Nature and Hierarchy of Non-Covalent Interactions in Gas-phase

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Nature and Hierarchy of Non-Covalent Interactions in GasPhase Binary Complexes of Indole and Benzimidazole with Ethers Aditi Bhattacherjee, and Sanjay J. Wategaonkar J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.7b08627 • Publication Date (Web): 24 Oct 2017 Downloaded from http://pubs.acs.org on November 2, 2017

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The Journal of Physical Chemistry

Nature and Hierarchy of Non-Covalent Interactions in Gas-phase Binary Complexes of Indole and Benzimidazole with Ethers

Aditi Bhattacherjee# and Sanjay Wategaonkar* Department of Chemical Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Mumbai 400 005, India

Submitted to Journal of Physical Chemistry A

AUTHOR EMAIL ADDRESS: [email protected], [email protected] # Present address: School of Chemistry, University of Bristol, Bristol BS8 1TH, United Kingdom

Address for correspondence:

Sanjay Wategaonkar Telephone: 91-22-2278-2259, Fax: 91-22-2278-2106, E-mail: [email protected]

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Abstract Hierarchy among the weak noncovalent interactions such as van der Waals, electrostatic, hydrogen bonding etc. dictates the secondary and tertiary structures of proteins as well as their interactions with various ligands. In this work, we investigate the competition between conventional (N−H···O), unconventional (C−H···O) hydrogen bonds, and van der Waals interaction in the model compounds of the chromophores of the amino acids, tryptophan and histidine. These include indole (IND), benzimidazole (BIM), and its N-methylated analog (N-methylbenzimidazole, MBIM) which present multiple docking sites. The binary complexes of these molecules with ethers (dimethyl ether, diethyl ether, and tetrahydrofuran) which possess high proton affinity but lack acidic protons (thereby only act as hydrogen bond acceptors) are investigated. The complexes are formed in a supersonic jet and jointly studied by electronic and vibrational spectroscopy as well as quantum chemical calculations. Only the N−H···O bound structures are observed for the complexes of IND and BIM with ethers, although computations predict reasonably competent C−H···O type of structures. Remarkably, IND and BIM produce three (N−H···O) conformers with Me2O but single conformers with Et2O and THF. In the case of MBIM, which lacks a conventional hydrogen bond donor, no evidence for C(2)−H···O hydrogen bonds is seen; instead, the complexes are found to be bound purely by van der Waals interactions. The results indicate that strong N−H···O and even weak van der Waals interactions are thermodynamically favored over C(2)−H···O bound structures in these binary gas-phase complexes.


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1. Introduction Non-covalent interactions such as hydrogen bonds play a vital role in regulating the structure and dynamics of a large number of biomolecules.1-2 It is one of the important factors that govern base pairing in nucleic acids, the secondary structures of proteins, and packing in crystals. While strong hydrogen bonds involving polar groups such as O−H and N−H play a dominant role in directing conformational preferences in small peptides and proteins, weak H-bonding groups such as C−H often provide additional secondary stabilization. A large number of surveys on the high-resolution crystal structures of proteins have revealed short C−H···O contacts as H-bonding interactions.3-5 In most cases, these interactions involve a C(α)−H bond which is activated by neighboring electronegative groups (such as N−H and C=O) and the activated CH groups in the heteronuclear aromatic side chains of amino acids such as histidine (His) and tryptophan (Trp). Hydrogen bonds, depending on their type, can span a wide multitude of interaction energies, ranging from the weak van der Waals limit (< 1 kcal mol-1) to the strong covalent limit (> 40 kcal mol-1).6 Conventional H-bonds of the O−H···O or N−H···O type, with typical binding energies of 4 to 15 kcal mol-1, are expected to be most effective in controlling the conformational preferences of small molecules as well as complex hetero-structures owing to their strength and directionality. The effect of weak interactions such as C−H···O (binding energies of 0.25 to 4 kcal mol-1), on the other hand, may become substantial when their cumulative effect is taken into account. This becomes especially important in the context of large macromolecules where many such intra-/intermolecular contacts coexist.7-13 The result of several structural analyses/quantum chemical calculations show the strength of C−H···O interactions involving a backbone C(α) atom to be reasonably competitive with conventional hydrogen bonds.14-17 Thus, it is hardly a surprise that the application of statistical potentials to a set of 469 protein-protein complexes revealed the average energy contribution of conventional and C−H···O H-bonds as 30% and 17%, respectively.18 In fact, in some cases, the energy contribution of the latter can be as high as 40 to 50%. Thus, it is strikingly evident that C−H···O H-bonds have a significant contribution towards protein structures, protein-protein interfaces, and protein-ligand interactions. Among the standard amino acids, the side chains of Trp and His possess the most activated C−H bond. In addition, they also contain a conventional N-H H-bond donor. A computational study 3 ACS Paragon Plus Environment


