18.825		9.413
				7.530
				1.882
1.c		16.315		6.903
				8.158
				1.255
1.d				10.668
				6.902
				8.785
1.e		18.825		6.903
				8.158

---

On comparing the results obtained for binding energy calculations, it shows that the homodimer formed between the theophylline molecules which is present in complexes 1.a, 1.c and 1.e shows lowest energy among all the motifs present in the crystal structures of 1.a, 1.c–e. This can be attributed to centrosymmetric cyclic dimer present between strong hydrogen bond donor and acceptor atoms, resulted into the formation of strong hydrogen bonded dimer.

Heterodimers formed by boronic acids with theophylline shows topological difference hence binding energy required to form these motifs also differs significantly. Heterodimer formed between d and theophylline involves strong N–H⋯O and O–H⋯O hydrogen bonds hence it shows lowest energy among all heterodimers formed by boronic acid with theophylline which involves weak C–H⋯O hydrogen bond in their dimer formation. Heteromer formed between hydroxyl group and theophylline in complex 1.d shows lowest energy among heteromers formed by other functional groups such as boronic acid and halo groups. Though the heteromer formed by hydroxy group is more stable compared to heteromer formed by boronic acid, the difference in energy is very less (0.627 kcal mol⁻¹).

Haloboronic acid complexes are iso-structural and form similar structural motifs in their crystal structures, but these motifs differ significantly in their binding energy. Such variations may be accounted for the difference in the electronic factors between –Cl and –I atoms. Thus, heteromers with pair-wise hydrogen bonds formed by a are lower in energy (−9.413 kcal mol⁻¹) compared to the corresponding ones formed by c (−6.903 kcal mol⁻¹) and also a similar trend is observed in case of C–H⋯X (X–, Cl, I). In contrast, single hydrogen bonded heteromers appear to be favourable in 1.c (−8.158 kcal mol⁻¹) than in 1.a (−7.530 kcal mol⁻¹). However, in overall, 1.a shows more stability compared to 1.c by an amount of −2.509 kcal mol⁻¹, taken into account energy of all the interactions.

Conclusion

This study supports the use of boronic acid functionality as a good chromophore for the synthesis of co-crystals of pharmaceutically important ingredients (APIs) and will help to study further physico-chemical properties of such complexes. It is important to note that despite the affinity of 1 for hydration under humid conditions, the complexes are anhydrous except 1.e. Further, from the structural aspects, the molecular recognition patterns in the form of homomeric and heteromeric interactions play an important role in the formation of co-crystal, except in case of complex 1.d wherein only heteromeric interactions are present in the crystal structure.

Theoretical calculations indicate that binding energy of structural motifs depends upon type of functional groups involved in the motif formation. Haloboronic acids though form iso-structural motifs, differs significantly in their binding energies. The energy difference between the heteromers formed by boronic acid and hydroxyl group is very less which supports our previous study indicating boronic acid is as competitive as hydroxyl group in the formation of hydrogen bonded complexes.

Acknowledgements

We are thankful to the computational resources provided by the Swedish National Infrastructure for Computing (SNIC) at HPC2N and PDC. LG and VRP thank IIT Bhubaneswar for Infrastructure facilities and LG thanks MHRD for Senior Research Fellowship.

