Spectroscopic Characterization of Nicotinoyl and Isonicotinoyl

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A: Spectroscopy, Molecular Structure, and Quantum Chemistry

Spectroscopic Characterization of Nicotinoyl and Isonicotinoyl Nitrenes and the Photointerconversion of 4-Pyridylnitrene with Diazacycloheptatetraene Qian Liu, Yuanyuan Qin, Yan Lu, Curt Wentrup, and Xiaoqing Zeng J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.9b01680 • Publication Date (Web): 12 Apr 2019 Downloaded from http://pubs.acs.org on April 13, 2019

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The Journal of Physical Chemistry

Spectroscopic Characterization of Nicotinoyl and Isonicotinoyl Nitrenes and the Photointerconversion of 4-Pyridylnitrene with Diazacycloheptatetraene

Qian Liu,† Yuanyuan Qin,† Yan Lu,† Curt Wentrup,*,‡ Xiaoqing Zeng*,† †

College of Chemistry, Chemical Engineering and Materials Science, Soochow University, 215123 Suzhou, China E-mail: [email protected]

‡School

of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland 4072, Australia E-mail: [email protected]

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Abstract: Recently, nicotinoyl nitrene (2) has been generated from the photodecomposition of nicotinoyl azide (1) and used as the key intermediate in probing nucleobase solvent accessibility inside cells. Following the 266 nm laser photolysis of nicotinoyl azide (1) and isonicotinoyl azide (5) in solid N2-matrices at 15 K, nicotinoyl nitrene (2) and isonicotinoyl nitrene (6) have now been identified by matrix-isolation IR spectroscopy. Both aroyl nitrenes 2 and 6 adopt closed-shell singlet ground states stabilized by significant Nnitrene···O interactions, consistent with the spectroscopic analysis and calculations at the CBS-QB3 level of theory. Upon subsequent visible-light irradiations, 2 (400 ± 20 nm) and 6 (532 nm) undergo rearrangement to pyridyl isocyanates 3 and 7. Further dissociation of 3 and 7 under 193 nm laser irradiation results in CO-elimination and formation of ketenimines 12 and 13 via the ring-opening of elusive pyridyl nitrenes 4 and 8, respectively. In addition to the IR spectroscopic identification of 8 in the triplet ground state, its reversible photointerconversion with ring-expansion to diazacycloheptatetraene 9 has been observed directly. The spectroscopic identification of the nitrene intermediates was aided by calculations at the B3LYP/6-311++G(3df,3pd) level, and the mechanism for their generation in stepwise decompositions of the azides is discussed in the light of CBS-QB3 calculations.

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Introduction Nitrenes (R–N) are highly reactive intermediates that have been fascinating chemists for decades.1-4 As versatile reagents, nitrenes can be easily generated through either thermal, photolytic, or catalytic decomposition of their corresponding azide precursors (R–N3). They have been broadly used in diverse chemical transformations such as C-H amination,5,6 intramolecular insertion for the synthesis of biologically active N-heterocycles such as azirinobenzoxazole and benzoxazines,7 and transition-mental catalyzed synthesis of nitrogen-containing compounds.8-10 Transient nitrenes have also been used in functionalization of carbon nanomaterials11,12 and cross-coupling of polymers.13 Acyl nitrenes (RC(O)–N), the key intermediates in the stepwise Curtius-rearrangement of acyl azides (RC(O)–N3),14 are also useful intermediates in organic synthesis and biology, for examples, benzoyl nitrene (PhC(O)N), a parent aroylnitrene, has been used for photocatalyzed C–H amidation of electron rich heteroarenes.15 In biological systems, aroylnitrenes can be quickly protonated by solvent to form strong electrophilic and carcinogenic aroyl nitrenium ions.16 Aside from the applications of acyl nitrenes, their spectroscopy, molecular structures, ground state multiplicities, and rearrangement reactions have also been the focus of numerous computational and experimental studies. For instance, benzoyl nitrene, generated by photolysis of either benzoyl azide or a sulfilimine-based nitrene precursor, has been directly observed by time resolved infrared spectroscopy in solution17,18 and matrix-isolation IR and UV-vis spectroscopy.19,20 Both experimental results and extensive quantum chemical calculations have confirmed a closed-shell singlet ground-state. Several other acyl nitrenes such as MeOC(O)N,21,22 FC(O)N,23,24 CF3C(O)N,25,26 H2NC(O)N,27 2-naphthoyl nitrene,28,29 pyrroyl nitrenes,30 and 3-furoylnitrene31 3



have also been spectroscopically characterized. In contrast, knowledge about the nicotinoyl nitrene (2, Scheme 1) and isonicotinoyl nitrene (6) is scarce, although the Curtius-rearrangement of their azide precursors 1 and 5 to the corresponding isocyanates 3 and 7 have been investigated in solution32 and on Pt-surfaces.33

Scheme 1. The Curtius-rearrangement of nicotinoyl azides 1 and 5.

