Conformer-Specific Heavy-Atom Tunneling in the Rearrangement Of

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Cite This: J. Org. Chem. 2019, 84, 16013−16018 pubs.acs.org/joc

Conformer-Speciﬁc Heavy-Atom Tunneling in the Rearrangement of Benzazirines to Ketenimines † ⊥ † ∥ ⊥ † † ‡ Tim Schleif, , Joel Mieres-Perez, , , Stefan Henkel, Enrique Mendez-Vega, Hiroshi Inui, § † Robert J. McMahon, and Wolfram Sander*, † Lehrstuhl fu r Organische Chemie II, Ruhr-Universitat Bochum, 44801 Bochum, Germany ‡ Department of Chemistry, School of Science, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan § Department of Chemistry, University of Wisconsin−Madison, 1101 University Avenue, Madison, Wisconsin 53706-1322, United States

*S Supporting Information

ABSTRACT: 5-Methoxy-2H-benzazirine was prepared via irradiation of the corresponding phenyl azide, isolated in an argon matrix at cryogenic temperatures. It undergoes ring expansion to the corresponding ketenimine in the dark at T <30K despite a calculated activation barrier of 4.9 kcal mol−1 [B3LYP/6-311++G(d,p)]. Since this rearrangement proceeds with a rate constant in the order of 10−4 s−1, exhibiting only a shallow temperature dependence, the results are interpreted in terms of heavy-atom tunneling. Of the four isomeric benzazirines resulting from the initial photolysis, only one can be observed to rearrange; this conformer speciﬁcity is explained by the other potentially observable rearrangements being either too fast or too slow to be detected due to the diﬀerences in heights and widths of their respective activation barriers.

■ INTRODUCTION Scheme 1. Previously Reported Reactions with Experimental Evidence for Heavy-Atom Tunneling When Hund first formulated his seminal paper on quantum- Involving the Ring Opening of Strained Three-Membered mechanical tunneling (QMT), i.e., the passage of light particles Rings, including Several Benzazirine Derivatives4,6,7 through a barrier that is too high to be overcome classically, its great physical relevance could not yet be foreseen.1 Even after the discovery of the significance of QMT in hydrogen-transfer reactions, Bell, as an authority in the theoretical description of tunneling processes, firmly excluded the possibility of tunneling for “all atoms heavier than helium”.2 Only within the last 20 years, heavy-atom tunneling has gained appreciation as a reaction mode, facilitating, e.g., intramolecular rearrange-

Downloaded via UNIV OF WISCONSIN-MADISON on December 21, 2019 at 16:23:41 (UTC). ments, and recently has been shown to potentially contribute 3 See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. to common organic reactions. However, this phenomenon’s comprehensive study has been hindered by the lack of a systematic approach to its investigation, with only about a dozen seemingly unrelated examples having been reported so far, like the automerization of 1,5-dimethylsemibullvalene (1)8 or the ring opening of bicyclo[3.1.0]hexa-3,5-dien-2-one (2)9 (Scheme 1). One of the latest additions to this short list of molecular idea by investigating the photochemistry of triplet 2-formyl rearrangements facilitated by heavy-atom tunneling came from phenylnitrene, whose ability to undergo rearrangement via 5 Inui et al. in 2013. They reported the ring expansion of hydrogen tunneling they had previously reported. They found benzazirine 4-SMe to ketenimine 5-SMe proceeding at that benzazirine 6 undergoes the analogous rearrangement to 6 cryogenic temperatures with no discernible temperature ketenimine 7 under similar conditions. Furthermore, Nunes dependence and despite a considerable activation barrier of and Schreiner et al. recently observed the ring expansion of − 3.4 kcal mol 1 (calculated at the B3LYP/6-31G(d) level of benzazirine 4-NH2 via QMT (which actually competes with theory).4 Curiously, the expansion of the lighter homologue 4- OMe to ketenimine 5-OMe does not proceed in the dark, i.e., Received: September 12, 2019 via tunneling (see Scheme 2). Nunes et al. expanded upon this Published: November 15, 2019

Scheme 2. Photochemistry of 3-Methoxyphenylazide (8) and Its Isomer 4-Methoxyphenyl Azide (14)4

