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Tautomer-Selective Spectroscopy of Nucleobases, Isolated in the Gas Phase Mattanjah S

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Tautomer-Selective Spectroscopy of Nucleobases, Isolated in the Gas Phase Mattanjah S 177 7 Tautomer-Selective Spectroscopy of Nucleobases, Isolated in the Gas Phase Mattanjah S. de Vries 7.1 Introduction In his book The Double Helix, James Watson describes an early proposal for DNA structure in which equal bases pair with each other. He writes: ‘‘My scheme was torn to shreds the following noon. Against me was the awkward chemical fact that I had chosen the wrong tautomeric forms for guanine and thymine.’’ This fact was pointed out to him by the American crystallographer Jerry Donahue who ‘‘ ... protested that the idea would not work. The tautomeric forms I had copied out of Davidson’s book were, in Jerry’s opinion, incorrectly assigned. My immediate retort that several other texts also pictured guanine and thymine in the enol form cut no ice with Jerry. Happily he let out that for years organic chemists have been arbitrarily favoring particular tautomeric forms over the alternatives on only the flimsiest of grounds’’ [1]. Without the correct keto form of these bases, Watson and Crick could not have arrived at their successful structure of DNA. In fact, for each of the bases, the keto tautomer is the form normally occurring in DNA. The rare imino and enol forms can lead to alternate base-pair combinations and thus cause mutations in replication. This type of mutation is called a tautomeric shift [2, 3]. Possible mismatches include iminoC–A, enolT–G, C–iminoA, and T–enolG. Tautomerization can occur in DNA by single or double proton transfer. In solution equilibrium, generally the keto form dominates, complicating efforts to study the properties of the individual forms. One approach to studying tautomeric properties is double-resonant gas-phase spectroscopy, as this technique offers isomeric selectivity. This chapter summarizes the results from such investigations. 7.2 Techniques As molecules can exist in tautomeric equilibria, most experimental techniques need to address mixtures of tautomer populations. Double-resonant techniques in Tautomerism: Methods and Theories, First Edition. Edited by Liudmil Antonov. © 2014 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2014 by Wiley-VCH Verlag GmbH & Co. KGaA. 178 7 Tautomer-Selective Spectroscopy of Nucleobases, Isolated in the Gas Phase the gas phase offer opportunities to perform isomer-selective spectroscopy. This capability makes it possible to obtain detailed spectroscopy of individual tautomers. The first challenge is to form molecular beams with nucleobases that are thermally labile and have low vapor pressures. One solution is the combination of laser desorption and jet cooling. The process of neutral laser desorption is very poorly understood. The general idea is that fragmentation is minimized when the timescale for heating is shortened. The rates required to desorb molecules without fragmentation are of the order of 1011 Ks−1, which corresponds to a 1000 K temperature jump in a typical 10-ns laser pulse. Entraining the desorbed molecules in a supersonic expansion to achieve jet cooling offers three advantages: cooling (i) improves spectroscopic resolution, (ii) reduces fragmentation, and (iii) provides a pathway for cluster formation. Such combination requires careful optimization of the geometry of the apparatus [4–7]. By analyzing rotational profiles, Meijer et al. showed in the case of anthracene, entrained in helium, that a rotational temperature ◦ of less than 15 K is attainable. Commonly, the sample is moved to expose a fresh part of the sample in subsequent shots by a translating bar [6], a rotating rod [8], or a rotating wheel [9]. For ions, generally introduced by a electrospray, even better cooling can be achieved in a liquid- helium-cooled 22-pole trap [10]. The lowest temperatures are achieved in liquid helium droplets into which nucleobases have been introduced in a pickup source [11]. In principle, any molecular beam or gas- phase technique can be combined with such sources but the most relevant ones for investigating tautomer properties are forms of spectroscopy, particularly resonant two-photon ionization (R2PI), laser-induced fluorescence (LIF), hole-burning or double-resonant spectroscopy, microwave spectroscopy, infrared (IR) absorption, and combinations of these with any spectrometry and electron spectroscopy. The combination of R2PI and hole-burning makes it possible to obtain spec- troscopy of selected individual tautomers. The resonant absorption of a primary photon is recorded by the detection of a photo-ion formed by successive absorption of a second photon [12]. Ions lend themselves to very sensitive detection and to mass selection. These properties provide several advantages: (i) good signal to noise, (ii) cluster selection, and (iii) potentially additional information from fragmentation. Similar to LIF, the technique is blind to