The Rich Solid-State Phase Behavior of l-Phenylalanine: Disappearing Polymorphs and High Temperature Forms

Area of Science:

• Crystallography
• Solid-state chemistry
• Materials science

Background:

• The solid-state structure of l-phenylalanine has been a subject of debate.
• Four polymorphic forms (I, II, III, IV) have been previously reported.
• Polymorph I and III share similar symmetry (P21) but differ in molecular bilayer arrangement.

Purpose of the Study:

• To investigate the high-temperature behavior of l-phenylalanine polymorphs.
• To identify new phases and understand phase transitions.
• To elucidate the dynamic conformational changes influencing crystal structure.

Main Methods:

• Single-crystal X-ray diffraction
• Differential scanning calorimetry
• Molecular Dynamics (MD) simulations
• Metadynamics simulations

Main Results:

• Two new high-temperature phases (Ih and IIIh) were identified for l-phenylalanine.
• Phase transitions occur above 458 K (form I) and 440 K (form III), involving dynamic side-chain flipping.
• Transitions lead to reduced asymmetry (Z'=4 to Z'=2) and altered crystal symmetry.
• An instance of a disappearing polymorph (form I) was observed.
• Form III can irreversibly convert to form I via bilayer sliding at elevated temperatures.
• No interconversion between Ih and IIIh was detected.

Conclusions:

• l-phenylalanine exhibits complex polymorphism with temperature-dependent phase transitions.
• Dynamic conformational changes in side chains are key to high-temperature phase behavior.
• MD and metadynamics simulations support crystallographic findings, particularly for the form I-III system.