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Arylpyran Pseudoacid Racemization: Rate Estimation and Structural Influences

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Abstract

Arylpyran pseudoacids showed slow ring-opening to the oxocarboxylic acids, and fast ring-closure to the lactols (pseudoacids) in a process that amounts to racemization. Compounds studied were patterned on “Cooper’s Pseudoacid” [3-hydroxy-4,4-dimethylisobenzopyran-1-one, 1], to which modifications were introduced to influence racemization rates by steric compression. Pseudoacid 1 in d6-DMSO had a barrier to racemization (ΔH‡) of +77.8(3) kJ/mol determined by dynamic nuclear magnetic resonance line-broadening measured from 25 °C to 100 °C, and coalescence of its diastereotopic gem-dimethyl signals at 78.5 °C. The solution half-life of 1 at room temperature is a few seconds. Introduction of various aryl 5-substituents lead to similar racemization barriers for the 5-fluoro-8-methyl derivative, and increasingly higher barriers for 5-methyl-8-methyl, 5-chloro-8-methyl, and 5-bromo-7-methyl derivatives. In 3-hydroxy-4,4,5,8-tetramethylisobenzopyran-1-one, the barrier was + 104(6) kJ/mol, and the solution enantiomer t1/2 at room temperature was of the order of hours. Chemical shift differences (ΔνMe) between diastereotopic methyls of 8-methyl-5-substituted enantiomeric pseudoacids were observed in the order F < CH3 < Cl, and generally decrease with increasing temperatures. The pseudoaxial and pseudoequatorial dispositions of the gem-dimethyl groups show smaller torsional differences in the presence of adjacent aryl 5-substituents. The crystal structures of 5-fluoro, 5-chloro and 5-methyl derivatives of 3-hydroxy-4,4,8-trimethylisobenzopyran-1-ones and of 5-bromo-3-hydroxy-4,4,7-trimethylisobenzopyran-1-one are reported, along with several relevant secondary endocyclic pseudoamide derivatives. Electronic energy computations (B3LYP/6-31 + (G(d,p) level of theory) generally support the steric compression model. Equilibration between diastereomeric pseudoacids 3-hydroxy-4-ethyl-4-methylisobenzopyran-1-one and 3-hydroxy-4,5,8-trimethyl-4-phenylisobenzopyran-1-one were rapid with trans isomers decreasingly favored as temperature increases, and cis isomers less stable by + 4.8(2) kJ/mol and + 7.0(4) kJ/mol, respectively. The first-order rate of cis → trans conversion was measureable for 3-hydroxy-4,5,8-trimethyl-4-phenylisobenzopyran-1-one at 25 °C was found to be 0.00403/min, t1/2 = 2.87 h. Attempts to produce 5-isopropyl, 5-t-butyl and 4-phenyl-5-methyl pseudoacid derivatives were frustrated by aryl substituent rearrangement upon ring closure to the intermediate indanones. Structures of rearranged 3-hydroxy-4-methyl-4-(2′-chloro-5′-methylphenyl)isobenzopyran-1-one (pseudoacid) and N-benzyl-6-isopropyl-4,4,8-trimethylisobenzopyrimidin-1-one (pseudoamide) are reported.

Graphic Abstract

Arylpyran pseudoacids undergo slow ring opening and fast ring closing in solution amounting to racemization, rates of which can be slowed considerably by steric compression between the 5-substituent and the adjacent gem-dimethyl groups.

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Acknowledgements

Thanks to NSF (MRI 0618148) for diffraction equipment. Thanks also to Ms. Vivian Pham for experimental assistance, and to Dr. Buck Taylor for assistance with computations; both are from the University of Portland. EJV expresses special appreciation to the John Felice Rome Center of Loyola University of Chicago and its Director Dr. Michael F. Andrews for a visiting lectureship and provision of space and time for composition and data analysis.

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  1. Department of Chemistry, University of Portland, 5000 North Willamette Blvd, Portland, OR, 97203, USA

    Jonathan Fung, Truc-Vi Duong, Keean C. A. Braceros, Marilyn L. Brooks, Katie Schloesser-Lingscheit, Tristen K. S. Tagawa, Johanna M. Wilson, Kevin K. Jones & Edward J. Valente

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Fung, J., Duong, TV., Braceros, K.C.A. et al. Arylpyran Pseudoacid Racemization: Rate Estimation and Structural Influences. J Chem Crystallogr 51, 14–41 (2021). https://doi.org/10.1007/s10870-020-00829-2

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