Unexpected polymorphism during a catalyzed mechanochemical Knoevenagel condensation

• Published in: Beilstein journal of organic chemistry Vol. 15; no. 1; pp. 1141 - 1148
• Main Authors: Haferkamp, Sebastian, Paul, Andrea, Michalchuk, Adam A L, Emmerling, Franziska
• Format: Journal Article
• Language: English
• Published: Germany Beilstein-Institut zur Föerderung der Chemischen Wissenschaften 2019; Beilstein-Institut
• Subjects: ball milling; Benzaldehyde; Chemistry; Condensation; C–C coupling; Full Research Paper; in situ; Mass spectrometry; mechanochemistry; Multivariate analysis; multivariate data analysis; Principal components analysis; Raman spectroscopy; Scientific imaging; Germany; C–C coupling; multivariate data analysis; mechanochemistry; ball milling; in situ
• ISSN: 1860-5397; 2195-951X; 1860-5397
• DOI: 10.3762/bjoc.15.110

The transformation of a base-catalyzed, mechano-assisted Knoevenagel condensation of mono-fluorinated benzaldehyde derivatives ( -, -, -benzaldehyde) with malonodinitrile was investigated in situ and in real time. Upon milling, the -substituted product was found to crystallize initially into two different polymorphic forms, depending on the quantity of catalyst used. For low catalyst concentrations, a mechanically metastable phase (monoclinic) was initially formed, converting to the mechanically stable phase (triclinic) upon further grinding. Instead, higher catalyst concentrations crystallize directly as the triclinic product. Inclusion of catalyst in the final product, as evidenced by mass spectrometric analysis, suggests this complex polymorphic pathway may be due to seeding effects. Multivariate analysis for the in situ Raman spectra supports this complex formation pathway, and offers a new approach to monitoring multi-phase reactions during ball milling.