Figure 1. IR difference spectra showing the tunneling reaction of 11a to 13a. (a) Spectrum obtained after keeping an argon matrix containing 10/11 and 12/13 in the dark for 19.1 h at 3 K. Bands the ring opening resulting in the corresponding nitrene),7 thus pointing upward assigned to 13a increase in intensity, and bands having established three examples for the involvement of pointing downward assigned to 11a are decreasing. (b) Theoretical heavy-atom tunneling in the ring expansions of 2- and 4- spectra of 13a (pointing upward) and 11a (pointing downward) substituted benzazirines, respectively. calculated at the B3LYP/6-311++G(d,p) level of theory. An intriguing aspect of the study of these benzazirines is the unique opportunity to systematically investigate the tunneling azirine moiety with respect to the methoxy substituent as well probability of the individual rotamers as a function of their as the rotation of the latter group (see Figures 2, S1, and S2). respective barrier heights and thermodynamic stability. Such conformer specificity has been experimentally demonstrated by Zuev et al. for the ring expansion of cyclobutylfluorocarbene10 and by Schreiner et al. for the hydrogen tunneling in trifluoromethylhydroxycarbene11 as well as theoretically predicted for the intramolecular C−C insertion of norada- mantylmethylcarbene.12 Whilethesethreeinvestigations highlighted how different conformers can directly influence tunneling reactions, our current experimental and computational study of the ring expansion of 5-methoxy-2H-benzazirine explores the influence of subtle conformational factors on tunneling processes by substituents that are remote from the site of reactivity. − ■ RESULTS AND DISCUSSION Figure 2. Reaction coordinates along the C C distance for the ring expansion of benzazirines 10 and 11 calculated at the B3LYP/6-311+ 3-Methoxyphenylazide (8) was deposited with a large excess of +G(d,p) level of theory. The relative energies of all benzazirines have argon onto a CsI window maintained at 3 K. Its IR deposition been set to zero; for an alternative plot, see Figure S7. spectrum can be reproduced by assuming a mixture of its four conformers 8a−d, in agreement with energy differences of less than 0.3 kcal mol−1 between these conformers calculated at the After keeping the photoproducts in the dark for several B3LYP/6-311++G(d,p) level of theory (see Table S1). hours, the IR signals of a benzazirine species decreased in Photolysis of the argon matrix containing 8 with λ = 405 nm intensity, while the bands of a ketenimine increased for 1 h at 3 K resulted in the decrease of all IR bands of 8 and concomitantly (Figure 1). This rearrangement occurs despite the appearance of a new set of bands with intense absorptions a considerable activation barrier of 4.9 kcal mol−1 [B3LYP/6- at 1888 and 1728 cm−1 (Figure 1). While the intense band at 311++G(d,p)], prohibitively high to be overcome thermally at 1888 cm−1 was assigned to the NCC cumulenic cryogenic temperatures, mirroring the findings of Inui et al. stretching vibration of ketenimines, based on published data regarding the rearrangement of the methylthio-substituted for similar species,13 the weaker band at 1728 cm−1 matches benzazirine 4-SMe at cryogenic temperatures.4 However, the characteristic CN stretching vibration for previously unlike this former report, the observed difference spectrum reported benzazirines regarding position and relative inten- could be exclusively assigned to the reaction of a single sity.4,14 The IR spectrum of the mixture of these benzazirines conformer 11a to its corresponding ketenimine 13a due to 10/11 and ketenimines 12/13 could be deconvoluted by pronounced differences in the IR spectra of 10/11 and 12/13 irradiation with different wavelengths, since photolysis with λ = in the regions between 650 and 850 cm−1 as well as between 254 nm generated 12/13 from 10/11, while irradiation with λ 950 and 1200 cm−1 (see Figures S1 and S2). Moreover, all = 450 nm reversed this reaction. As with the previous analysis increasing IR signals could be exclusively assigned to 13a for 8, the corresponding sets of signals assigned to 10/11 and without spectroscopic evidence for the formation of the 12/13 could be reproduced by considering a mixture of their corresponding nitrene, unlike the reported behavior of 7 respective conformers, resulting from the positioning of the benzazirine 4-NH2.

