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Abstract
4H-Pyrazoles are emerging scaffolds for “click” chemistry. Late-stage fluorination with Selectfluor® is found to provide a reliable route to 4-fluoro-4-methyl-4H-pyrazoles. 4-Fluoro-4-methyl-3,5-diphenyl-4H-pyrazole (MFP) manifested 7-fold lower Diels–Alder reactivity than did 4,4-difluoro-3,5-diphenyl-4H-pyrazole (DFP), but higher stability in the presence of biological nucleophiles. Calculations indicate that a large decrease in the hyperconjugative antiaromaticity in MFP relative to DFP does not lead to a large loss in Diels–Alder reactivity because the ground-state structure of MFP avoids hyperconjugative antiaromaticity by distorting into an envelope-like conformation like that in the Diels–Alder transition state. This predistortion enhances the reactivity of MFP and offsets the decrease in reactivity from the diminished hyperconjugative antiaromaticity.
Highlights
Discovered in 1928 [1], the Diels–Alder reaction has become a mainstay of synthetic organic chemistry and allied fields [2,3,4,5,6]
Density functional theory (DFT) calculations show that the uncatalyzed Diels–Alder reaction of 4,4-difluoro-3,5-diphenyl-4H-pyrazole (DFP) proceeds ~500,000 times faster than does the reaction of 4,4-dimethyl-3,5-diphenyl-4H-pyrazole with the strained alkyne, endo-bicyclo[6.1.0]non-4-yn-9-ylmethanol (BCN)
This increase in reactivity is the result of the hyperconjugative antiaromaticity [12,13,14,15] and the lowering of the lowest unoccupied molecular orbital (LUMO) energy induced by the electron-withdrawing fluoro substituents
Summary
Discovered in 1928 [1], the Diels–Alder reaction has become a mainstay of synthetic organic chemistry and allied fields [2,3,4,5,6]. Density functional theory (DFT) calculations show that the uncatalyzed Diels–Alder reaction of 4,4-difluoro-3,5-diphenyl-4H-pyrazole (DFP) proceeds ~500,000 times faster than does the reaction of 4,4-dimethyl-3,5-diphenyl-4H-pyrazole with the strained alkyne, endo-bicyclo[6.1.0]non-4-yn-9-ylmethanol (BCN) This increase in reactivity is the result of the hyperconjugative antiaromaticity [12,13,14,15] and the lowering of the lowest unoccupied molecular orbital (LUMO) energy induced by the electron-withdrawing fluoro substituents. Hortcomings aronudted.eWveeloaplsTmd[ao1he9agvee,k2eeeex0Tlnsol]peh.ptecehSltroayerpaonragrlnteedeih-vznddweieeiositritdtuisahohslindilmsezyroaeaDrefcdwecatpiomihsenomeoeglrcstptdohes–lundiosAfdbdhossyeleftrddonlietsrtuecbhysteyrerynnotrnrtipetcsetahhhlracoieeotlcswiiusncitztieigfezivrlnuaittigonoht1ryegHeDilnne-FoepecuPltyfdcerr(loiaRceafnfoznti-=rpocduolhePeelninfhtlwi.i)c-scTiidiauteothnyneicdttnfioiwr4figcctHoutsihe-4emapeqnHnyvufatrlei-ulavn4opzoatgHoryltsielhner-niepssaats,tszseyewhodosrfoehalp1woesz-yrocn.otrhucaillogzneomhorsStloi,ecnma,hwngweesomtehthahienyscedlho2r- ught another r4o-fuluteo.rWo-e1,a4l-sdoiaezxopnloiarbeidcythcleoD[2i.e2l.s2–]oAcltdaenrerebaicst(itveittryafoluf oanroebnosruaitne)g 4(SHe-lpeyctrfaluzoolre®.), which is a highly reactive electrophilic fluorinating agent [21,22,23] This route suffers from a limited substrate scope when electron-withdrawing substituents are present at the 3- and 5-positions of the pyrazole ring.
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