Very recently, Spitale et al.34,35 reported the application of nicotinoyl azide (1) in probing the solvent accessibility of purine nucleobases in RNA and identifying rapid structural changes resulting from ligand binding in a metabolite-responsive RNA inside cells (Scheme 2). The method is known as Light Activated Structural Examination of RNA (LASER). Mechanistic studies on the reactions of the azide with purines in CCl4 with time-resolved IR spectroscopy suggests that the photolytically (310 nm) generated transient nicotinoyl nitrene (2) plays the key role in LASER by reacting with purines at the nonhydrogen-bonding C8 position, and the resulting bulky modification can be easily read out by its terminating effect on reverse transcription. As for the most straightforward evidence for the formation of 2 in the singlet ground state, a weak and broad band centered around 1734 cm–1 and a very short (picoseconds) lifetime were observed in CCl4 at room temperature by time-resolved IR spectroscopy. 4


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Scheme 2. Proposed mechanism of nicotinoyl azide (1) activation and C8 adducts formation with purines.34,35

Given the potential applications of nicotinoyl azide and the important role of nicotinoyl nitrene in biology, herein we report a study on the photochemistry of nicotinoyl azide (1) and isonicotinoyl azide (5) by combining matrix-isolation and quantum chemical calculations. In addition to the characterization of the two heteroaroyl nitrenes 2 and 6, their rearrangement to isocyanates 3 and 7 and secondary photodecomposition to ketenimines via the intermediacy of pyridylnitrenes 4 and 8 have been determined (Scheme 3). Furthermore, the previously proposed36 reversible interconversion of pyridylnitrene 8 with diazacycloheptatetraene (9) has also been observed directly. These two species have already been detected by matrix-isolation EPR37 and IR spectroscopy,38 respectively.

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Scheme 3. Decomposition pathways of 3 and 7.

Experimental Section Sample synthesis Nicotinoyl azide (1) was synthesized and purified according to the literature.39,40 Briefly, a N,N-dimethylformamide (DMF) solution (0.4 mL) of diphenyl phosphorazidate (DPPA, 1.1 mL, 5 mmol) was added dropwise over 20 minutes to a DMF (4.0 mL) solution of nicotinic acid (0.615 g, 5 mmol) and triethylamine (0.7 mL) at 0 ºC. The vessel was warmed to 35 ºC and stirred for 4 h. The reaction mixture was quenched immediately by pouring into a mixture of ether and ice. The requisite product was extracted with ether (3  10 mL), and the organic layers were washed with a 10% solution of sodium bicarbonate and water, and then dried over Na2SO4. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography using hexane/diethyl ether (1:1) to give the crude nicotinoyl azide. The desired product was obtained passing through three successive cold U-traps (–15, –60, and –196 ºC). The azide (ca. 0.149 g, 1 mmol) was isolated from the first trap as a pale yellow solid. The quality of the sample was checked by NMR spectroscopy. 1H NMR (600 MHz, CDCl3): δ = 9.21 (m, 1H), 8.82 (m, 1H), 8.29 (m, 1H), 7.43 (m, 1H) ppm and

13C

NMR (150 MHz, CDCl3): δ = 171.4, 154.6, 150.7, 137.0, 6


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126.8, 123.7 ppm. IR (3099, 2137, 1688, 1586, 1479, 1421, 1331, 1260, 1235, 1180, 1124, 1042, 1029, 992, 867, 832, 722, 712, 699, 622, 565 cm–1). Isonicotinoyl azide (5) was synthesized and purified in a similar manner. 1H NMR (600 MHz, DMSO): δ = 8.84 (m, 2H), 7.82 (m, 2H) and

C NMR (150 MHz, DMSO): δ = 171.5, 151.1,

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137.2, 122.0 ppm. IR (3054, 2136, 1692, 1595, 1564, 1491, 1407, 1325, 1241, 1210, 1169, 1128, 1089, 1064, 1006, 867, 841, 748, 686, 664 cm–1). Matrix IR Spectroscopy Matrix IR spectra were recorded on a Fourier transform infrared (FT-IR) spectrometer (Bruker 70V) in a reflectance mode using a transfer optic. A KBr beam splitter and liquid nitrogen cooled mercury cadmium telluride (MCT) detector were used in the mid-IR region (4000–500 cm–1). For each spectrum, 200 scans at a resolution of 0.5 cm–1 were co-added. The gaseous sample was mixed by passing a flow of N2 gas through a U-trap (nicotinoyl azide: 5 ºC, isonicotinoyl azide: –5 ºC) containing ca. 10 mg of the azide. Then the mixture (sample/matrix gas ≈ 1 : 1000 estimated) was passed through an aluminium oxide furnace (o.d. 2.0 mm, i.d. 1.0 mm), which can be heated over a length of ca. 25 mm by a tantalum wire (o.d. 0.4 mm, resistance 0.4 Ω), and immediately deposited (2 mmol/h) onto the Rh-plated copper block matrix support (15 K for N2) in a high vacuum (10–6 Pa). Photolysis was performed using an ArF excimer laser (Gamlaser EX5/250, 193 nm), a Nd3+:YAG laser (266 nm, 532 nm, MPL-F-266, 10 mW), UV lamp (365 nm, 24 W), and a high-power flashlight (Boyu T648, 20 W) with adjustable sources of purple light (400 ± 20 nm).

