Importance of Solvent-Bridged Structures of Fluorinated Diphenylalanines: Synthesis, Detailed NMR Analysis, and Rotational Profiles of Phe(2-F)-Phe(2-F), Phe(2-F)-Phe, and Phe-Phe(2-F).

The crystal structure of l-phenylalanyl l-phenylalanine (Phe-Phe, FF, a.k.a. diphenylalanine) is not merely noncentrosymmetric, but it is highly dipole parallel aligned. It is for this reason that FF is a nonlinear optical (NLO) material and exhibits strong second harmonic generation (SHG). Enhancement of the SHG response by fluorination was demonstrated. Crystallization is nontrivial, and learning about the zwitterion structures in solution is important for the rational improvement of the crystallization process. Here, we present an NMR study of di-fluorinated FF (Phe(2-F)-Phe(2-F)) and mono-fluorinated FF isomers (Phe(2-F)-Phe and Phe-Phe(2-F)). The dipeptides were prepared by solid-phase synthesis and purified by high-performance liquid chromatography (HPLC). Their H and C NMR spectra were recorded in partially deuterated water (10% DO), and two-dimensional (2D) NMR techniques were employed for signal assignments. The unambiguous assignments are reported of all chemical shifts for the aliphatic H and C atoms and of the C atoms of the carboxylate, the amide carbonyl, the CF carbons, and of every arene C atom in each phenyl ring. The dipeptides are amides and intramolecular hydrogen bonding between the ammonium group and the amide carbonyl restricts the HN-CH-C(O) geometry. We explored the rotational profile of the diphenylalanines as a function of the τ = ∠(C-N-C-CO) dihedral angle at the SMD(B3LYP/6-31G*) level without and with specific hydration and report the associated Karplus curves (θ) vs θ = ∠(H-N-C-H). The rotational profiles show a maximum of three stationary structures, and relative conformer stabilities of the free diphenylalanines show that the conformation found in the crystal is the least stable among the three, > ≫ . Specific water solvation makes all of the difference and adds a large competitive advantage to the water-bridged ion pair . In fact, becomes the most stable and dominant conformation for the parent diphenylalanine and mono1 F-FF and becomes competitive with for mono2 F-FF and di F-FF. Implications are discussed regarding the importance of the conformational preorganization of diphenylalanines in solution and the facility for their crystallization.