Neutral iodotriazoles as scaffolds for stable halogen-bonded assemblies in solution

Computational and experimental data are used to demonstrate that the halogen bond (XB) donor properties of neutral 1,4-diaryl-5-iodo-1,2,3-triazoles are competitive with the classic pentafluoroiodobenzene XB donor.


Introduction
The non-covalent interaction between an electron decient halogen atom and an electron donor has found 1 a clear denition in the term halogen bonding. Halogen bonds (XBs) have proven to be a powerful tool in a wide range of chemistries. The contribution of Metrangolo, Resnati and co-workers has revolutionised 2 the conception of XB, making it a valuable tool in all the areas of chemistry where molecular recognition plays a central role. 3 A signicant effort has also been invested in unravelling the fundamental structural and energetic features of XBs. Computational 4 and experimental 5 studies made signicant contribution to the understanding of the so-called "s-hole" 4ba zone of low electron density displaying a positive electrostatic potential. Simplifying XBs to merely electrostatic interactions is, however, reductive: the factors contributing to the stability of a XB are a convolution of electrostatic, 4a polarisation, 6 charge transfer 7 and dispersion 8 forces and the role played by each of these factors is inuenced signicantly by the molecular components involved and the medium where the interaction takes place. It is generally recognised though that the ability of a halogen atom to participate in a XB increases with the electron withdrawing effect of the group to which the halogen is attached. The plethora of halogenated molecules constitutes a huge set of XB donors. Among these, a simple demarcation in XB ability can be made between cationic and neutral XB donors. Cationic XB donors are generally halogenated (mainly Br and I) ve or six membered nitrogen heterocycles, where one of the nitrogen atoms is quaternarised with an alkyl group. The interaction of such XB donors with XB acceptors is in fact dened 9 as 'charge-assisted XB' and these interactions are signicantly stronger than those between two neutral XB partners. Beer and co-workers, for example, have designed and synthesised 10 a variety of macrocycles, catenanes and rotaxanes incorporating halotriazolium and haloimidazolium units able to perform anion sensing in organic and aqueous media via charge-assisted XB. Pyridinium 11 and imidazolium 12,13 XB donors have been used extensively by the group of Huber to catalyse C-Br bond cleavage reactions in organic media.
On the other hand, when a polarisable halogen atom is bonded to a neutral organic backbone, its ability to act as a XB donor depends greatly on the electronic properties of the organic residue. It is, therefore, not surprising that the most common neutral XB donors are peruorohalocarbons (PFHCs  19 F NMR spectroscopy. The association strength could be correlated to the s Hammett parameter for the X substituent. More recently multivalent PFHC-based XB donors have been successfully exploited in molecular recognition 16 and catalysis. 17 The quest for new and less conventional organic XB donors has been tackled 18 by several research groups and haloalkenes, 19 haloalkynes, 20 N-haloimides 21 and halogenated metallic complexes 22 have been found to be strong XB donors in the solid state. Iodoalkynes have been shown 23 to behave as XB donors in solution as well as in the solid state.
In this paper, we describe the development of an underexplored 24 class of iodinated scaffolds, 1,4-diaryl-5-iodo-1,2,3triazoles, as a progenitor for assemblies supported by XBs. The XB properties have been examined computationally, in the solid state and in solution. During the course of these studies, a serendipitous discovery led us to design a system containing both a diaryliodotriazole and a Lewis base, thus generating a molecule capable of undergoing dimerisation through self-complementary XBs. A detailed NMR study of the self-assembled dimer in solution has allowed us to evaluate the efficiency of chelate cooperativity on the dimerisation process.

Results and discussion
Iodotriazole 1 can be prepared readily and in high yield through the Cu-catalysed reaction of pentauorophenyl azide and iodophenylacetylene. The solid state structure ( Fig. 1) of compound 1, determined by single crystal X-ray diffraction, exhibits antiparallel tapes in which the molecules are connected by a series of short, nitrogen to iodine contacts (r(N/I) ¼ 2.973Å) indicative of the presence of a halogen bond between the iodotriazole rings.
The presence of these close contacts in the solid state structure of 1 suggested that appropriately designed diaryl-5iodo-1,2,3-triazoles could function as viable XB donors.