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of the possible interactions involving amino acids with aromatic side chains revealed that conventional H-bonds of the O−H···O or N−H···O type are strong and usually preferred to unconventional H bonds, such as C−H···O, which mostly occur as secondary interactions.14 The most stable conformation of Trp, isolated and studied in the gas phase, showed an interaction between the carbonyl oxygen and C−H of the pyrrole ring.19 High resolution structures of Trp residues in proteins with a particular "off-rotamer" conformation showed that they are stabilized by bridging C−H···Y···H−C hydrogen bonds.20 The C(2)−H group of the His side chain imidazole, on the other hand, is known to be the most acidic among all amino acids.3 In the active site of multiple serine hydrolases, the C(2)−H bond of His is found to be in close proximity with the oxygen atom of carbonyl group of peptide backbone, imparting important bioactivity to the enzyme.21-22 A possible alternate scheme of binding, namely van der Waals (or dispersion) interaction, is often found to occur between tryptophan and phenylalanine residues, and has also been recently characterized in the indole-hexafluorobenzene intermolecular complex.23 In this article, we study the competition and hierarchy between the N−H···O, C−H···O, and van der Waals interactions in simple model molecules which represent the UV chromophores of Trp and His.24-26 These include indole (IND) and benzimidazole (BIM) as well as the N-methylated analogue of the latter, N-methylbenzimidazole (MBIM). Ethers such as dimethyl ether (Me2O), diethyl ether (Et2O), and tetrahydrofuran (THF) were chosen as solvents for this study which can act only as H-bond acceptors. The 1:1 complexes were prepared by supersonic expansion and studied with the help of IR/UV double-resonance spectroscopy. The IR spectral range covered both the NH and CH regions of the vibrational spectrum. The experimental results were compared with the ab initio computed IR spectra using DFT functionals that account for dispersion interaction. The predictions of multiple conformers and accurate validation of the experimentally observed spectra constitute a test of quantum chemical calculations which are widely used to predict the geometry, conformations, and interaction strengths of clusters.


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2. Methods The experimental apparatus has been described in detail elsewhere.27 In brief, the hydrogenbonded complexes were formed using supersonic expansion and investigated by means of several UV and IR spectroscopic techniques such as laser induced fluorescence (LIF), resonance enhanced twophoton ionization (R2PI), UV-UV hole burning, fluorescence depletion by infrared (FDIR), and IRUV hole burning. The samples IND, BIM, and MBIM (Sigma Aldrich) were heated in a stainlesssteel cell placed behind the nozzle assembly at 65°C, 90°C, and 60°C, respectively, in order to generate sufficient vapor pressure and co-expanded with a buffer gas (He) through a pulsed nozzle. The relevant hydrogen-bonded clusters were prepared by using a premix of Me2O or Et2O or THF in Helium as the buffer gas, with concentrations varying from 0.1 to 0.5 %. The excitation spectra of the jet-cooled complexes were recorded by monitoring the total fluorescence (LIF) as well as the mass selected ion signal (R2PI). An Nd3+:YAG (Quantel YG781C; FWHM ~ 6ns) pumped tunable dye laser (Quantel TDL70) was used as the excitation laser for these experiments. The dye fundamental was calibrated against the fringe spectrum of an etalon. For the R2PI measurements, a second Nd3+:YAG (Quantel Brilliant; FWHM ~ 5ns) pumped tunable dye laser (Pulsare, Fine adjustment) was used as the ionization laser. The excitation and ionization laser pulses travelled in a copropagating manner and were spatially and temporally overlapped on the supersonic jet. IR spectra were recorded in the spectral range between 3600 cm-1 to 2800 cm-1 (covering the NH and CH fundamental stretching regions) using an Nd3+:YAG (Quantel Brilliant; FWHM ~ 5ns) pumped IRLiNbO3 OPO with a bandwidth lowering (~ 0.5 cm-1) etalon (Laser Vision). For all the complexes, each transition observed in the LIF/R2PI spectrum was probed using FDIR spectroscopy. The IR wavelength calibration was performed by measuring and comparing the photoacoustic spectra of NH3 and CH4 gas with the reference lines provided in the HITRAN database.28 The IR pulse was counterpropagated with respect to the exciting UV pulse and preceded it by ~50 ns. Typical IR pulse energies used in the experiment were < 1 mJ in the N-H region, and ~3 mJ in the C-H region. To ascertain the presence of multiple conformers in hydrogen bonded complexes of IND and BIM, IR-UV hole burning spectra were recorded. In these measurements, the UV laser was scanned



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while the IR beam (fired 50 ns prior to the UV pulse) was kept in resonance with a previously measured H-bonded NH stretch of a particular conformer. All transitions corresponding to the same conformer suffered a loss in signal intensity. This confirmed the assignment of multiple conformers of the H-bonded complexes. UV-UV hole burning experiments were carried out (in case of van der Waals complexes of MBIM) to determine whether multiple transitions observed in the LIF/ R2PI spectra originated from the same or different conformers. For these experiments, a higher energy (0.5 mJ) hole-burning UV laser (Quantel Brilliant, FWHM ~ 5ns pumped Quantel TDL90) was scanned through the excitation spectrum of the complex, 150 to 200 ns prior to the probe laser (Quantel YG781C FWHM ~ 6ns pumped Quantel TDL 70), that was fixed at a particular transition in the excitation spectrum. All the transitions in the excitation spectrum which originate from the conformer being probed showed depletion in the hole-burning spectrum. Geometry optimization and harmonic frequency calculation of the N-H···O and C-H···O bound (and van der Waals) complexes was carried out at different levels of DFT (B3LYP, M06-2X, ωB97X-D and LC-ωPBE) using standard Pople type and Dunning type basis sets with diffuse and polarization functions. A correction due to basis set superposition error (BSSE) and zero-point energy (ZPE) was applied to all the clusters to obtain their binding energies. The harmonic frequencies were scaled to match the NH stretching frequencies of the monomers and the same scaling factors were applied to the complexes.27 In case of Et2O and THF, which can possess multiple conformers in the gas phase, all the possible conformers were optimized, although, experimentally the complexes were found to exist mostly in a single conformation. All calculations were performed with the Gaussian 09 suite of programs.29 3. Results and Discussion (a) Complexes of IND with Me2O, Et2O, and THF Figure 1 shows the 2c-R2PI spectra of indole and its complexes with Me2O, Et2O, and THF. The excitation spectra were also measured by monitoring the total fluorescence; a direct comparison of the LIF spectra for the complexes with the R2PI spectra is shown in Figure S1. The band-origin of the monomer, identified at 35240 cm-1, is in good agreement with previous reports.30-32 In the 1:1 intermolecular complexes, the red shift in the band origin transition progressively increases from 6 ACS Paragon Plus Environment

