Chemical Force Microscopy Nanoscale Probing of Fundamental Chemical Interactions

Intermolecular forces impact a wide spectrum of problems in condensed phases: from molecular recognition, self-assembly, and protein folding at the molecular and nanometer scale, to interfacial fracture, friction, and lubrication at a macroscopic length scale. Understanding these phenomena, regardless of the length scale, requires fundamental knowledge of the magnitude and range of underlying weak interactions between basic chemical functionalities in these systems (Figure 1). While the theoretical description has long recognized that intermolecular forces are necessarily microscopic in origin, experimental efforts in direct force measurements at the microscopic level have been lagging behind and have only intensified in the course of the last decade. Atomic force microscopy (AFM)1,2 is an ideal tool for probing interactions between various chemical groups, since it has pico-Newton force sensitivity (i.e., several orders of magnitude better than the weakest chemical bond3) and sub-nanometer spatial resolution (i.e., approaching the length of a chemical bond). These features enable AFM to produce nanometer to micron scale images of surface topography, adhesion, friction, and compliance, and make it an essential characterization technique for fields ranging from materials science to biology. As the name implies, intermolecular forces are at the center of the AFM operation. However, during the routine use of this technique the specific chemical groups on an AFM probe tip are typically ill-defined. To overcome this inherent limitation of the AFM, Lieber and coworkers introduced the concept of chemical modification of force probes to make them sensitive to specific molecular interactions4. By using chemically-functionalized tips, a force microscope can be transformed into a tool that can (i) quantify forces between different molecular groups, (ii) probe surface free energies on a nanometer scale, (iii) determine pKa values of the surface acid/base groups locally, and (iv) map the spatial distribution of specific functional groups and their ionization state. This ability to discriminate between chemically distinct functional groups has led the Lieber group to name the variation of force microscopy carried out with specifically functionalized tips “chemical force microscopy” (CFM)4. 3