AAAA-DDDD Quadruple Hydrogen-Bond Arrays Featuring NH···N and CH···N Hydrogen Bonds

The X-ray crystal structure of a previously reported extremely strong quadruple NH···N AAAA-DDDD hydrogen-bond array [5·4] (Ka = 1.5 × 10 6 M−1 in CH3CN; Ka > 3 × 10 12 M−1 in CH2Cl2) features four short linear hydrogen bonds. Changing the two benzimidazole groups of the DDDD unit to triazole groups replaces two of the NH···N hydrogen bonds with CH···N interactions (complex [5·6]), but only reduces the association constant in CH3CN by 2 orders of magnitude (Ka = 2.6 × 10 4 M−1 in CH3CN; Ka > 1 × 10 7 M−1 in CH2Cl2). Related complexes without the triazole groups range in Ka from 18 to 270 M −1 in CH3CN, suggesting that the CH···N interactions can be considered part of a strong AAAA-DDDD quadruple hydrogen-bonding array. The NH···N/CH···N AAAA-DDDD motif can be repeatedly switched “on” and “off” in CDCl3 through successive additions of acid and base. ■ INTRODUCTION While individual hydrogen bonds are generally weak and have short lifetimes, their enthalpy of formation is additive, meaning that multipoint hydrogen-bonding arrays can very effectively hold together supramolecular assemblies and materials. Secondary electrostatic interactions between adjacent hydrogen bonds have a significant influence on the stability of a supramolecular complex. The binding strength is theoretically maximized if all the hydrogen-bond donors (D) are on one component and all the hydrogen-bond acceptors (A) are on the other, a trend that has been experimentally demonstrated with triple and quadruple (e.g., AADD-DDAA [1·1] < ADDADAAD [2·3] < AAAA-DDDD [5·4], Figure 1) hydrogen-bond motifs involving N−H donors and N or O hydrogen-bond acceptors. Although C−H groups are generally much weaker hydrogen-bond donors than hydrogens bound to heteroatoms, CH···N/O interactions can play important roles in molecular recognition and assembly processes, including protein−protein interactions, anion recognition, and extended crystal lattices. We recently reported an extremely strong (Ka > 3 × 10 12 M−1 in CH2Cl2) AAAA-DDDD quadruple hydrogen-bonding array ([5·4], Figure 1) based on four NH···N intercomponent hydrogen bonds. Here we report the X-ray crystal structure of [5·4] and the effect on the strength of binding of the quadruple hydrogen-bond array of replacing two of the NH···N hydrogen bonds with CH···N interactions. ■ RESULTS AND DISCUSSION A single crystal of [5·4]BArF− (BArF− = [(3,5(CF3)2C6H3)4B] −) suitable for X-ray diffraction was obtained by slow diffusion of hexane vapor into a saturated solution of [5·4]BArF− in CH2Cl2. The X-ray crystal structure (Figure 2) shows that the conformation of 4 is locked by two intramolecular hydrogen bonds that present the four N−H hydrogen-bond donors along one edge of the molecule. The hydrogen-bonding edge of 5 shows a slight curve in the solid state, with the outer pyridine rings closer to the acceptor array than the inner pyridine rings. Accordingly, the peripheral NH···N hydrogen bond lengths (1.769 and 1.807 Å) are significantly shorter than the inner NH···N distances (1.899 and 2.032 Å) (Figure 2a). The four NH···N hydrogen bonds are all close to linear, in contrast to the staggered arrangement observed in the X-ray structure of an AAA-DDD hydrogenbond array. The phenyl groups of 5 are slightly twisted away from the plane formed by the fused pyridine rings (Figure 2b). The N−H groups of the benzimidazole groups of DDDD partner 4 still partake in short, close-to-linear hydrogen bonds despite being in five-membered rings which are not optimal for presenting the NH groups parallel to each other. It seemed that this geometry could be closely mirrored by triazole groups, readily introduced through a copper-catalyzed alkyne−azide cycloaddition (CuAAC) reaction, which would allow the effect of replacing NH···N hydrogen bonds with CH···N interactions in a multipoint hydrogen-bond array to be evaluated. A potential quadruple N−H/C-H hydrogen-bond donor 6 was synthesized in five steps from triazole 7 as shown in Scheme 1 (see Supporting Information for details). Amine 8 was produced via a Curtius rearrangement followed by deprotection with trifluoroacetic acid and subsequent thiourea formation with carbon disulfide in pyridine (Scheme 1, i−ii). Thiourea 9 was transformed into guanidine 10 via a carbodiimide intermediate and precipitated as the hexafluorReceived: May 6, 2013 Published: June 13, 2013 Article