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Me2O (198 cm-1; most red-shifted transition) to Et2O (236 cm-1) to THF (281 cm-1), indicating enhanced stabilization of the excited state by these solvents. Such large red-shifts in the electronic origin of H-bonded complexes are usually characteristic of conventional H-bonded complexes, and therefore are already indicative of the existence of an NH···O H-bond. A notable counterintuitive feature is the significantly richer excitation spectrum of IND-Me2O compared to IND-Et2O and INDTHF complexes. The IND-Me2O complex produced multiple close-lying, moderately strong and strong features at 35042, 35052, 35064, 35072, 35107 and 35115 cm-1. These peaks, red-shifted from the band origin of the monomer by 198, 188, 176, 168, 133, and 125 cm-1, respectively, could be due to multiple conformers or the vibrational progressions of a single (multiple) conformer(s). The specific assignment of the features is deferred till the discussion of the IR spectroscopic data. In contrast, both IND-Et2O and IND-THF gave a single, strong, red-shifted peak at 35004 cm-1 and 34959 cm-1, respectively, which could be unambiguously assigned to their band origin transitions (see Figure S1). The intermolecular H-bond stretching frequency in the S1 state for these two complexes was identified at 86 cm-1 and 154 cm-1 with respect to their respective band origin transitions. The weak feature at 34958 cm-1 in the R2PI spectrum of IND-Et2O was assigned to the IND-(Et2O)2 complex, which appears in the IND-(Et2O)1 R2PI spectrum due to prompt fragmentation either in the S1 state or upon ionization (see Figure S2). The spectral features observed for the IND-THF complex are in good agreement with a previous report.33 The rich excitation spectrum of IND-Me2O is quite unique compared to other 1:1 complexes of indole with oxygen containing solvents, such as water, methanol, and THF.33-34



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Figure 1: 2c-R2PI spectra of (a) IND monomer (b) IND-Me2O, (c) IND-Et2O, and (d) IND-THF obtained by gating the respective masses. The ionization laser energy was set at ~32050 cm-1.

Figure 2: FDIR spectra obtained by probing the electronic transitions of (a) IND monomer at 35240 cm-1, (b) IND-Me2O complex at 35115 cm-1/ 35107 cm-1, (c) 35072 cm-1/ 35064 cm-1/ 35052 cm-1, (d) 35042 cm-1, (e) IND-Et2O complex at 35004 cm-1, and (f) IND-THF complex at 34959 cm-1. The FDIR spectra of IND and its complexes in the NH and CH regions, recorded by probing their band origin transitions, are shown in Figure 2. The NH stretch of the monomer was observed at 8 ACS Paragon Plus Environment

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3527 cm-1 while the CH stretches appeared in the 3020-3150 cm-1 region, in good agreement with previous reports. The IR spectrum of IND in supersonic jet was first reported by Carney et al.34 and subsequently also measured by various groups.31,35 The C(2)–H oscillator in IND is not a local oscillator, unlike that in BIM or MBIM.27 Instead, it is coupled with the C(3)–H to give rise to the symmetric and antisymmetric normal modes. The highest frequency dual feature observed in the CH region at 3147 and 3140 cm-1 are assigned to these two vibrational modes of the pyrrole ring. The remaining four observed at 3092, 3073, 3054, and 3030 cm-1 are assigned to the CH modes of the phenyl ring (Figure S3). The weak features obtained at 3119 cm-1 and 3098 cm-1 are perhaps due to combination bands. In case of any H-bonding that involves the C(2)–H of indole, the features obtained at 3147 cm-1 and 3140 cm-1 would be expected to shift and show an enhancement in the intensity. In complexes of IND with all three solvents, the N-H stretch was substantially shifted to lower frequencies, indicative of solvent molecules attached at the N-H site. No frequency shifts or intensity enhancements are observed for the CH modes of the pyrrole ring. The peaks appearing below 3020 cm-1 correspond to the alkyl CH stretches of the solvent molecule. Interestingly, the INDMe2O complex showed the presence of three N-H bound conformers while the IND-Et2O and INDTHF complexes gave a single conformer each. When the probe laser was set on the red-most electronic transition at 35042 cm-1 in the LIF spectrum of IND-Me2O, the NH stretching frequency of 3278 cm-1 was obtained. Similarly, upon setting the probe on the LIF peaks at 35052, 35064, and 35072 cm-1 gave the same NH stretching frequency of 3381 cm-1 whereas the transitions at 35107 cm-1 and 35115 cm-1 gave a shifted NH peak at 3345 cm-1. Thus, the observed three sets of LIF transitions correspond to three distinctly different conformers, named as conformer A (35042 cm-1), B (35052, 35064, 35072 cm-1), and C (35107 and 35115 cm-1), with red-shifts in the NH stretching frequency of 249 cm-1, 146 cm-1, and 182 cm-1. It appears that the conformer that is most stabilized in the S1 state is also the one for which the red shift in the ground-state NH stretching frequency is the highest. While the alkyl stretches of conformers A and B (figure 2 c, d) are very similar, those corresponding to conformer C (figure 2b) are distinctly different. The assignment of the electronic transitions to