16014 DOI: 10.1021/acs.joc.9b02482 J. Org. Chem. 2019, 84, 16013−16018 The Journal of Organic Chemistry Article

To study the kinetics of the ring expansion, the changes over In order to elucidate this conformer-specific tunneling time of the IR bands of 11a and 13a were recorded and process, quantum-chemical calculations of the reaction quantitatively analyzed. While for 13a the increase of the coordinate were performed (Figure 2). In accordance with characteristic band at 1888 cm−1 was monitored, for 11a a Hammond’s postulate,17 a higher exothermicity in the band at 1407 cm−1 (instead of the band at 1728 cm−1, assigned respective ring expansion leads to a narrower barrier18,19 to the CN stretch) was chosen due to its high intensity. which, coupled with the lower activation barriers, results in an Neither of these bands overlap with any other band, thus enhanced tunneling probability. Thus, qualitatively one can reducing the risk of systematic errors during integration. Since predict that within this series of conformers the rearrangement it is known that IR irradiation might accelerate tunneling via QMT of 11b to 13b will be fastest, while the endothermic processes,9 even being reported to have a pronounced effect on reaction of 10a to 12a cannot proceed without influx of the related rearrangement of 6 to 7 by Nunes et al.,6 external energy as it would violate the conservation of energy. experiments were undertaken to evaluate its effect on the Utilizing the Wentzel−Kramers−Brillouin approximation, it reaction reported herein. In this instance, however, IR is possible to estimate the relative tunneling probability Prel of irradiation did not have an effect. The kinetic data obtained each of the three benzazirines 10/11 via eq 2. For this analysis, from experiments either using a band-pass filter blocking all the barrier width w was evaluated at half-height of the light above 2000 cm−1 or keeping the matrix in the dark apart activation barrier, according to instructions by Kozuch.19,20 As from short IR scans were indistinguishable from experiments a further rule of thumb, Kozuch introduced the “tunneling ” under constant exposure to light from the IR Globar source. limit TL as a means to assess the chance of spectroscopically The evaluation of these kinetic data was complicated by the observing any given heavy-atom tunneling process (eq 3).19 dispersive kinetics frequently found in solid-state reactions: −π 2wmEh2/ Weak, nonuniform interactions between the host molecules P()E = L A (2) and the matrix environment cause a distribution of rate constants instead of the single rate constant expected for TLA= wmE (3) unimolecular reactions in the gas phase. For this phenomenon, These estimates (Table 2) substantiate the qualitative the stretched exponential approach has been derived by conclusions drawn from Figure 2: Of the three potentially Wildman and Siebrand,15 assuming a continuum of reaction rates by introducing the dispersion coefficient β (eq 1); the P T fi Table 2. Tunneling Probabilities ( rel) and Limits ( L) parameter c takes into account the ratio of the initial and nal Derived by eqs 2 and 3 for the Ring Expansion of intensity of the corresponding IR signal in the course of the 16 Benzazirines 10/11, 4-OMe, and 16 as Well as for the experiment: Unsubstituted Parent Benzazirine −()kt β I =·Ie0 + c (1) EA (kcal −1 reaction mol ) w (Å) Prel TL kexp (at 3 K) Since the rearrangement shown in Figure 1 could be → × −6 λ 10b 12b 7.6 0.41 2.1 10 3.9 reversed via irradiation with = 450 nm, it was possible to → × −4 −1 → 11a 13a 4.9 0.28 1 2.1 1 10 s investigate the kinetics of the transformation 11a 13a at → × 3 ff 11b 13b 2.4 0.21 1.6 10 1.1 di erent temperatures in the same matrix (for an exemplary 4a-OMe → 5a- 6.4 0.35 7.6 × 10−5 3.1 plot, see Figure S3). If this reaction was facilitated by QMT, OMe one would expect a very shallow temperature-dependence of 4b-OMe → 3.5 0.25 5.6 × 102 1.6 the reaction rates, in contrast to a classical thermal reaction 5b-OMe − − − which should show Arrhenius behavior. Indeed, as Table 1 16 → 17 4.7 0.34 4.4 × 10 2 2.5 7 × 10 6 s 1 parent 3.1 0.29 1.6 × 101 1.7 k τ Table 1. Rate Constants and (Apparent) Half-lives app As Fitted to eq 1 with β = 0.6 for the Ring Expansion of observable rearrangements of 3- or 5-methoxy-2H-benzazir- a Benzazirine 11a to Ketenimine 13a in Argon Matrices ines, only 11a → 13a falls into the spectroscopic window fi ≤ ≤ de ned by Kozuch of ca. 2 TL 3. The other two isomers T (K) k (10−4 s−1) τ (h) t (h) app final exhibit relative tunneling probabilities Prel indicating reactions 3b 1.07 ± 0.02 1.3 20.6 that should proceed either too fast (11b → 13b) or too slow 3 1.13 ± 0.02 1.4 19.1 (10b → 12b) to be observed within the typical time frame of a 8 1.54 ± 0.03 1.0 20.5 matrix-isolation experiment. 15 1.94 ± 0.05 0.8 18.6 Furthermore, this analysis also allows for the interpretation 20 1.06 ± 0.04 1.4 15.3 of the lack of any observable rearrangement of the isomeric 4- 25 1.01 ± 0.08 1.5 11.5 methoxy-2H-benzazirine 4-OMe in the dark as a consequence a b fi tfinal is the maximum time for kinetic measurements. Using a lter of the corresponding tunneling process being either too slow with a cutoff of ṽ> 2000 cm−1 (4a-OMe → 5a-OMe) or too fast (4b-OMe → 5b-OMe)to be detected. This hypothesis is in line with the finding that isomer 4b-OMe could not be observed upon irradiation of shows, the reaction rate of this ring expansion is virtually ketenimine 5b-OMe, though thermal rotamerizations cannot temperature-independent over an 8-fold increase in absolute be excluded in this case due to their low activation barriers4 temperature, thus indicating a nonthermal process. The (unlike the significant barriers for 10/11 and 12/13, see shallow temperature-dependence, as well as the fact that this Figures S4 and S5). rearrangement can be observed in the dark at cryogenic As a test for the predictive power of these simple model temperatures despite a prohibitively high activation barrier, are calculations and as a reference experiment, the rearrangement clear indications for a process facilitated by QMT. of difluorosubstituted benzazirine 16 was investigated, which