■ INTRODUCTION
While individual hydrogen bonds are generally weak and have short lifetimes, their enthalpy of formation is additive, meaning that multipoint hydrogen-bonding arrays 1 can very effectively hold together supramolecular assemblies and materials. 2 Secondary electrostatic interactions between adjacent hydrogen bonds have a significant influence on the stability of a supramolecular complex. 3 The binding strength is theoretically maximized if all the hydrogen-bond donors (D) are on one component and all the hydrogen-bond acceptors (A) are on the other, 3 a trend that has been experimentally demonstrated with triple 4 and quadruple 5 (e.g., AADD-DDAA [1·1] < ADDA-DAAD [2·3] < AAAA-DDDD [5·4], Figure 1) hydrogen-bond motifs involving N−H donors and N or O hydrogen-bond acceptors. Although C−H groups are generally much weaker hydrogen-bond donors than hydrogens bound to heteroatoms, CH···N/O interactions can play important roles in molecular recognition and assembly processes, 6 including protein−protein interactions, 7 anion recognition, 8 and extended crystal lattices. 9 We recently reported 5 an extremely strong (K a > 3 × 10 12 M −1 in CH 2 Cl 2 ) AAAA-DDDD quadruple hydrogen-bonding array ([5·4], Figure 1) based on four NH···N intercomponent hydrogen bonds. 10 Here we report the X-ray crystal structure of [5·4] and the effect on the strength of binding of the quadruple hydrogen-bond array of replacing two of the NH···N hydrogen bonds with CH···N interactions.