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specific conformers with distinct H-bonded stretches was further confirmer by IR-UV hole-burning spectroscopy (Figure S4). The structures of these conformers will be discussed in section 3(d). The IND-Et2O and IND-THF complexes showed only one N–H···O bound conformer each. The H-bonded NH stretches in these complexes were obtained at 3378 cm-1 and 3320 cm-1, red-shifted from the monomer by 149 cm-1 and 207 cm-1, respectively. Table 1 summarizes the IR spectroscopic data of the IND-Me2O, IND-Et2O, and IND-THF complexes. It is noteworthy that the red-shifts in the H-bonded stretching frequency lay in the order IND-Et2O (149 cm-1) < IND-THF (207 cm-1) < INDMe2O (249 cm-1; the most red-shifted one). The proton affinities of the solvents, however, lie in exactly the opposite order, i.e., Me2O (8.24 eV) < THF (8.55 eV) < Et2O (8.62 eV).36 This suggests that factors other than proton affinity, such as steric factors, may be playing a counter-stabilizing role in IND-Et2O and IND-THF complexes. (b) Complexes of BIM with Me2O, Et2O, and THF The R2PI spectra of BIM and its complexes with Me2O, Et2O, and THF are presented in Figure 3. The band origins of the hydrogen-bonded complexes with all the solvents were red-shifted with respect to that of the monomer (36022 cm-1). While BIM-Et2O and BIM-THF produced single peaks in the R2PI spectra at 35862 cm-1 and 35830 cm-1, red-shifted from the monomer band origin transition by 160 cm-1 and 192 cm-1, respectively, multiple features were observed for the BIM-Me2O complex. The spectral features of the complexes were very similar to those of IND-Me2O complex. Five transitions were identified in the R2PI spectrum of BIM-Me2O at 35900, 35908, 35912, 35920, and 35929 cm-1, which were red-shifted from the band origin of the monomer by 122, 114, 110, 102, and 93 cm-1, respectively. The red-shifts in the electronic origins of the BIM complexes were found to be systematically smaller compared to the case of IND; nonetheless, the red-shifts of ~100 cm-1 are strongly indicative of conventional (NH···O) H-bonding interactions. The assignment of these features to specific conformers or their vibronic modes was done with the help of IR spectroscopy, which will be discussed in Section 3(d). A comparison of the LIF spectra of these complexes with the R2PI spectra is shown in Figure S1.


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Figure 3: 2c-R2PI spectra of (a) BIM monomer and (b) BIM-Me2O, (c) BIM-Et2O, and (d) BIM-THF complexes obtained by gating the respective masses. The ionization laser energy was set at ~ 33600 cm-1.

Figure 4: FDIR spectra obtained by probing the electronic transitions of (a) BIM monomer at 36022 cm-1, BIM-Me2O complex at (b) 35900 cm-1/ 35912 cm-1 (c) 35908 cm-1 (d) 35920 cm-1/ 35929 cm-1, BIM-Et2O complex at (e) 35862 cm-1, and BIM-THF complex at (f) 35830 cm-1. 11 ACS Paragon Plus Environment


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The FDIR spectra of the complexes of BIM are shown in Figure 4. The N-H stretch of the monomer appeared at 3519 cm-1 while the C(2)-H stretch of the imidazole ring appeared at 3095 cm-1.27 In BIM, the C(2)-H stretch (unlike indole) is a local mode. The complexes of BIM with all the solvents showed the presence of a red-shifted NH stretch whereas no changes were identified in the C(2)-H stretching frequency/ intensity. Thus, as in the case of IND, the 1:1 complexes of BIM are all N-H···O bound. Even in the BIM-Me2O complex, which gave multiple features in the excitation spectrum, C-H···O bound structure was not observed. Details of the UV and IR spectral features have been provided in Table 1. Table 1: Summary of the transitions observed in the electronic (νel) and vibrational (νIR) spectra of IND, BIM and MBIM complexes with Me2O, Et2O, and THF and the shifts with respect to the band origin transition (∆νel) and the H-bond donor (NH or C(2)-H) stretching frequencies (∆νIR) of the respective monomers (provided in parentheses at the top of the table). Solvent

Me2O

IND (35240 cm-1/3527 cm-1) νel ∆νel νIR ∆νIR /cm-1 /cm-1 /cm-1 /cm-1 35042

-198

3278

-249

35052 35064 35072 35107 35115

-188 -176 -168 -133 -125

3381 3381 3381 3345 3345

-146 -146 -146 -182 -182

BIM (36022 cm-1/3519 cm-1) νel ∆νel νIR ∆νIR /cm-1 /cm-1 /cm-1 /cm-1 35900 -122 3329 -190 35912 -110 3329 -190 35908

