An infrared spectroscopic study of protonated and cationic indazole

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Abstract

The mid-infrared vibrational spectra of the cationic and protonated forms of the molecule indazole (C7N2H6) are recorded in the gas phase, applying the method of free electron laser induced multiple photon dissociation spectroscopy in a quadrupole ion trap. The spectra are compared to density functional theory calculations, which for the protonated species suggests that the proton attaches to the pyridine-like nitrogen atom. The spectrum of the indazole cation raises the question whether indazole undergoes an N1–N2 H atom shift upon ionization. The spectra for the charged species are further discussed in comparison with the spectrum of neutral indazole. Although the spectral range probed in this study, 600–1800 cm−1, does not cover the hydrogen stretching modes, the spectra are found to be very distinct, indicating how a subtle change in electron distribution can have major effects on the vibrational spectrum of a conjugated system.

Introduction

In recent years, there has been a growing interest in the spectroscopic investigation of biologically relevant molecules in the gas phase [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], aiming at a characterization of their intrinsic structural properties, free from any environmental effects. Particularly the “fingerprint” mid-infrared wavelength range of the spectrum is effective to obtain structural information. Elegant UV–IR pump-probe methods have been developed to obtain conformer specific infrared spectra. Systems studied include nucleic acid bases [5] and base pairs [1], amino acids [6], [7], saccharides [8], small peptides [9], [10], [11], neurotransmitters [12], et cetera.

Evidently, protonation is a process of key biochemical interest. Obtaining infrared spectra of protonated species, however, involves the study of ionic species in the gas phase, and this is, in general, not a sinecure [13]. Several small, prototypical, protonated molecules such as H3+, H3O+, and HCO+[14] have been investigated with IR spectroscopy in the 1970s and 1980s. In these studies, mainly discharge and electron impact ionization sources have been used, which are not well suited for larger, biologically relevant molecules as they induce severe or even complete fragmentation of those species. The use of more gentle and/or mass-selective methods of ionization, inherently decreases the ion densities and therefore generally precludes the application of direct absorption spectroscopy. Recently, however, several spectroscopic studies of gas-phase protonated species have been reported [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], based mainly on infrared photo-dissociation spectroscopy. Among others, these studies have been very successful in determining the protonation site. In addition, IR spectra of some proton-bound dimers, most notably the protonated water dimer H5O2+, have recently been reported [24], [25], [26], [27], [28]. Other recent exciting studies are the infrared spectrum of protonated methane (CH5+), obtained using laser induced reaction in a low-temperature ion trap [29], and the infrared spectra of multiply protonated proteins [30], [31].

Initially, most of these studies were performed in the wavelength region around 3 μ m (where table-top laser systems are widely available) as the hydrogen stretching modes in this range are obviously very sensitive to protonation. Since the coupling of ion trapping devices to infrared free electron lasers at our institute [32], [33] as well as at Orsay, France [34], the mid/far-infrared range became accessible and multiple photon dissociation spectroscopy of several protonated systems has been reported [18], [20], [22], [23], [25], [26]. Although not directly probing the H stretching modes, these experiments allow, in combination with DFT computations, to locate the protonation site equally well.

The IR photo-dissociation studies can roughly be divided into two groups: one where with a relatively low intensity laser a weakly bound messenger atom is detached, and one where with the use of powerful lasers, the ionic molecule itself is dissociated through the absorption of multiple photons. The experiments belonging to the second group are almost exclusively carried out in ion traps, where the parent ion is first mass selectively isolated and IR induced fragments are subsequently detected in the mass analyzer. This strategy is similar to the one used in extenso by Lifshitz and co-workers, in her studies of the dissociation behavior of molecular ions following electronic excitation [35], [36]. The rate of internal energy conversion plays an extremely important role in this behavior; when it is relatively slow, dissociation may occur on electronically excited potential energy surfaces, which may be markedly different from those originating from the electronic ground state. The understanding of the resulting non-statistical dissociation behavior has been one of the major achievements of the work of Lifshitz [37]. Unlike electronic excitation, pure vibrational excitation, as is used in IR multiple photon dissociation (IRMPD), involves only the ground electronic state. Here, energy randomization is governed by intramolecular vibrational redistribution (IVR) and the associated relaxation rates are in general very fast for polyatomic molecules. Therefore, IR induced fragmentation is commonly believed to follow statistical unimolecular dissociation behavior. In IRMPD spectroscopy, this is of importance since it allows one to assume that dissociation rates depend only on the internal energy distribution obtained and not on the particular vibration that was excited. Thus, relative intensities in the observed spectrum can be considered to be meaningful.