In order to gain some insight into the potential interactions between this class of compounds and XB acceptors, we performed a series of calculations that compared the interaction of iodotriazole 1 and pentauoroiodobenzene 2 with a series of pyridine-based XB acceptors (Fig. 2). These calculations were performed at the TPSSh/def2-TZVP level of theory.
suggest that iodotriazole 1 should interact strongly with suitable electron donors. Indeed, the calculated geometries for the complexes formed between the three pyridines shown in Fig. 2b and compound 1 all possess N/I distances much shorter than the sum of the van der Waals radii and signicantly negative enthalpies of complexation at 298 K (Fig. 2b). These structural and energetic parameters are all similar to those for the complexes formed between the well-known halogen bond donor 2 and the same set of pyridines. Natural bond order (NBO) analyses (see ESI † for details) demonstrated that, in all six complexes, there are signicant interactions between the nitrogen lone pair and the s* orbital associated with the C-I bond present in the donor. Intermolecular interaction isosurfaces, generated 26 through an analysis of the reduced gradient of the electron density, have been used 27 extensively to identify non-covalent interactions that stabilise intermolecular complexes. Analyses of the complexes [1$5] (Fig. 2c) and [2$5] (Fig. 2d) using this method (see ESI † for details) reveal signicant low density, low gradient regions that are consistent with the presence of a halogen bond between the interacting partners in both complexes. The similarities between the results for [1$5] and [2$5] suggest that the neutral iodotriazole might be used interchangeably with the peruorinated iodobenzene as a halogen bond donor.
Encouraged by these computational results, we examined the interaction of iodotriazole 1 and the pyridine-based XB acceptors 3 and 5 in solution. Initially, we examined the interaction of 1 and 4-methylpyridine 3 in d 8 -toluene. Titration of increasing amounts of 3 into a solution of 1 in d 8 -toluene did not result in any signicant chemical shi changes in the 19 F NMR spectrum of 1. However, when the titration was performed again, this time titrating increasing amounts of 1 into a solution of 3 in d 8 -toluene at 293 K, a series of 1 H-15 N HMBC experiments revealed signicant upeld 15 N chemical shi changes for the pyridine ring nitrogen atom. The 15 N chemical shi data were tted 28 to a 1 : 1 binding model for the complex [1$3] affording (see ESI † for details) a stability constant for this complex in d 8 -toluene at room temperature of 1.67 AE 0.55 M À1 . For comparison purposes, we repeated this analysis, this time using pentauoroiodobenzene 2 as the halogen bond donor. The 15 N chemical shi data from this experiment were once again tted 28 to a 1 : 1 binding model for the complex [2$3] (see ESI † for details) affording a stability constant for this complex in d 8 -toluene at 293 K of 2.67 AE 0.69 M À1 . These results conrm experimentally the outcome of our calculationsiodotriazole 1 and pentauoroiodobenzene 2 have similar halogen bond donor abilities towards pyridine acceptors.
From the set of pyridine XB acceptors studied computationally, DMAP 5 was predicted to form the most stable complexes. When we performed an experiment where increasing amounts of 5 were titrated into a solution of 1 in d 8 -toluene, signicant chemical shi changes in the 376.4 MHz 19 F NMR spectrum of 1 were observed (Fig. 3a). In particular, the resonance for the uorine atom para to the iodotriazole ring exhibited a signicant upeld shi (Fig. 3a, dotted line) from d À148.7 to d À149.6, consistent with the formation of the [1$5] complex. However, this chemical shi data could not be tted to a 1 : 1 binding model for the [1$5] complex and close examination of the NMR samples revealed that a precipitate had formed in all samples. Clearly, the formation of the [1$5] complex was accompanied by a concomitant chemical transformation.
Intrigued by the presence of this precipitate, we repeated this titration experiment using CD 3 CN as the solvent. In this case, no precipitate was formed. However, the 376.4 MHz 19 F NMR spectrum revealed a new set of resonances at d À143.1 and d À145.9 (Fig. 3b, blue circles) that were consistent with the presence of a 1,4-disubstituted tetrauorobenzene ring. We attributed these resonances to the presence of the insoluble pyridinium salt 6. This product arises from the nucleophilic aromatic substitution 29,30 (S N Ar) of the uorine para to the triazole ring in 1 by DMAP 5 and analysis of the precipitate formed in d 8 -toluene conrmed its identity as the pyridinium salt 6.