-114

3335

-184

35920 35929

-102 -93

3298 3298

-221 -221

Et2O

35004

-236

3378

-149

35862

-160

3336

-183

THF

34959

-281

3320

-207

35830

-192

3267

-252

MBIM (35595 cm-1/3103 cm-1) νel ∆νel νIR ∆νIR /cm-1 /cm-1 /cm-1 /cm-1 35549

-46

3108

5

35564 35573 35582 35593

-31 -22 -13 -2

3100 3100 3100 3100

-3 -3 -3 -3

35570 35590 35604 35616 35505 35520 35532 35543 35549 35565

-25 -5 9 21 -90 -75 -63 -52 -46 -30

3102 3101 3101 3101 3098 3098 3098 3098 3098 3098

-1 -2 -2 -2 -5 -5 -5 -5 -5 -5

Similar to the IND-Me2O complex, the BIM-Me2O complex also showed the presence of three conformers in the jet, all of which were N–H···O bound. The LIF features at 35900/35912, 35908, and 35920/35929 cm-1, gave three distinct H-bonded NH stretching frequencies at 3329, 3335, and 3298 cm-1, respectively. They were red-shifted by 190, 184, and 221 cm-1, respectively, with respect to the NH stretching frequency of the monomer and are labeled conformers A, B, and C, respectively. For the least stabilized conformer in the S1 state (conformer C), the features obtained in the alkyl CH region (Figure 4d) were similar to those of conformer C of IND-Me2O (Figure 3b) 12 ACS Paragon Plus Environment

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suggesting that the methyl groups may be oriented similarly in both structures (the conformer C in both BIM-Me2O and IND-Me2O complexes registered the lowest red shift in the band origin transition among all three conformers). The ground-state NH stretching frequency in the former, however, showed the highest red-shift while that of conformer C of the IND-Me2O complex was found to be intermediate among its three conformers. The IR-UV hole burning spectra of the BIM-Me2O complex is shown in Figure S5. The BIM-Et2O and BIM-THF complexes gave only one N–H···O bound conformer. The Hbonded NH stretches in these complexes were obtained at 3336 and 3267 cm-1, red-shifted from the monomer by 183 and 252 cm-1, respectively. Table 1 summarizes the IR spectroscopic data of the BIM-Me2O, BIM-Et2O, and BIM-THF complexes. The red-shifts in the H-bonded stretching frequency were in the order BIM-Et2O (183 cm-1) < BIM-Me2O (221 cm-1, 190 cm-1, and 184 cm-1,) < BIM-THF (252 cm-1) while the proton affinities of the solvents are in the order Me2O (8.24 eV) < THF (8.55 eV) < Et2O (8.62 eV),36 implicating the operation of a similar steric effect in destabilizing the BIM-Et2O complex. (c) Complexes of MBIM with Me2O, Et2O, THF Previous reports on the 1:2 and higher stoichiometric clusters of MBIM with water, methanol, and ethanol have showed that they contain hydrogen-bonded bridges stabilized by a C(2)-H···O H-bond.37-38 Therefore, complexes of MBIM with Me2O, Et2O, and THF were also investigated to see whether these solvents with greater proton affinities would bind at the C(2)-H site. Figure 5 shows the 2c-R2PI spectra of MBIM and its complexes with Me2O, Et2O, and THF. The excitation spectra recorded in the LIF mode reproduced the transitions observed in the R2PI spectra (Figure S6). The band origin of MBIM monomer appeared at 35595 cm-1. Multiple features were obtained in the massgated R2PI spectra of the 1:1 complexes of MBIM with each of the ether molecules. The appearance of new features in the electronic spectra of these complexes showed that the ethers bind to MBIM to form a stable complex despite the absence of the NH H-bond donor. The only possible H-bonded structures for these complexes must involve the C(2)–H group (or the phenyl CH) of the chromophore. In the electronic spectra of the MBIM-ether complexes, two major differences were noted in comparison to those of BIM/IND; (i) the complexes of MBIM with all three ethers exhibited 13 ACS Paragon Plus Environment


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multiple features in the electronic spectra, suggesting that either multiple conformers exist for these complexes or the spectra are rich in low frequency intermolecular transitions, (ii) The magnitude of the red shifts in the electronic features was of the order of 5 to 90 cm-1 which are much smaller compared to the corresponding complexes with IND/BIM. Such small shifts in the electronic origin are characteristic of complexes that are weakly stabilized in the excited state. In addition, the MBIMEt2O complex also gave two features that were blue-shifted with respect to the band origin of the monomer at 35595 cm-1.

Figure 5: 2c-R2PI spectra of (a) MBIM monomer and (b) MBIM-Me2O, (c) MBIM-Et2O, and (d) MBIM-THF complexes obtained by gating the respective masses. The ionization laser energy was set at ~31750 cm-1. UV-UV hole-burning spectra of the complexes are also shown over the R2PI spectra along with the position of the probe laser. There was one to one correspondence between the LIF and R2PI features that were obtained for the 1:1 MBIM-Me2O complex at 35549, 35564, 35573, and 35582 cm-1 (Figure S6). An additional weak feature was obtained in the R2PI spectrum at 35593 cm-1 which was obscured in the LIF by the strong monomer resonance at 35595 cm-1. The MBIM-Et2O complex gave features at 35570, 35590,


