Geometrical and Stereochemical Factors in Metal-Promoted Amide Hydrolysis

John Taylor Groves, R. Rife Chambers

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The importance of the precise geometric orientation of a metal in metal-promoted amide hydrolysis has been demonstrated. Large rate enhancements (103–106) at neutral pH were found in zinc and copper complexes in which the metal is forced to lie above the plane of an amide. For this study, lactams l-[(6-(dimethylamino)methyl)-2-pyridyl)methyl]hexahydro-l,4-diazepin-5-one (1) and l-[(6-((bis(carboxymethyl)amino)methyl)-2-pyridyl)methyl]hexahydro-l,4-diazepin-5-one (2) were synthesized. Titrimetrically determined formation constants indicated that both 1 and 2 readily bind divalent metals (Cu2+, Ni2+, Zn2+, Co2+). Detailed investigations of the various metal complexes were possible over a wide range of pH. At 50 ∘C, the Cu2+-promoted hydrolysis of 1 exhibited a sigmoidal pH-rate profile. The rates increased commensurate with the ionization of a metal-bound water molecule. A similar behavior was observed with the 2−Zn2+ complex at 70 ∘C. Both Cu2+ and Zn2+ greatly facilitate amide hydrolysis at pH 7. Compared to base hydrolysis of the lactams with no metal, a rate enhancement of 9 × 105 and 1.0 × 103 was observed with the l-Cu-OH2 and 2-Zn-OH2 complexes, respectively. Activation parameters for the metal-promoted hydrolyses indicated that catalysis results from a substantial increase in ΔS. These observations are interpreted in terms of nucleophilic catalysis by a metal-hydroxo species in basic media. Concurrent carbonyl oxygen exchange accompanied base hydrolysis of 1. By contrast, significant oxygen-18 exchange was not observed during the Cu2+-promoted hydrolysis of 1. These results are considered in the context of the known stereoelectronic control in the cleavage of.tetrahedral intermediates.

Original languageEnglish (US)
Pages (from-to)630-638
Number of pages9
JournalJournal of the American Chemical Society
Issue number3
StatePublished - Feb 1 1984

All Science Journal Classification (ASJC) codes

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry


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