■ RESULTS AND DISCUSSION
A single crystal of [5·4]BArF − (BArF − = [(3,5-(CF 3 ) 2 C 6 H 3 ) 4 B] − ) 5 suitable for X-ray diffraction was obtained by slow diffusion of hexane vapor into a saturated solution of [5·4]BArF − in CH 2 Cl 2 . The X-ray crystal structure ( Figure 2) shows that the conformation of 4 is locked by two intramolecular hydrogen bonds that present the four N−H hydrogen-bond donors along one edge of the molecule. The hydrogen-bonding edge of 5 shows a slight curve in the solid state, with the outer pyridine rings closer to the acceptor array than the inner pyridine rings. Accordingly, the peripheral NH···N hydrogen bond lengths (1.769 and 1.807 Å) are significantly shorter than the inner NH···N distances (1.899 and 2.032 Å) (Figure 2a). The four NH···N hydrogen bonds are all close to linear, in contrast to the staggered arrangement observed in the X-ray structure of an AAA-DDD hydrogenbond array. 4d The phenyl groups of 5 are slightly twisted away from the plane formed by the fused pyridine rings (Figure 2b).
The N−H groups of the benzimidazole groups of DDDD partner 4 still partake in short, close-to-linear hydrogen bonds despite being in five-membered rings which are not optimal for presenting the NH groups parallel to each other. It seemed that this geometry could be closely mirrored by triazole groups, readily introduced through a copper-catalyzed alkyne−azide cycloaddition (CuAAC) reaction, 11 which would allow the effect of replacing NH···N hydrogen bonds with CH···N interactions in a multipoint hydrogen-bond array to be evaluated.
A potential quadruple N−H/C-H hydrogen-bond donor 6 was synthesized in five steps from triazole 7 12 as shown in Scheme 1 (see Supporting Information for details). Amine 8 was produced via a Curtius rearrangement followed by deprotection with trifluoroacetic acid and subsequent thiourea formation with carbon disulfide in pyridine (Scheme 1, i−ii). Thiourea 9 was transformed into guanidine 10 via a carbodiimide intermediate and precipitated as the hexafluor-ophosphate salt 6 (Scheme 1, iii−iv). In principle, 6 can exist in several conformations and tautomers stabilized by different intramolecular hydrogen-bonding arrangements (e.g., 6 and 6′, Scheme 1).
Characterization of NH···N/CH···N AAAA-DDDD Quadruple Hydrogen-Bond Array [5·6]. Addition of 6 to 5 in CD 2 Cl 2 to form a 1:1 stoichiometry immediately led to considerable shifts in the 1 H NMR spectra of both components ( Figure 3). The triazole C−H protons of 6 (H a ) are broadened and shifted downfield by ∼1 ppm, consistent with very close positioning to, and polarization by, a region of high electron density (e.g., a heteroatom lone pair). Some protons of the pyridyl rings of 5 also undergo significant shielding (e.g., H A ) and deshielding (e.g., H B ) in the complex. Intermolecular NOE crosspeaks between H B and H b (Supporting Information, Figure S8) of 5 and 6 are consistent with the geometry of [5·6] being the anticipated edge-to-edge complex. A 1:1 stoichiometry complex was observed by electrospray ionization mass spectroscopy (ESI-MS) ([5·6] + m/z = 806.06, see Supporting Information, Figures S10−S12).
The association constant of [5·6] proved to be too large to be measured directly in CD 2 Cl 2 by 1 H NMR or UV/vis spectroscopy. However, a titration of 6 with 5 at 10 −4 M concentrations in CH 3 CN (298 K) showed a decrease in UV/ vis absorption spectrum of 5 (λ max = 426 nm), accompanied by a new species with a bathochromic shift (Δλ) of 11 nm ( Figure  4). From these data the K a of [5·6] in CH 3 CN was determined to be 2.6 × 10 4 M −1 (see Supporting Information). This means that replacing two of the NH···N hydrogen bonds in [5·4] (K a = 1.5 × 10 6 M −1 ) with the two CH···N interactions in [5·6] (K a = 2.6 × 10 4 M −1 ) results in only a ∼60-fold decrease in the K a value in CH 3 CN.
Supramolecular Complexes Featuring Two Intercomponent NH···N Hydrogen Bonds and Zero, One, or Two CH···N Interactions. To further probe the contribution of the CH···N interactions to the overall stability of the hydrogenbonding array, a series of binding constant measurements were   made between compounds with increasing numbers of contiguous acceptor sites (11 with two acceptor sites, 12 with three, 5 with four) and donors containing two NH's from a central guanidinium core plus either two additional contiguous NH groups (4), two additional contiguous CH groups (6), or no additional groups (13) able to interact with the acceptor pyridine sites ( Figure 5). The rationale for the study is that, with each of 5, 11, and 12, two pyridine sites would satisfy the hydrogen-bond requirements of the two NH groups of 4, 6, and 13, but 11 has no further pyridine groups to engage in CH···N interactions, and 12 has only one. Although this comparison can give some indication of the ability of CH···N interactions to contribute to the strength of an extended hydrogen-bond array, there are many approximations implicit in the study. For example, the solvation of the different hydrogen-bond donors and acceptors will vary, and also the electrostatic interactions that enhance the hydrogen-bondaccepting ability of neighboring pyridine groups should be more pronounced in 5 than in 11 or 12. 13 Despite the limitations of the study, the results show some interesting trends ( Figure 5). The simple guanidinium derivative 13, which can only form two NH···N hydrogen bonds with any of the partners, forms relatively weak complexes in CH 3 CN, with the association constant increasing by only an order of magnitude across the series 11→12→5 (K a = 18−270 M −1 ). In contrast, bis-triazole 6, which can form up to two CH···N interactions in addition to the two NH···N hydrogen bonds, binds AAAA partner 5 (K a = 2.6 × 10 4 M −1 ) 2 orders of magnitude more strongly than it binds the 1,8-naphthyridine derivative 11 (K a = 240 M −1 ). The peripheral triazole CH hydrogen-bonding groups clearly play a significant role in affecting the stability of the multipoint hydrogen-bond array,   although the effect is much smaller than that of NH hydrogenbond donors (the binding constant for four-NH donor 4 increases 3 orders of magnitude across the series 11→12→5 in CH 3 CN (K a = 1.2 × 10 3 −1.5 × 10 6 M −1 ). The significant difference in binding strength between [11·6] (K a = 270 M −1 ), which features two NH···N hydrogen bonds, and [5·6] (K a = 2.6 × 10 4 M −1 ), which has two NH···N hydrogen bonds plus two CH···N interactions in an aligned AAAA-DDDD array, suggests that CH···N interactions involving triazole groups probably benefit from secondary electrostatic interactions from adjacent hydrogen bonds in a similar manner to conventional hydrogen bonds involving NH donors.
Switching "On" and "Off" NH···N/CH···N AAAA-DDDD Complex Formation. As the hydrogen-bond donors 4 and 6 are protonated salts, in order to induce preorganization and display the desired recognition motif, the interaction can be switched "off" by the addition of an appropriate base ( Figure  6). Addition of 1 equiv of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to a solution of [5·6] in CDCl 3 deprotonated the guanidinium group and disrupted the strong association of 5 and 6, as evidenced by shifts of H A and H B in the 1 H NMR spectrum to positions consistent with the uncomplexed building block ( Figure 5). Reprotonation with 1 equiv of HI 14 in CD 3 CN smoothly re-formed [5·6] (Figure 6 and Supporting Information, Figure S6). In this way complex [5·6] could be switched "off" and "on" repeatedly by successive additions of base and acid.