Although DMAP 5 is potentially the best halogen bond acceptor, it is clearly much too reactive towards the per-uorinated aromatic ring present in 1. We therefore turned to alkoxypyridines as halogen bond acceptors. We performed a series of calculations examining the interaction of iodotriazole 1 with 3-methoxypyridine at the TPSSh/def2-TZVP level of theory. These calculations reveal (Fig. 4a, le) a complex that is very similar in structure (r(N/I) ¼ 2.836Å, :C-I/N ¼ 179.5 ) and with a similar calculated enthalpy of complexation at 298 K (À23.6 kJ mol À1 ) to that formed between 1 and 4-methylpyridine 3. Titration of 7, a more soluble variant of 1, into a solution of 3-pentyloxypyridine 8 in d 8 -toluene at 298 K resulted in small, but signicant, chemical shi changes in the 700.1 MHz 1 H NMR spectrum for the resonances arising from the pyridine ring protons of 8. A series of 1 H-15 N HMBC experiments (Fig. 4b), performed on the same sample set, also reveal significant 15 N chemical shi changes for the pyridine ring nitrogen atom. Both the 1 H and the 15 N chemical shi data were tted 28 to a 1 : 1 binding model for the complex [7$8] affording (see ESI † for details) a stability constant for this complex in d 8 -toluene at 293 K of 1.44 AE 0.24 M À1 .
For comparison purposes, we also evaluated the stability of the complex formed between pentauoroiodobenzene 2 and 3-methoxypyridine at the same level of theory. These calculations reveal (Fig. 4a, right) a complex with a halogen bond that is similar in geometry (r(N/I) ¼ 2.808Å, :C-I/N ¼ 179.0 ) and a similar calculated enthalpy of complexation at 298 K (À19.6 kJ mol À1 ) to the complex formed between 3-methoxypyridine and iodotriazole 1. Analysis of a titration of 2 into a solution of 3-pentyloxypyridine 8 in d 8 -toluene using a series of 700.1 MHz 1 H-15 N HMBC experiments (Fig. 4c)  It is clear from these data that the interactions between both 2 and 8 and 7 and 8 are is not particularly strong in d 8 -toluene at 298 K. However, we reasoned that the reactivity observed between 1 and nucleophiles, such as an amino-or hydroxypyridine, should allow us to construct rapidly a molecule that possessed both a pyridine ring and an iodotriazole. Such a molecule would be self-complementary and could, potentially, benet from cooperative binding 31 between the self-complementary recognition sites, thus forming a halogen-bonded dimer.
Accordingly, we designed compound 9a (Fig. 5a), which was prepared in two steps, in high yield, from 5-(2-iodoethynyl)-1,3bis(tert-butyl)benzene and 1-azido-2,3,4,5,6-pentauoro benzene (see ESI † for details). We envisaged that 9a might be able to form a halogen-bonded dimer in which the pyridine ring of one molecule interacts with the iodotriazole of a second molecule. This expectation was supported by calculations (Fig. 5b) at the TPSSh/def2-TZVP level of theory on compound 9bidentical to 9a save for the replacement of the tert-butyl groups by hydrogen atoms in the interests of computational efficiency.
A doubly halogen-bonded homodimeric structure was located that possessed approximate C 2 symmetry and in which the tetrauoroaromatic rings in the two molecules of 9b are rotated by around 120 with respect to each other. The two halogen bonds showed almost identical lengths and geometries (r(N/I) ¼ 2.887Å; :C-I/N ¼ 175.2 and r(N/I) ¼ 2.890Å; :C-I/N ¼ 174.7 ). The calculated enthalpy of dimerisation at 298 K for [9b$9b] is À30.6 kJ at this level of theory. Comparison of [9b$9b] with the corresponding monodentate interactionas represented by the calculated structure of the complex formed between 1 and pyridine 10 at the same level of theory (Fig. 5b, le)is instructive. The calculated geometry of the halogen bond in [1$10] (r(N/I) ¼ 2.875Å; :C-I/N ¼ 178.5 ) reveals an interaction that is marginally shorter and more linear than those in [9b$9b]. The geometry of the [1$10] complex, together with the calculated enthalpy of dimerisation at 298 K (À17.9 kJ) more than half the total for [9b$9b], suggested that a slight structural mismatch may be present in the [9b$9b] complex, preventing it from taking full advantage of both halogen bonds.
