α-Fluoro Phosphonocarboxylates: the NMR Analysis of the Heteronuclear ABMX Spin System

Abstract

The α-fluorophosphonocarboxylate analogs of bisphosphonates have recently received attention due to their activity against Rab geranylgeranyl transferase, an enzyme implicated in a number of disease conditions. Most of the NMR data reported in the literature describing dialkyl α-fluorophosphonates are defined as first-order spectra. Here, we report a second-order pattern observed in ¹⁹F NMR spectrum, being a part of heteronuclear ABMX spin system. Such a spin system, CH₂C(F)P, was subjected to NMR analysis supported by iteration.

GRAPHICAL ABSTRACT

Keywords:

• Trialkyl α-fluorophosphonocarboxylates
• ABMX spin system
• multinuclear coupling

Notes

Recently, a novel method of JHF determination, utilizing 2D-TOCSY technique, was described by Espinosa,⁴ extending the toolkit of the methods thus far applied, and overcoming the necessity of using spectrometer with two NMR probes.

Only when considering two small coupling constants (1.1 Hz), the spectrum could be iterated properly.

ABXY system for α-fluorophosphonocarboxylates has been reported previously only by Odinets et al.¹⁴ Authors described the ¹⁹F NMR spectrum as ddd, with the following parameters, determined for seven compounds (ranges are quoted): Δv_H = 0.24–0.26 ppm, ²J_HH 15.8–16.0 Hz, ³J_FH 11.4–13.2 and 38.5–39.0 Hz, ³J_PH 8.0–12.6 and 4.0–6.0 Hz, ²J_PF 82.6–83.4 Hz.

On acquiring higher resolution spectra, we found peaks of small integration next to 12 lines representing ABMX system. We suppose they might result from ¹⁹F–¹³C couplings through 1, 2, and 3 bonds. Such hypothesis is additionally supported by small variations of peak integrations between experimental and iterated (without taking into account this coupling) spectra.

Additional information

Funding

Financial support by the National Science Center and Ministry of Science and Higher Education in Poland (N N204 519839) is gratefully acknowledged.