■ CONCLUSIONS
The first X-ray crystal structure of an AAAA-DDDD complex, [5·4], shows that, in contrast to the staggered arrangement present in the only X-ray structure of an AAA-DDD system reported to date, 4d it has a close-to-linear array of four short intercomponent NH···N hydrogen bonds in the solid state. Changing the two benzimidazole groups of the DDDD unit to triazole groups replaces two of the NH···N hydrogen bonds with CH···N interactions (complex [5·6]), but reduces the association constant in CH 3 CN by only 2 orders of magnitude (K a = 2.6 × 10 4 M −1 in CH 3 CN; K a > 1 × 10 7 M −1 in CH 2 Cl 2 ), suggesting that the CH···N interactions can be considered part of a AAAA-DDDD quadruple hydrogen-bonding array. The NH···N/CH···N AAAA-DDDD motif can be repeatedly switched "on" and "off" through successive additions of acid and base. The switching "on" and "off" of a strong hydrogenbonding array may prove useful for the design of supramolecular polymers, gels, nanofibers, fibrils, and materials that can be assembled or disassembled in response to a simple stimulus. 15 ■ ASSOCIATED CONTENT

* S Supporting Information
Experimental procedures and spectral data for all compounds, details of X-ray analysis, and complexation studies. This material is available free of charge via the Internet at http:// pubs.acs.org.

■ AUTHOR INFORMATION
Corresponding Author david.leigh@manchester.ac.uk

Notes
The authors declare no competing financial interest.

■ ACKNOWLEDGMENTS
We thank Dr. Scott Cockroft for useful discussions and Prof. Chris Hunter for the use of AllMaster fitting software. This work was supported by the EPSRC.