Mechanism of reactions of unsaturated ethers and thioethers. VII: Linear free energy relationships and inverse secondary deuterium isotope effect in the addition of water to 1‐alkynyl thioethers

The thermal reaction between nitrosoarenes and alkynes produces N-hydroxyindoles as the major products. The mechanism of these novel reactions has been probed using a combination of experimental and computational methods. The reaction of nitrosobenzene (NB) with an excess of phenyl acetylene (PA) is determined to be first order in each reactant in benzene at 75° C. The reaction rates have been determined for reactions between phenyl acetylene with a set of p-substituted nitrosoarenes, 4-X-C 6 H 4 NO, and of 4-O 2 N-C 6 H 4 NO with a set of p-substituted arylalkynes, 4-Y-C 6 H 4 C≡CH. The former reactions are accelerated by electron-withdrawing X-groups (ρ = + 0.4), while the latter are faster with electron-donating Y groups (ρ = − 0.9). The kinetic isotope effect for the reaction of C 6 H 5 NO/C 6 D 5 NO with PhC≡CH is found to be 1.1 (± 0.1) while that between PhC≡CH/PhC≡CD with PhNO is also 1.1 (± 0.1). The reaction between nitrosobenzene and the radical clock probe cyclopropylacetylene affords 3-cyclopropyl indole in low yield. In addition to 3-carbomethoxy-N-hydroxyindole, the reaction between PA and o-carbomethoxy-nitrosobenzene also affords a tricyclic indole derivative 3, likely derived from trapping of an intermediate indoline nitrone with PA and subsequent rearrangement. Computational studies of the reaction mechanism were carried out with density functional theory at the (U)B3LYP/6-31+G(d) level. The lowest energy pathway of the reaction of PhNO with alkynes was found to be stepwise; the N-C bond between nitrosoarene and acetylene is formed first, the resulting vinyl diradical undergoes cis-trans isomerization, and then the C-C bond forms. Conjugating substituents Z on the alkyne, Z-C≡CH, lower the calculated (and observed) activation barrier, Z=-H (19 kcal/mol), -Ph (15.8 kcal/mol) and -C(O)H (13 kcal/mol). The regioselectivity of the reaction, with formation of the 3-substituted indole, was reproduced by the calculations of PhNO + PhC≡CH; the rate-limiting step for formation of the 2-substituted indole is higher in energy by 11.6 kcal/mol. The effects of -NO 2 , -CN, -Cl, -Br, -Me, and -OMe substituents were computed for the reactions of p-X-C 6 H 4 NO with PhC≡CH and of PhNO and/or p-NO 2 -C 6 H 4 NO with p-Y-C 6 H 4 C≡CH. The activation energies for the set of p-XC 6 H 4 NO vary by 4.3 kcal/mol and follow the trend found experimentally, with electron withdrawing X-groups accelerating the reactions. The range of barriers for the p-Y-C 6 H 4 C≡CH reactions is smaller, about 1.5 kcal/mol and 1.8 kcal/mol in the cases of PhNO and p-NO 2 -PhNO, respectively. In agreement with the experiments, electron donating Y-groups on the alkyne accelerate the reactions with p-NO 2 -C 6 H 4 NO, while both ED and EW groups are predicted to facilitate the reaction. The calculated kinetic isotope effect for the reaction of C 6 H 5 NO/C 6 D 5 NO with PhC≡CH is negligible (as found experimentally) while that for PhC≡CH/PhC≡CD with PhNO (0.7) differs somewhat from the experiment (1.1). Taken together the experimen...

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“…1−1.5, as found experimentally. This magnitude of KIE has been observed in other addition reactions of PhCCH(D) …”

Section: Resultsmentioning

confidence: 98%

“…1.4−1.5 giving a combined effect of ca. 1.1−1.3 . The observed value of 1.1 is thus consistent with developing N−C1 bond formation in the transition state but does not rule out rate-limiting C(arom)−C2 bond formation; the latter, however, is unlikely on the basis of the above PhNO/ d 5 -PhNO result.…”

Section: Resultsmentioning

confidence: 99%