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35604, and 35616 cm-1 both in the LIF and the R2PI spectra of 1:1 complex. Additional peaks were observed in the LIF spectrum at 35516, 35559, and 35580 cm-1. Among them, the first two were found to be due to the 1:2 and 1:3 complexes of MBIM with Et2O from mass gated R2PI spectra of the respective clusters (Figure S6), respectively. The peak at 35580 cm-1 in the LIF spectrum remains unassigned at present but possibly arises due to higher order cluster. For the MBIM-THF complex the features obtained in the LIF spectrum up to 35500 cm-1 were all reproduced by the R2PI spectrum of the 1:1 complex. The weak features appearing in the LIF at 35450 cm-1 and 35428 cm-1 were found to arise from the 1:2 complex of MBIM with THF from the mass-gated R2PI spectrum (Figure S6). The positions of the electronic features for the complexes of IND, BIM, and MBIM with all the ethers as well as their shifts from the band origin transition of the respective monomers are summarized in Table 1. Since the complexes of MBIM with all the ethers gave multiple features in the electronic spectra, UV-UV fluorescence hole-burning (HB) spectra of the complexes (Figure 5) were measured in order to investigate the number of conformers corresponding to each complex. In these experiments, the probe UV laser was tuned to a particular transition in the R2PI spectrum while scanning the pump UV laser. The MBIM-Me2O complex showed the presence of two conformers in the UV-UV HB spectra obtained when the probe laser was set at 35549 cm-1 and 35573 cm-1. While the former selectively removed only the feature at 35549 cm-1, the latter yielded dips in the signal for the remaining four peaks (35564, 35573, 35582, 35593 cm-1) which must therefore arise from the same conformer. These two conformers of the MBIM-Me2O complex have band origin transitions at 35549 cm-1 and 35564 cm-1. The UV-UV HB spectra for MBIM-Et2O, obtained by probing the transitions at 35570 and 35590 cm-1, also revealed the presence of two conformers. While the latter selectively removed three of the electronic transitions, the former produced a dip at 35570 cm-1. Additional bands that appear in the former are due to the high intensity of the pump (hole-burning) laser.39-43 The HB spectrum of the MBIM-THF complex obtained upon setting the probe laser at 35505 cm-1 depleted all the features, showing that the MBIM-THF complex consists of only one conformer.



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Figure 6: FDIR spectra obtained by probing the electronic transitions of (a) MBIM monomer at 35595 cm-1, (b) MBIM-Me2O complex at 35549 cm-1 (c) 35564, 35573, 35582, and 35593 cm-1, (d) MBIM-Et2O complex at 35590, 35604, and 35616 cm-1 (e) 35570 cm-1, and (f) MBIM-THF complex at 35505, 35520, 35532, 35543, 35549, and 35565 cm-1. The FDIR spectra of MBIM and its complexes are shown in Figure 6 in the spectral range covering the aromatic and aliphatic C-H stretching fundamentals. Trace (a) shows the IR spectrum of the monomer by probing its band origin at 35595 cm-1. The assignment of the monomer C-H stretches has been described in detail in an earlier report.27 Briefly, the C(2)-H stretch of imidazole is obtained at 3103 cm-1; the next three stretches at 3077 cm-1, 3065 cm-1, and 3056 cm-1 are ascribed to the C-H stretches of the phenyl ring while the ones at 3047 cm-1, 3004 cm-1, and 2968 cm-1 are assigned to the C-H stretches of the methyl group. Any involvement of the C(2)–H as an H-bond donor in these complexes must manifest as a shifted and/or intense IR absorption of the corresponding mode in the IR spectrum. The FDIR spectra of the complexes along with those of the multiple conformers (where applicable) are shown in the successive traces. The positions of the probe laser corresponding to these spectra were 35549 cm-1 (b, MBIM-Me2O), 35564, 35573, 35582, and 35593 cm-1 (c, MBIM-Me2O), 35590, 35604, and 35616 cm-1 (d, MBIM-Et2O), 35570 cm-1 (e, MBIM-Et2O), and 35505, 35520, 35532, 35543, 35549, and 35565 cm-1 (f, MBIM-THF). The peaks between 3040 and 3150 cm-1 in the 16 ACS Paragon Plus Environment

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FDIR spectra shown in Figure 6 represent the stretching frequencies of the aromatic C–H stretches of the chromophore whereas those below 3015 cm-1 are due to the aliphatic C–H stretches of the solvent molecules. No enhancement in the C(2)–H mode could be detected in any of the complexes indicating that it is not involved in H-bonding. Since the C(2)–H bond is the only possible H-bond donor in these intermolecular complexes, it is concluded that these are not H-bonded but are bound by van der Waals interaction. As van der Waals complexes lack the directionality unique to H-bonds, it is difficult to map out the specific structural characteristics in the conformers of the MBIM-Me2O and MBIM-Et2O complexes. Table 1 lists the IR spectroscopic data of the complexes of MBIM with the ethers. (d) Nature and hierarchy of the intermolecular interactions The band origin transition in all the N-H···O bound complexes of IND and BIM investigated in this study showed large red shifts in the range of 100 to 285 cm-1. It is interesting to note that analogous O-H···O bound complexes of p-fluorophenol (phenol is the aromatic side-chain of tyrosine) with Me2O and THF produced much larger red-shifts of 530 and 565 cm-1, respectively, reflecting very strong stabilization of the excited state.44 This is because phenol is a strong photoacid, i.e. its acidity is higher in the excited state compared to the ground state.45 This is also consistent with the finding that O-H···O bonds where Tyr acts as donor are stronger than N-H···O bonds in Trp.14 Figure 7 shows how the shifts in the band origin of the N-H···O bound complexes of IND and BIM scale with the proton affinity of the solvent. Spectroscopic data corresponding to the complexes of BIM with H2O, MeOH, and EtOH reported in the previous reports were used to obtain the correlation.36 The relevant spectroscopic data for the IND-H2O, IND-MeOH, and IND-EtOH complexes were obtained from the literature.30, 33-34, 46-47 It can be seen from the figure that the redshift in the band origin transition of the N–H···O bonded complexes scales linearly with the proton affinity of the solvent. Linear correlation coefficients of 0.863 and 0.898 were obtained respectively for IND and BIM. This implies that the relative stabilization of these complexes in the excited state in comparison to the ground states are enhanced with increasing the proton affinity of the solvent, as also observed in the case of O-H···O/N H-bonded phenols.48-49 Similarly, the red shift of the bonded NH stretching frequency in the ground state of the complexes (Figure 7) also yielded a linear correlation with the proton affinity of the acceptor molecules with correlation coefficients of 0.995 (IND) and 17 ACS Paragon Plus Environment