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Computational Details Structures and IR frequencies of stationary points were calculated using the DFT-B3LYP41 method with the 6-311++G(3df,3pd) basis set. Local minima were confirmed by vibrational frequency analysis, and transition states were further confirmed by intrinsic reaction coordinate (IRC) calculations.42,43 Time-dependent (TD) DFT (B3LYP/6-311++G(3df,3pd)) calculations44,45 were performed for the prediction of UV-vis transitions. The energies of singlet and triplet nitrenes were calculated accurately by applying several sophisticated theoretical methods, such as CCSD(T)/aug-cc-pVTZ//B3LYP/6-311++G(3df,3pd),46-48 CBS-QB3,49,50 and a modified version of CASPT2 (referred to as “RS2C” in Molpro),51 which accounts for dynamic correlation, using the CASSCF wave functions as references in the RS2C calculation. The active space includes 12 electrons and 11 active orbitals, i.e. CASPT2(12,11). All CASPT2 calculations were based on the CASSCF(12,11)/cc-pVTZ geometries. The DFT and CBS-QB3 calculations were performed using the Gaussian 09 software package.52 The CCSD(T) and CASPT2//CASSCF calculations were performed with the MOLPRO 2012 program.53

Results and Discussion Photodecomposition of nicotinoyl azide (1) A typical matrix IR spectrum obtained upon 266 nm laser photolysis of nicotinoyl azide (1) is shown in Figure 1. After 15 s of irradiation, depletion of the azide occurs by 80 % (Figure 1a). The expected Curtius-rearrangement product 3-pyridyl isocyanate (3) forms indicated by the appearance of a strong band at 2264.7 cm–1 (Figure 1b), the band position is in good agreement with the observed broad band in the range of 2310–2185 cm–1 detected by time-resolved IR spectroscopy.34 Interestingly, a distinct IR band at 1765.0 cm–1 appears immediately after the 266 nm laser irradiation of 1, and its intensity reaches a maximum in 15 s (Figure 1c). The assignment of this band to closed-shell singlet nicotinoyl nitrene (2) is in agreement with both the previously observed frequency of 1734 cm–1 of 2 in CCl4 34 and the B3LYP/6-311++G(3df,3pd) calculated strongest IR band for the nitrene 2 in the singlet ground state (syn conformer: 1752 cm–1, anti conformer: 1753 cm–1, Table 1). Furthermore, it is very close to those of the most characteristic C=N stretching vibration frequencies in other closed-shell singlet aroyl nitrenes such as PhC(O)N 8


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(1760 cm–1 in CD3CN),18,19 2-NpC(O)N (1737 cm–1 in CCl4),28,29 2-furoylnitrene (1752.3 cm–1 in Ne-matrix), and 3-furoylnitrene (1764.2 cm–1 in Ne-matrix).31 In line with experimental observations for triplet acyl nitrenes (e.g., MeOC(O)N: syn: 1644.8, anti: 1607.2 cm–1,21 FC(O)N: 1678.1 cm–1,23 and H2NC(O)N: 1643.7 cm–1 27), the calculated C=O stretching frequencies for the two conformers of nicotinyl nitrene in the triplet state (syn: 1499, anti: 1497 cm–1) are much lower than the observed bands (Table 1).

Figure 1. N2-matrix IR spectra at 15 K. (a) IR spectra showing the photolytic behavior of nicotinoyl azide (1) after irradiating 266 nm and subsequently 400 ± 20 nm. (b) IR spectra showing the photolytic behavior of 3-pyridyl isocyanate (3) after irradiating 266 nm and subsequently 400 ±20 nm. (c) IR spectra showing the photolytic behavior of nicotinoyl nitrene (2) after irradiating 266 nm and subsequently 400 ±20 nm.

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Table 1. Experimentally observed and calculated vibrational frequencies (> 500 cm–1) of nicotinoyl nitrene (2) and isonicotinoyl nitrene (6). Nicotinoyl nitrene (2) Isonicotinoyl nitrene (6) a b Calculated Observed Calculateda Observedb Assignmentc syn-triplet anti-triplet syn-singlet anti-singlet N2-matrix triplet singlet N2-matrix 3100 (6) 3103 (5) 3102 (5) 3104 (4) 3107 (2) 3101 (

Spectroscopic Characterization of Nicotinoyl and Isonicotinoyl

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