References

1. D. G. Hall, Boronic Acids: Prep. and Appl. in Organic Synth. and Med., 2006, p. 1.
2. (a) X. Lu and S. Lin, J. Org. Chem., 2005, 70, 9651; (b) D. J. Paymode and C. V. Ramana, J. Org. Chem., 2015, 80, 11551.
3. N. Miyaura, Bull. Chem. Soc. Jpn., 2008, 81, 1535.
4. H. Rao, H. Fu, Y. Jiang and Y. Zhao, Angew. Chem., Int. Ed., 2009, 48, 1114.
5. Z. Tang and Q. Hu, J. Am. Chem. Soc., 2004, 126, 3058.
6. M. Li, W. Zhu, F. Marken and T. D. James, Chem. Commun., 2015, 51, 14562.
7. T. D. James, K. R. A. S. Sandanayake and S. Shinkal, Nature, 1995, 374, 345.
8. E. W. Miller, A. E. Albers, A. Pralle, E. Y. Isacoff and C. J. Chang, J. Am. Chem. Soc., 2005, 127, 16652.
9. A. Schiller, R. A. Wessling and B. A Singaram, Angew. Chem., Int. Ed., 2007, 46, 6457.
10. J. C. Pickup, F. Hussain, N. D. Evans, O. J. Rolinski and D. J. S. Birch, Biosens. Bioelectron., 2005, 20, 2555.
11. J. R. Hunt, C. J. Doonan, J. D. LeVangie, A. P. Côté and O. M. Yaghi, J. Am. Chem. Soc., 2008, 130, 11872.
12. M. A. Mehta, T. Fujinami, S. Inoue, K. Matsushita, T. Miwa and T. Inoue, Electrochim. Acta, 2000, 45, 1175.
13. D. Salazar-Mendoza, J. Guerrero-Alvarez and H. Höpfl, Chem. Commun., 2008, 6543.
14. G. Zhang, O. Presly, F. White, I. M. Oppel and M. A Mastalerz, Angew. Chem., Int. Ed., 2014, 53, 1516.
15. J. N. Cambre and B. S. Sumerlin, Polymer, 2011, 52, 4631.
16. P. C. Trippler and C. McGuigan, MedChemComm, 2010, 1, 183.
17. M. Sung, L. Bagain, Z. Chen, T. Karpova, X. Yang, C. Silvin, T. C. Voss, J. G. McNally, C. Van Waes and G. L. Hager, Mol. Pharmacol., 2008, 74, 1215.
18. D. B. Carter, D. A. Ross, K. S. Ishaq, G. M. Suarez and C. Chae, Biochim. Biophys. Acta, 1977, 484, 103.
19. J. Liu, H. Zhang, Z. Xiao, F. Wang, X. Wang and Y. Wang, Int. J. Mol. Sci., 2011, 12, 1807.
20. Y. Zhu, S. Yao, B. Xu, Z. Ge, J. Cui, T. Cheng and R. Li, Bioorg. Med. Chem., 2009, 17, 6851.
21. M. K. Cyrański, A. Jezierska, P. Klimentowska, J. J. Panek, G. Z. Zukowska and A. Sporzyński, J. Chem. Phys., 2008, 128.
22. M. Kurt, T. R. Sertbakan and M. Özduran, Spectrochim. Acta, Part A, 2008, 70, 664.
23. R. Nishiyabu, Y. Kubo, T. D. James and J. S. Fossey, Chem. Commun., 2011, 47, 1124.
24. R. Nishiyabu, Y. Kubo, T. D. James and J. S. Fossey, Chem. Commun., 2011, 47, 1106.
25. (a) P. De, S. R. Gondi, D. Roy and B. S. Sumerlin, Macromolecules, 2009, 42, 5614; (b) J. Fournier, T. Maris, J. D. Wuest, W. Guo and E. Galoppini, Molecular tectonics, J. Am. Chem. Soc., 2003, 125, 1002; (c) P. M. Mitrasinovic, Curr. Org. Synth., 2012, 9, 233; (d) Y. Zhang, M. Li, S. Chandrasekaran, X. Gao, X. Fang, H. Lee, K. Hardcastle, J. Yang and B. A. Wang, Tetrahedron, 2007, 63, 3287; (e) P. Rogowska, M. K. Cyranski, A. Sporzynski and A. Ciesielski, Tetrahedron Lett., 2006, 47, 1389.
26. (a) V. R. Pedireddi and N. SeethaLekshmi, Tetrahedron Lett., 2004, 45, 1903; (b) S. Seethalekshmi, S. Varughese, L. Giri and V. R. Pedireddi, Cryst. Growth Des., 2014, 14, 4143; (c) M. R. Shimpi, N. Seethalekshmi and V. R. Pedireddi, Cryst. Growth Des., 2007, 7, 1958.