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0.948 (BIM). Data points corresponding to Et2O were not included in the analysis as they were clear outliers (possibly due to steric hindrance). Thus, it may be inferred that the N–H···O H-bond also obeys the acid-base formalism of hydrogen bonding, similar to the O–H···O interaction.44

Figure 7: Correlation between (left) red-shifts in the band origin of the S0–S1 electronic transitions and proton affinity of the acceptor molecules, (right) red-shifts of the bonded NH vibrational frequencies and proton affinity of the acceptor molecules (data-points corresponding to Et2O are outliers and not included in the fit). We now turn to the structures corresponding to the multiple conformers observed in the experiment for some of the NH···O bound complexes. The different structures optimized for each of the NH···O bound complexes include lin, ph, py (im), and ⊥ (Figure 8), which are used to denote the orientation of the C2 axis (or C–O–C angle bisector) of the solvent molecule (Me2O, Et2O, THF) either lying in line with the H-bond (lin), tilted towards the phenyl ring (ph), tilted towards the pyrrole/imidazole ring (py/im), or perpendicular to the aromatic plane (⊥).31 These structures were optimized using B3LYP and the DFT functionals with dispersion correction (M06-2X, ωB97X-D, and LC-ωPBE). It must be mentioned that none of the functionals yielded all of the aforementioned structures as stable optimized geometries. While the lin conformer could only be obtained at the B3LYP and LC-ωPBE levels, the ph, py (im), and ⊥ conformers were primarily favored at the M062X and ωB97X-D levels. This rendered the unambiguous assignment (especially for the IND-Me2O and BIM-Me2O complexes) difficult as can be seen from the comparison of the experimental and computed spectra in Figure S7. Extensive summary of the computations at various levels of theory along with their respective binding energies are given in Tables S1-S3.


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Figure 8: Optimized structures of the lin, ph, py(im), and ⊥ structures of the complexes of IND/BIM with Me2O, Et2O, and THF obtained at the LC-ωPBE/aug-cc-pVDZ level (lin) and ωB97-xD/aug-ccpVDZ level (ph, py(im), and ⊥) showing the H···O bond lengths (in Å) and N–H···O bond angles (in °). An alternative means of binding to the aromatic groups of IND and BIM is via the CH bonds. There are a number of CH bonds in IND and BIM, however, the one that binds most strongly is located on the five-membered ring, next to the N atom. The interaction energy of IND-water has been reported as 2.1 kcal mol-1 for the C(2)-H, lower by 1 kcal mol-1 for the C(3)-H, and lower still (almost comparable to benzene) for the phenyl CH bonds.14 The presence of two N atoms in BIM renders the C(2)-H more acidic, with an estimated binding strength of 2.4 kcal mol-1 with water,14 comparable to the C(α)H of amino acids.



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Figure 9: Optimized structures of the C(2)–H···O bound complexes of IND, BIM, and MBIM with Me2O, Et2O, and THF computed at the ωB97-xD/aug-cc-pVDZ level, showing the H···O bond lengths (in Å) and C–H···O bond angles (in °). Figure 9 shows the C(2)-H···O bound structures obtained as local minima at the ωB97xD/aug-cc-pVDZ level. The CH···O bond distances were found to lie between 2.18 to 2.34 Å, systematically higher by 0.3 to 0.4 Å in comparison to the N–H···O bound structures. In addition to the primary C(2)-H···O H-bond, the computed CH-bound structures of BIM and MBIM with all three solvents also showed a secondary alkyl C-H···N type of interaction. The binding energies of these complexes were found to lie in the range 2.7-4.5 kcal mol-1, which was about one-half to two-thirds of those of the N–H···O bound complexes. Table 2 summarizes the binding energies (ZPE and BSSE corrected), change in the XH (donor) bond distance, and the red shifts in the XH stretching frequency of the complexes. Even though their computed binding energies were reasonably competitive to the N-H···O bound structures (Table 2), they were not detected experimentally. Computed frequency shifts of the H-bonded C(2)–H stretching mode were found to be in the range of 10 cm-1 to 40 cm-1 to the red side of the monomer C(2)–H frequency. As expected, the N–H···O H-bonding interaction dominates the binding preference of these chromophores; the unconventional CH donor is thermodynamically weaker to compete with the NH site. However, even when the NH site is blocked (in MBIM), there was no evidence of the C(2)-H···O interaction in the FDIR spectra (Figure 6). The 20 ACS Paragon Plus Environment