short-lived dark states: if the excited-state lifetime is significantly shorter than the laser pulse, absorption of the second photon becomes very weak. Another problem occurs when the ionization potential is more than twice the resonant excitation energy. In that case, a two-color scheme may be required. For spectral hole-burning, the ionization step is preceded by a pulse from a tunable IR laser. This pulse resonantly alters a specific population in the beam, which is probed as a decrease in the ion signal [13–18]. This technique produces ground-state IR absorption spectra of optically selected as well as mass-selected molecules. The OH and NH stretching frequencies are especially highly specific for different tautomeric forms as well as for hydrogen-bonded structures. Fourier transform microwave spectroscopy can provide highly specific tautomeric data as well as conformational analysis derived from rotational spectra (Figure 7.1). Alonso and coworkers [19–21] have combined this approach with laser desorption 7.3 Guanine 179 (a) (b) (c) IP S1 S0 R2PI UV–UV IR–UV Figure 7.1 Schematic diagram of spectroscopic techniques based on two-photon ioniza- tion and used in gas-phase experiments. Dashed arrows indicate tuned laser pulses; solid arrows indicate fixed wavelength laser pulses. In schemes (b) and (c), these are used as burn and probe lasers, respectively. jet cooling and applied the combination to the study of conformations of a number of amino acids. Their approach features a molecular beam along the axis of a large microwave cavity (55-cm mirrors) which monitors emission following a short microwave excitation pulse. Rotational analysis permits determination of all conformations present in the beam. For example, this technique identified six conformations for aspartic acid [20]. It is not clear at this point what maximum size will be amenable to this type of analysis. Helium droplets spectroscopy is usually performed in the IR. Resonant absorp- tion by specific vibrational modes implies heating, resulting in helium atoms boiling off the droplets. By recording this effect in a mass spectrometer or with a bolometer, IR absorption spectra can be obtained. However, in this approach tautomeric selection is not possible. Progress in experimental capabilities is bolstered by the simultaneous progress in computational capabilities, creating a great synergy between experiment and theory. While quantum chemical calculations guide interpretation of spectra and help model structures and dynamics, at the same time gas-phase experimental data help calibrate algorithms, force fields, and functionals [22]. 7.3 Guanine The first gas-phase spectroscopy of nucleobases was reported by Levy and coworkers in 1988 [23]. They measured the electronic spectra of the pyrimidine bases uracil and thymine in a supersonic molecular beam both by LIF and REMPI. The observed spectra were very broad and featureless, in spite of efficient jet cooling. 180 7 Tautomer-Selective Spectroscopy of Nucleobases, Isolated in the Gas Phase OO O O O 1 6 5 N7 N N N N N 8 N N N N 2 4 N9 N N N N N N3 N N N N N N N N Watson–Crick Keto-N7H Keto-N9H trans-Enol-N9H cis-Enol-N9H trans-Enol-N7H 0 184 203 310 1189 O O O O O N N N N N N N N N N N N N N N N N N N N N N N N N Keto-N3H-N7H Keto-imino-down-N7H Keto-imino-up-N7H cis-Enol-N7H Keto-imino-up-N9H 2073 2438 2464 3646 5128 O O O O O N N N N N N N N N N N N N N N N N N N N N N N N N Keto-imino-down-N9H trans-Enol-imino-up-N7H Keto-N3H-N9H trans-Enol-imino-down-N7H trans-Enol-imino-up-N9H 5729 6523 6539 8084 6523 Figure 7.2 Fifteen of the lowest energy tautomers of guanine. Relative energies are in wavenumbers. From Ref. [27]. Solidly shaded structures are observed in gas-phase nanosecond R2PI experiments. Hashed structures have subpicosecond excited-state lifetimes. The rectangle marks the structures observed in helium droplets. Keto-N9H is the Watson–Crick structure. 7.3 Guanine 181 The authors speculated about photo-tautomerization as a possible explanation for such a spectrum. The absence of useful vibronic features discouraged the pursuit of gas-phase spectroscopy of nucleobases for a decade until Nir et al. [24] published a well-resolved R2PI spectrum of guanine. This finding was followed by similar spectra of adenine and cytosine [25, 26]. These initial spectra contained contributions of all the tautomers present in the beam, complicating interpretation. Such an R2PI spectrum could potentially consist of overlapping spectra of a number of tautomers. Figure 7.2 shows the 15 lowest energy tautomer structures of guanine with their energies given in wave numbers as computed by Seefeld et al. (B3LYP/TZVPP//RIMP2/cc-pVQZ, ZPE corrected) [27]. The second most stable form, keto-N9H at 184 cm−1, is the form in Watson–Crick base-pairing in DNA. In solution the keto forms dominate. In matrix-isolation IR observation of C=O stretch, frequencies points to keto forms but too many lines are present in the spectra to be able to exclude other tautomers as well [28].
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