16015 DOI: 10.1021/acs.joc.9b02482 J. Org. Chem. 2019, 84, 16013−16018 The Journal of Organic Chemistry Article lacks the potential for any diﬀerent conformers due to the Scheme 3. Comparison of the Calculated Energetic corresponding nitrene’ssymmetricstructure(Figure 3). Diﬀerences of the Respective Rotameric Pairs of Benzazirines 10/11 and Ketenimines 12/13 with the Ones a Observed21 and Calculated for Methyl Vinyl Ether (18)

aThe respectively more stable rotamers are highlighted by boxes, with the energetic gaps between the respective rotamers stated below. Figure 3. IR difference spectra showing the tunneling reaction of 16 to 17. (a) Spectrum obtained after keeping an argon matrix minimization of the molecular dipole moment and the increase containing 16 in the dark for 56.0 h at 15 K. Bands pointing upward in conjugation of the oxygen perpendicular lone pair with the assigned to 17 increase in intensity, and bands pointing downward double bond. The former concept cannot be confirmed in the assigned to 16 are decreasing. (b) Theoretical spectra of 17 (pointing case of 10/11 and 12/13, as, e.g., 10b exhibits the smallest upward) and 16 (pointing downward) calculated at the B3LYP/6- 311++G(d,p) level of theory. dipole moment of all investigated conformers (presumably due to the interference of the strongly polarized CN bond) but is higher in energy than 10a (Table S1). However, the latter ff Indeed, the rearrangement of 16 to 17 could be observed at factor seems to explain the energy di erences in 10/11 and cryogenic temperatures in the dark despite a significant 12/13 (as well as in the isomers of 4-OMe and 5-OMe) as the −  activation barrier of 4.7 kcal mol 1 [B3LYP/6-311++G(d,p)], increased polarization of the C C bond that Bond and exhibiting a temperature-independent rate constant of ca. 6 × Schleyer showed via natural charge analysis for methyl vinyl 10−6 s−1 (see Table S2). No spectroscopic evidence for the ether (18) can be nicely reproduced for the benzazirines and ring opening to the corresponding nitrene was found. The ketenimines (Table 3). higher tunneling limit and lower tunneling probability (Table 2)of16 compared to 11a agree well with the smaller Table 3. Natural Charges in the Conformers of Methyl Vinyl Ether (18), Benzazirines 10/11 and Ketenimines 12/13 as experimental rate constant. In fact, the observed decrease in a rate by a factor of ca. 18× quantitatively fits the predicted Well as 4-OMe and 5-OMe relative tunneling probabilities, though this might be due to Molecule C C O fortuitous error canceling. 1 2 ff 18a (syn) −0.51 0.16 −0.55 While the energy di erence between the two pairs of − − structural isomers 10 and 11 as well as 12 and 13 is to be 18b (anti) 0.45 0.14 0.56 ff 10a (syn) −0.36 0.36 −0.52 expected, one might be surprised by the large di erence − − resulting from the rotation of the methoxy group. However, a 10b (anti) 0.31 0.36 0.54 11a (syn) −0.38 0.36 −0.53 comparison with the extensively studied conformational − − isomerism in methyl vinyl ether (18) provides helpful insight: 11b (anti) 0.32 0.35 0.54 4a-OMe (syn) −0.30 0.30 −0.54 The rotameric pairs of the benzazirines 10/11 and ketenimines − − 12/13 prefer the syn-staggered conformation of the methoxy 4b-OMe (anti) 0.23 0.29 0.55  12a (oop) −0.01 0.25 −0.57 group with respect to the adjacent C C double bond as also − − observed as a global minimum for 18. The respective 12b (syn) 0.08 0.28 0.54 ff 13a (anti) −0.28 0.37 −0.53 calculated energy di erences of the isomers mirror those of − − 18 within the limits of chemical accuracy (Scheme 3). 