Single crystals of 9a, suitable for analysis by X-ray diffraction, were grown by slow evaporation of a solution of 9a in toluene. The solid-state structure of 9a (Fig. 6) reveals antiparallel chains of molecules connected by halogen bonds between the pyridine of one molecule and the iodotriazole of the next. The geometry of these close contacts between the pyridine ring nitrogen atoms and the iodotriazole rings are suggestive of strong halogen bondsr(N/I) ¼ 2.767Å; :C-I/N ¼ 176.5 .
Despite the absence of homodimers in the solid state structure of 9a, we wished to characterise the stability of the [9a$9a] complex in solution. Accordingly, we performed a dilution experiment in order to assess the stability of the [9a$9a] dimer in C 6 D 6 solution. From a starting concentration of 200 mM, progressive dilution of a solution of 9a resulted in chemical shi changes in the 1 H NMR spectrum for the resonances associated with the pyridine ring. These chemical shi changes were tted 28 (see ESI † for details) to a dimerisation binding model, affording a stability constant for the [9a$9a] dimer in C 6 D 6 of 3.4 AE 0.7 M À1 . This value was disappointingly low and indicated that the [9a$9a] dimer benets from little, if any, cooperativity 31 arising from the connection of the halogen bond donor and acceptor within the same molecule.
In order to characterise the association of 9a in C 6 D 6 solution further, we turned to DOSY NMR experiments to assess the nature of the assembly formed. A series of DOSY experiments were performed (Fig. 7a) on sample 9a in C 6 D 6 , at concentrations ranging from 200 mM down to 1.0 mM. The diffusion coefficients of 9a and that of the solvent were measured at each concentration. The observed variations of the diffusion coefficient of the solvent were interpreted as a variation in the viscosity of the sample.
Using this data, the diffusion coefficients of solute 9a were corrected for viscosity changes using the diffusion coefficient    [1$10]. (c) Left: intermolecular interaction isosurfaces for the [9b$9b] dimer, generated by NCIPLOT, 26 for s ¼ 0.5 and À0.05 < sign(l 2 )r < 0.05 (colour scale: attractive (blue) / repulsive (red)). Right: plot of sign(l 2 )r vs. reduced gradient highlighting the favourable interaction corresponding to the halogen bonds at sign(l 2 )r $ À0.035. Atom colouring in molecular structures: C atoms ¼ grey, N atoms ¼ blue, O atoms ¼ red, F atoms ¼ light green, I atoms ¼ purple. H atoms are omitted for clarity.
for the solvent (C 6 D 6 ) measured on the same samples. The variation of these corrected diffusion coefficients for 9a across the concentration range studied were then tted (Fig. 7b, see ESI † for further details) to a simple dimerisation model, using the model 32 of Morris and co-workers for estimating the diffusion of the dimer. The results of this tting procedure conrm the presence of dimer [9a$9a] in solution, and the estimated value of the stability constant for [9a$9a] at 298 K -2.1 AE 0.4 M À1 was in good agreement with that obtained using the more conventional NMR titration method.

Conclusions
We have demonstrated that 1,4-diaryl-5-iodo-1,2,3-triazoles possess XB properties that make them reliable, neutral XB donors in organic solvents, able to interact with pyridine XB acceptors with efficiencies similar to those displayed by the iconic XB donor iodopentauorobenzene. The synthetic versatility of these molecular scaffolds allowed the facile construction a self-complementary molecular module, incorporating both an XB donor and an XB acceptor, that was capable of forming a homodimer through the formation of two neutral XB interactions. The stability of this dimeric assembly was evaluated by means of DFT calculations and in C 6 D 6 solutions using 1 H NMR and DOSY experiments. The results of these investigations showed that, despite the increased stability of the dimeric assembly, full exploitation of the chelate effect could not be achieved as a result of a partial structural mismatch between the two monomeric units. Nevertheless, the application of chelate cooperativity represents a valid strategy to reinforce XB interactions between two neutral partners in solution and further studies directed towards the optimisation of the monomer design are currently underway in our laboratory.