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possible inference is that in the case of MBIM-ether complexes, the solvent molecules are bound by van der Waals interaction in preference to the C(2)–H···O H-bonded ones. Figure S8 shows the computed structures of MBIM-ether complexes at the ωB97-xD/aug-cc-pVDZ level. These results in conjunction with our earlier work on the microsolvation of BIM/MBIM with water,27, 37 methanol,38 and ethanol38 suggest that a C–H···O interaction in tryptophan/histidine analogues can perhaps only serve as a secondary interaction, lending additional stabilization to stronger hydrogen bonds. Table 2: Binding energies (D0, kcal mol-1), change in the bond length of the H-bond donor (∆X-H, Å) and red shifts in the XH stretching frequency (∆ν) for various conformers (N–H···O, C(2)–H···O, and van der Waals) of the complexes of IND, BIM, and MBIM with ethers, computed at the ωB97-xD/ aug-cc-pVDZ level. (Only the ph conformer is included for the N–H···O bound complexes. For the vdw complexes, the shift of the C(2)-H which is not H-bonded is included only for comparison) Complex IND-Me2O IND-Et2O IND-THF BIM-Me2O BIM-Et2O BIM-THF MBIM-Me2O MBIM-Et2O MBIM-THF

Conformer N–H···O C–H···O N–H···O C–H···O N–H···O C–H···O N–H···O C–H···O N–H···O C–H···O N–H···O C–H···O vdw C–H···O vdw C–H···O vdw C–H···O

D0 (kcal mol-1) 5.689 2.671 7.955 3.280 7.514 3.626 6.356 3.531 8.282 3.747 8.169 4.315 4.382 3.154 5.887 3.998 7.371 5.131

∆X-H (Å) 0.0105 0.0016 0.0087 0.0016 0.0126 0.0022 0.0120 0.0022 0.0090 0.0025 0.0147 0.0026 -0.0009 0.0019 -0.0004 0.0020 -0.0003 0.0027

∆νX-H (cm-1) 168 19 140 28 205 30 192 37 136 42 245 40 -7 35 0 33 -1 38

It must be mentioned that the proton affinities of the solvents in the present study Me2O (7.95 eV), Et2O (8.33 eV), and THF (8.26 eV) are higher than those of H2O (7.19 eV), MeOH (7.84 eV), and EtOH (8.07 eV),36 for which a clear evidence of a C(2)-H···O H-bond was found for clusters with stoichiometry greater than 1:1 in BIM/MBIM.37-38 In spite of that, the C(2)–H···O structures are not seen to be strong enough to compete with conventional H-bonding interaction of the N–H···O type. Interestingly, when the N–H donor is methylated in BIM, the structures of the resulting MBIM-ether 21 ACS Paragon Plus Environment


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complexes are seen to prefer van der Waals type of interaction rather than a C(2)–H···O H-bond. Two inferences can be drawn from these observations; first, the weakly activated C(2)–H bond in the five-membered pyrrole/imidazole ring is not strong enough to compete with the more conventional N–H donor, and second, the C(2)–H bond can perhaps only cooperatively strengthen an H-bonded system as a source of secondary stabilization27, 37 as van der Waals interactions seem to be preferred for the binary complexes with the ethers. 4. Conclusion The complexes of IND, BIM, and MBIM with Me2O, Et2O, and THF were studied with a focus on the competition between conventional (N–H···O), unconventional (C–H···O) H-bonding interactions and van der Waals interactions in the model compounds of the amino acids Trp and His. While the electronic spectra of the complexes of IND and BIM with Me2O showed the presence of multiple features, those with Et2O and THF showed only one feature corresponding to the 1:1 complex. IR-UV double resonance and hole burning spectra revealed the existence of three conformers each for the IND-Me2O and BIM-Me2O complexes whereas only single conformers were identified in case of the complexes of IND and BIM with Et2O and THF. Upon probing each of the electronic transitions of the H-bonded complexes with IR, it was seen that they were all N–H···O bound. The shifts in the bound N–H stretching frequency in the H-bonded complexes were found to be 150 to 250 cm-1 for the three complexes of IND and 180 to 250 cm-1 for the complexes of BIM. No changes could be identified in the aromatic CH region of the vibrational spectrum, suggesting that the CH modes of the chromophore are not affected by the H-bonding interaction. Multiple conformers were found to exist for the IND-Me2O and BIM-Me2O complexes. It is unclear why multiple conformers were identified in the complexes of IND and BIM with Me2O while only single conformers were found in case of the complexes with Et2O and THF. It requires further theoretical investigation in the future and may likely be due to higher barriers for interconversion in Me2O compared to Et2O/ THF due to which the former gets trapped into multiple local minima while the latter are channelized into the global minimum by multiple collisions with the buffer gas. In case of the MBIM-ether complexes, there was no clear evidence of a C(2)H···O interaction and hence it is inferred that these complexes are bound by van der Waals interaction. These results provide insight 22 ACS Paragon Plus Environment

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into the nature, strength, and hierarchy of common non-covalent interactions in fundamental binary gas-phase complexes.

Supporting Information: Comparison of the LIF and 2c-R2PI spectra, FDIR spectrum of IND monomer in the CH region, IR-UV hole burning spectra of the IND/BIM–Me2O complex, computed IR stick spectra, binding energies and molecular co-ordinates of selected H-bonded complexes.

Acknowledgement: A.B. and S.W. gratefully acknowledge funding from the Tata Institute of Fundamental Research, India.



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Nature and Hierarchy of Non-Covalent Interactions in Gas-phase

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