There has been much interest in the spectroscopy and structure of nitrogen containing aromatic heterocycles (5/6 rings) mainly because of their close resemblance to various biochemically relevant compounds, particularly to the nucleic acid bases adenine and guanine and to the amino acid tryptophane. The gas-phase spectrum of indazole, C7H6N2(see Fig. 1), has been studied throughout the microwave, infrared, visible, and ultraviolet wavelength ranges [38], [39], [40], [41], [42]. A central question in these studies has been the 1H–2H tautomerization, i.e., the N1–N2 hydride shift (see structures Aand Bin Fig. 1). Based on these spectroscopic studies as well as on thermodynamical studies [43], the 1H-tautomer was determined to be more stable both in the electronic ground state as well as in the first electronically excited (ππ) state. This was rationalized by the higher aromaticity of 1H-indazole, making this form energetically more favorable than 2H-indazole by 2–4 kcal/mol [38], [43], [44]. To the best of our knowledge, no infrared data for the charged species have been reported to date. A mass-analyzed threshold ionization (MATI) spectrum of indazole, giving information on the vibrational structure in the cation, was very recently reported [45]. Here, we present infrared spectra for protonated indazole as well as for bare cationic indazole and compare these to the spectrum of neutral indazole [39]. Despite the fact that the hydrogen stretching modes, which would obviously be quite different for the protonated species, are not probed in this study, the spectra are found to be very distinct. The mid-infrared spectral range investigated mainly contains the more delocalized heavy atom stretching modes of the C/N skeleton, as well as some hydrogen bending modes. Apparently, the relatively small changes in electron densities leave a strong imprint on the vibrational spectrum.

Section snippets

Experimental

The infrared spectra are obtained via free electron laser (FEL) induced multiple photon dissociation spectroscopy of the ions stored in an ion trap. The experimental apparatus, described in detail elsewhere [32], consists of a Paul-type quadrupole ion trap [46] coupled to a time-of-flight mass spectrometer. It follows the original design of Lubman and co-workers [47] that was also used in many of the studies of Lifshitz and co-workers [35]. Vapor-phase indazole is non-resonantly ionized using

Results and discussion

The mass resolution of the ion trap, which is just sufficient to resolve the 118 and 119 mass peaks in the TOF trace (see Fig. 2), is insufficient to selectively isolate one of the two species. Therefore, the IR photo-dissociation spectra of the protonated and cationic indazole molecule are recorded simultaneously, where it is assumed that the cationic molecule dissociates solely into mass channel 91 and the protonated molecule solely into m/z=92, and that there is no cross-talk between the two

Conclusions

Gas-phase infrared spectra are presented for protonated as well as for cationic indazole. The spectra are compared to DFT computed spectra and to the spectrum of the neutral molecule. The protonation site of the molecule has been established to be the pyridine-like nitrogen atom, which is the most negatively charged site in the neutral molecule. The agreement between computed and experimental spectra is reasonable for the closed-shell species, the protonated and neutral molecule, but somewhat

Acknowledgments

We would like to thank one of the reviewers for alerting us to the issue of tautomerism in indazole and we further thank Dr. G. Berden and Dr. E. Jalviste for helpful discussions on this subject. This work is part of the research program of FOM, which is financially supported by the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO). We highly appreciate the skillful assistance by the FELIX staff.

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