Experimental and DFT studies on the transmission mechanisms of analogous NMR JCH and JCC couplings in 1-X- and 1-X-3-methylbicyclo[1.1.1]-pentanes.

The main aim of this work is to compare the transmission mechanisms for the Fermi contact term of spin-spin couplings, SSCCs, in series 1-X-bicyclo[1.1.1]-pentane, (1), and 1-X-3-methylbicyclo[1.1.1]pentane, (2), and from that comparison to gain insight into some subtle aspects of the FC transmission. To this end, 18 members of the latter series were isotopically enriched in (13)C at the methyl position and the following couplings were measured; 1JC3CMe, 3JC1CMe and 4JCXCMe. These three types of SSCCs in (2) are compared, respectively, with 1JC3H3, 3JC1H3 and 4JCXH in (1); these latter values were taken from previous works. Since electron delocalization plays an important role in the transmission of the FC interaction, the natural bond orbital (NBO) method is employed to quantify electron delocalization interactions within selected members of series (1) and (2). It is found that 1JC3H3 SSCCs in (1) is more efficiently transmitted than 1JC3CMe SSCCs in (2). On the other hand, 3JC1H3 and 4JCXH SSCCs in (1) are notably less efficiently transmitted than 3JC1CMe and 4JCXCMe SSCCs in (2), although substituent effects on these two SSCCs show the opposite trends. These different efficiencies are rationalized in terms of different sigma-hyperconjugative interactions in both series of compounds.

Experimental and theoretical study of hyperconjugative interaction effects on NMR 1J(CH) scalar couplings.

Hyperconjugative and electrostatic interactions effects on 1J(CH) spin-spin coupling constants (SSCCs) are critically studied from both theoretical and experimental points of view. A qualitative model is used to predict how the former affect such SSCCs, while electrostatic interactions are modeled with a point charge placed in the vicinity of the corresponding sigma(CH) bond. Hyperconjugative interactions are calculated using the "natural bond orbital" approach, and using the point-charge model, it is shown how intertwined are both types of interactions. Several members of the series 1-X-bicyclo[1.1.1]pentane and 1-X-3-methylbicyclo[1.1.1]pentane are chosen as model compounds for measuring 1J(CH) SSCCs; in some of them were performed also DFT-SSCC calculations. The strained cage substrate in these series defines strong sigma-hyperconjugative interactions, making these compounds excellent examples to verify the qualitative model presented in this work. It is verified that (a) hyperconjugative interactions from the sigma(CH) bond or into the sigma(CH) antibond containing the coupling nuclei yield a decrease of the corresponding 1J(CH) SSCC and (b) hyperconjugative interactions from other bonds involving the coupling C nucleus yield an increase of that 1J(CH) SSCC.

Influence of sigma-hyperconjugative interactions on 13C substituent chemical shifts: experimental and theoretical study in 1-X,3-CH3-bicyclo[1.1.1]pentanes.

(13)C chemical shifts were measured for 18 1-X,3-CH(3)-bicyclo[1.1.1]pentanes and the corresponding (13)C substituent chemical shifts (SCSs) were compared with those measured previously for the corresponding 1-X-bicyclo[1.1.1]pentanes. DFT-B3LYP calculations of GIAO magnetic shielding constants and of natural bond orbitals were carried out in order to gain an insight into factors defining the observed differences in (13)C SCSs in both series. These differences are rationalized in terms of substituent effects on sigma-hyperconjugative interactions.

The regiochemistry of cyclization of alpha-sulfenyl-, alpha-sulfinyl-, and alpha-sulfonyl-5-hexenyl radicals: procedures leading to regioselective syntheses of cyclic sulfones and sulfoxides.

