This article describes the result of predictions based on a novel continuum model for the effect of microstructure on deprotection reaction kinetics during postexposure bake (PEB). The effect of neighboring blocking groups is incorporated in a continuum PEB model. Provided blocking groups with neighbors react at a slower rate than isolated blocking groups, an up to 8% improvement in latent image contrast is predicted. In addition, a first principles calculation of the equilibrium structure for poly(methyl methacrylate-co-t-butyl methyl methacrylate) copolymer with acid present is reported. Hybrid quantum mechanics/molecular mechanics (QC/MM) results indicate that a strong hydrogen bond forms between blocked and unblocked neighbor sites in the presence of acid. The QC/MM prediction provides evidence confirming the rate constant for deprotection reaction with a neighboring blocked site is reduced relative to isolated blocking groups. The new PEB model form is shown to improve the fit to kinetic Fourier transform infrared data over conventional deprotection kinetics for those resists that contain carboxyl group deprotection chemistry. The new model also explains the difference in reaction rate between resists with otherwise identical deprotection chemistry by altering only neighboring blocked site content. Finally, a 50% greater lithographic advantage in development rate contrast is demonstrated for microstructure with increased neighboring blocked sites.