Hydrogen bonding peptides as asymmetric organocatalysts Brian R. Linton, Department of Chemistry, College of the Holy Cross
O Hydroxybenzotriazole (HOBt 1) is a common N N O EDC N RCO H additive to the peptide synthesis reactions for our 2 + N R N N 2 O CH2Cl2 R organocatalysts. The isolation of acylated HOBt N N N + derivatives unexpectedly produced two isomeric HO 1 3 4 O products (3 and 4), that differed in the regiochemistry after evaporation of the acylation reaction. to a solid The product ratios were determined to be a factor of steric bulk, solvent and a novel example of the CurtinHammett effect. Increased steric bulk on the acylating group disfavored the N-acyl form 4. Kinetic analysis showed the immediate formation of the O-acyl form 3, followed by an equilibration in solution to both isomers. The final product equilibrium product ratios were dependent on solvent, with more polar solvents favoring the O-acyl form 3. This appear to be a result of the tautomeric ratio of HOBt forms 1 and 1’, where the zwitterionic form is more favorable in more polar solvents. lower barrier for more nucleophilic oxygen
higher barrier for less nucleophilic nitrogen tautomerization
energy
An additional curiosity was observed with the complete isomerization to the N-acyl form 4 upon evaporation of the product mixture to a solid. This suggests that the N-acyl form 4 is the thermodynamic product, and formation of the O-acyl form 3 in solution is biased by the tautomeric equilibria of HOBt. Previously observed equilibrium product ratios were re-established by dissolving pure N-acyl isomer 4 in solvent and adding either nucleophilic or electrophilic reagents. This work was recently published in the Journal of Organic Chemistry.
O R
O
N N N
kinetic product
3
H N N N O
1
1'
stabilized in more polar solvents
reaction coordinate
N N N HO
4 R
O
disfavored with non-polar solvents and increased steric bulk
N favorable N N in the solid state O thermodynamic product