A study of the cyclization of alpha-sulfenyl-, alpha-sulfinyl-, and alpha-sulfonyl-5-hexenyl and 5-methyl-5-hexenyl radicals reveals a unique contrast in the mode of ring closure of the radicals. In the case of the 5-hexenyl radicals, the sulfinyl-substituted species displays unexpected regioselectivity relative to its analogues. Thus, while the alpha-S- and alpha-SO(2)-5-hexenyl radicals give measurable and increasing quantities of 6-endo product, the alpha-sulfinyl species cyclizes with high selectivity (95.5:4.5) via a 5-exo mode. By contrast, ring closure of the 5-methyl-5-hexenyl radicals is found to give substantially the 6-endo product in all cases. It is the alpha-sulfonyl-5-methyl-5-hexenyl radical that now exhibits high regioselectivity (97.5:2.5) for 6-endo closure: an illustration of the synthetic value of this observation is the independent synthesis of the model cyclohexyl sulfone 61 in high yield. It is found that ring closure under the conditions employed occurs irreversibly in all cases.

Regioselectivity of ring closure of 2-thia- and 2-sulfonyl-5-methyl-5-hexenyl radicals.

Ring closure of the alpha-substituted radicals 4 (X = S, SO(2)) is observed to be irreversible and to lead to significant amounts of the product of 6-endo cyclization. Indeed, reduction of the sulfonyl-based radical 4 (X = SO(2)), in which regioselectivity is believed to be controlled by a combination of both steric and FMO interactions, is found to provide an excellent route to the cyclic sulfone 7 (X = SO(2)) in high yield. [reaction: see text]

Synthesis of Bridgehead Nitrogen Heterocycles via Cyclization of alpha-Ammonio 5-Hexenyl Radicals.

Ring-closure of the 2,2-dimethyl-2-azonia-5-hexenyl radical (4) proceeds smoothly and efficiently to give the 5-exo isomer essentially quantitatively, in accordance with predictions based on MP4SDTQ/6-31G ab initio calculations on the thermodynamic stability of alpha-ammonio radicals. The corresponding 5-hexynyl radical species 15 and its 6-phenyl derivative 19 display similar behavior affording the analogous 5-exo-3-methylenepyrrolidinium salts in high yield. In none of these cases were the products of reduction were detected. All of the radical intermediates were generated conveniently by treatment of the iodomethyl and/or phenylselenomethyl salts with tributyltin hydride. Application of this procedure to monocyclic precursors such as 1-methyl-1-iodomethyl-4-methylene-1-azoniacyclohexyl iodide (31) provided an attractive entry into quaternary derivatives of the 1-azabicyclo[2.2.1]heptyl system in good yield via a three-step sequence from 1-methylpiperidone. Dequaternization of the bicyclic salts so obtained unexpectedly leads to rupture of one of the rings rather than loss of the N-methyl group. The 1-azabicyclo[2.2.1]heptane could be accessed readily via tin hydride-induced cyclization of the corresponding N-phenylethylammonium salt 54, followed by Hofmann elimination with potassium tert-butoxide.

Synthesis of Nitrogen Bridgehead Bicyclic Heterocycles via Ring-Closure of beta-Ammonio 5-Hexenyl Radicals.

The 2-(3-methylenepiperidinyl)ethyl radical (6) displays considerable reluctance to ring-closure under conditions which its carbocyclic analog, the 2-(3-methylenecyclohexyl)ethyl radical (2), cyclizes essentially completely. Molecular mechanics calculations suggest that the increased activation barrier associated with ring-closure of 6 is the result of a higher than expected transition state energy. A study of the behavior of beta-ammonio-substituted 5-hexenyl radicals, such as the 3,3-dimethyl-3-azonia-5-hexenyl radical (22), reveals that cyclization occurs readily. Treatment of 1-methyl-1-(2-(phenylselenyl)ethyl)-3-methylenepiperidinium iodide (20) with tributyltin hydride in tert-amyl alcohol yields the bridgehead nitrogen bicyclic heterocycle, 1,5-dimethyl-1-azoniabicyclo[3.2.1]octane iodide (26), in excellent yield and without contamination, thus providing an attractive synthetic route to this hitherto unknown heterocyclic system.