27. M. Talwelkar and V. R. Pedireddi, Tetrahedron Lett., 2010, 51, 6901.
28. N. SeethaLekshmi and V. R. Pedireddi, Cryst. Growth Des., 2007, 7, 944.
29. N. Seethalekshmi and V. R. Pedireddi, Inorg. Chem., 2006, 45, 2400.
30. C. B. Aakeröy, J. Desper and B. Levin, CrystEngComm, 2005, 7, 102.
31. P. Rodríguez-Cuamatzi, O. I. Arillo-Flores, M. I. Bernal-Uruchurtu and H. Höpfl, Cryst. Growth Des., 2005, 5, 167.
32. D. Tzeli, G. Theodorakopoulos, I. D. Petsalakis, D. Ajami and J. Rebek, J. Am. Chem. Soc., 2011, 133, 16977.
33. J. D. Larkin, K. L. Bhat, G. D. Markham, B. R. Brooks, H. F. Schaefer III and C. W. Bock, J. Phys. Chem. A, 2006, 110, 10633.
34. S. Varughese, S. B. Sinha and G. R. Desiraju, Sci. China: Chem., 2011, 54, 1909.
35. (a) S. Varughese, Y. Azim and G. R. Desiraju, J. Pharm. Sci., 2010, 99, 3743; (b) V. Dyulgerov, R. P. Nikolova, L. T. Dimova and B. L. Shivachev, Acta Crystallogr., Sect. E: Struct. Rep. Online, 2012, 68, o2320; (c) J. H-Paredes, A. L. Olvera-Tapia, J. I. Arenas-García, H. Höpfl, H. Morales-Rojas, D. Herrera-Ruiz, A. I. Gonzaga-Morales and L. Rodríguez-Fragoso, CrystEngComm, 2015, 17, 5166.
36. (a) C. T. Furukawa, G. G. Shapiro, C. W. Bierman, M. J. Kraemer, D. J Ward and W. E. Pierson, Pediatrics, 1984, 74, 453; (b) J. W. Jenne, Clin. Chest Med., 1984, 5, 645; (c) Y. Ono, T. Kondo, T. Tanigaki, Y. Syouyama, Y. Moue, U. Kamiya, G. Tazaki and Y. Ohta, Nihon Kokyuki Gakkai Zasshi, 2001, 39, 75; (d) M. Spears, I. Donnelly, L. Jolly, M. Brannigan, K. Ito, C. McSharry, J. Lafferty, R. Chaudhuri, G. Braganza, I. M. Adcock, P. J. Barnes, S. Wood and N. C. Thomson, Eur. Respir. J., 2009, 33, 1010; (e) A. E. B. Yassin, A. H. Aodah, S. Al-Suwayeh and E. I. Taha, Pharm. Dev. Technol., 2012, 17, 712.
37. M. Sung, L. Bagain, Z. Chen, T. Karpova, X. Yang, C. Silvin, T. C. Voss, J. G. McNally, C. Van Waes and G. L. Hager, Mol. Pharmacol., 2008, 74, 1215.
38. A. Paramore and S. Frantz, Drug Discov., 2003, 2, 611.
39. SAINT, Version 6.02, Bruker AXS, Inc., Analytical X-ray Systems, 5465 East Cheryl Parkway, Madison, WI, 2000, pp. 53711–55373.
40. SADABS [Area-Detector Absorption Correction], Siemens Industrial Automation, Inc., Madison, WI, 1996.
41. G. M. Sheldrick, SHELXTL, University of Gottingen, Gottingen, Germany, 1997.
42. (a) A. L. Spek, Acta Crystallogr., 2009, 65, 148; (b) A. L. Spek, PLATON, A Multipurpose Crystallographic Tool, Utrecht University, Utrecht, Netherland, 2002.
43. M. Valiev, E. J. Bylaska, N. Govind, K. Kowalski, T. P. Straatsma, H. J. J. Van Dam, D. Wang, J. Nieplocha, E. Apra, T. L. Windus and W. A. De Jong, Comput. Phys. Commun., 2010, 181, 1477.
44. S. Grimme, J. Antony, S. Ehrlich and H. Krieg, J. Chem. Phys., 2010, 132.
45. C. Lee, W. Yang and R. G. Parr, Phys. Rev. B: Condens. Matter Mater. Phys., 1988, 37(2), 785.
46. W. J. Hehre, K. Ditchfield and J. A. Pople, J. Chem. Phys., 1972, 56, 2257.

---

Footnote

† CCDC reference numbers for complexes 1.a, 1.c, 1.d and 1.e are 1440006–1440009, respectively. For crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra04100k

---