13b (syn) 0.33 0.37 0.53 ff 5a-OMe (oop) −0.20 0.30 −0.58 These energy di erences become more pronounced with − − increasing bond localization, from less than 0.3 kcal mol−1 in 5b-OMe (syn) 0.27 0.32 0.54 − a the phenyl azides 8 to more than 1 kcal mol 1 in the The nomenclature of 18 is applied; i.e., C2 bears a methoxy group benzazirines 10/11 and ketenimines 12/13.Theearly and engages in a double bond with C1. transition states exhibit energy differences close to those of benzazirines 10/11, albeit slightly smaller due to the greater As a result of the benzazirine → ketenimine electrocyclic extent of bond delocalization (Table S1). The cause of this rearrangement, every syn-conformer of 10/11 reacts to an anti- stabilization of the sterically more congested syn-conformation conformer of 12/13 (and vice versa). Due to the increased − in 18 has been debated by computational chemists22 24 with conjugation of the methoxy group with the adjacent double Bond and Schleyer providing the most extensive discussion of bond in the syn-conformers all rearrangements resulting in this the effects at play.25 They stressed the importance of the orientation (i.e., 10b → 12b and 11b → 13b) will exhibit a

16016 DOI: 10.1021/acs.joc.9b02482 J. Org. Chem. 2019, 84, 16013−16018 The Journal of Organic Chemistry Article greater exothermicity and thus tunneling probability than their Author Contributions ⊥ respective counterparts which is also corroborated by two- T.S. and J.M.-P. contributed equally. dimensional potential energy scans for these reactions (Figures Notes S4 and S5). The authors declare no competing financial interest. ■ CONCLUSION ■ ACKNOWLEDGMENTS By investigating the photochemistry of 3-methoxyphenyl azide This work was funded by the Deutsche Forschungsgemein- (8) in cryogenic matrices and the subsequent ring expansion of schaft (DFG, German Research Foundation) under Germany’s the corresponding benzazirines, a new example of conforma- Excellence Strategy − EXC-2033 − Projektnummer tional control of tunneling processes was discovered: While the 390677874 − RESOLV. R.J.M. gratefully acknowledges principal tunneling coordinate, i.e., the C−C distance, is not funding from the U.S. National Science Foundation (NSF- significantly altered in the four potential rearrangements, only 1664912). the reaction 11a → 13a could be observed to occur in the dark at cryogenic temperatures with a temperature-independent rate REFERENCES despite a considerable calculated activation barrier. It could be ■ demonstrated by simple estimates of the tunneling proba- (1) Hund, F. Zur Deutung der Molekelspektren. III. Eur. Phys. J. A 1927, 43, 805. bilities that the other three potential ring expansions would not ff fall into the spectroscopic window due to either proceeding too (2) The Tunnel E ect in Chemistry; Bell, R. P., Ed.; Chapman and Hall: London, 1980. slow or too fast to be observed. The applicability of these (3) Vetticatt, M. J.; Singleton, D. A. 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16018 DOI: 10.1021/acs.joc.9b02482 J. Org. Chem. 2019, 84, 16013−16018