Organic Fluorine involved Intramolecular Hydrogen Bonds in the Derivatives of Hydrazides and
Imides: NMR Evidence Substantiated by DFT based Theoretical Calculations
Sandeep Kumar Mishra and N. Suryaprakash
Solid State and Structural Chemistry Unit,
NMR Research Centre, Indian Institute of Science, Bangalore 560012
[email protected], http://nrc.iisc.ernet.in/nsp/; Tel: 080-22933300
We have detected rare intramolecular hydrogen bonds (HBs) of the type N–H˖˖˖F–C in the derivatives of Imides and Hydrazides in the low polarity solvent by using multidimensional and multinuclear solution state NMR experiments. The NMR results are corroborated with the DFT based theoretical calculations. The general chemical structures of
the molecules synthesized for the study are given in fig. 1.
The 1D proton and 2D 1H-15N HSQC NMR experiments provided the information
about the magnitudes and signs of through space couplings in fluorine containing
molecules. The combination of variable temperature 2D 1H-15N HSQC and 1H-19F
HOESY NMR experiments have been extensively employed for the detection of
hydrogen bond and also different existing conformations of the molecules in the
solution state.
Fig.1. the general structure of derivatives of (a) Hydrazide (b) Imides.
The lowering of temperature results in the strengthening of HB and causes excessive deshielding of protons due to displacement of the NH proton towards, an H-acceptor, providing
strong evidence for the presence of HB. The comparative study of the variation in the chemical shift of NH protons as a function of temperature (300–220 K) for the derivatives of
Hydrazides is reported in Fig. 2a. It is well known that DMSO is a very good HB acceptor. The observed variation in the chemical shifts as a function of the incremental addition of
DMSO-d6 is graphically illustrated for the derivatives of Hydrazides in Fig. 2b. Disruption of intramolecular HB by the solvent DMSO resulted in the deshielding of NH protons. In
contrast, for some molecules a high field shift of NH protons was detected. This is due to the fact that in these molecules HB is stronger than the DMSO interaction and the high
field shift of hydrogen bonded NH proton is due to an equilibrium stabilization between intra- and inter- molecular hydrogen bonded species. Another interesting feature observed is
the change in the through space JFH value in the 1H NMR spectrum. Such a variation is possible only when the coupling of NH is mediated through HB. The variation in the
coupling constant (through space) as a function of temperature for the derivatives of Imides is reported in Fig. 2c.
Fig.2. Plot (a-b) change in the chemical shift of NH
proton as a function of temperature and volume of
DMSO-d6 respectively, for the derivatives of
Hydrazide (c) change in through space coupling as a
function of temperature for the derivatives of Imide.
In the fluorine containing molecules the coupling for NH proton collapses into singlets in high polarity solvent. The similar information drawn from 1H{19F} 1D NMR experiments,
is represented in the fig. 3.
Fig.3. 400 MHz 1H NMR spectra of molecule 2fluoro-N-(2-fluorobenzoyl)benzamide; (a) in the
solvent CDCl3 ; (b) 1H{19F} NMR spectrum in the
solvent CDCl3 ; and (c) 1H NMR spectrum in the
solvent DMSO-d6.
However, the couplings other than 1hJFH are not detectable due to the symmetry of the molecule. For the determination of these values, we resorted to the technique of breaking the
symmetry and carried out the two dimensional proton-coupled 1H–15N HSQC experiments, where 15N is present in its natural abundance and the corresponding spectrum is
displayed in Fig. 4. The observation of through space couplings of significant strengths, such as 1hJFH, 2hJFN, 3hJFN and 4hJFH, gives strong and direct evidence for the involvement of
organic fluorine in the intramolecular HB.
Acknowledgement:
SKM would like to thank UGC, New Delhi, for SRF. NS gratefully
acknowledges the generous financial supported by Board of Research in
Nuclear Sciences, Mumbai (Grant No. 2013/37C/4/BRNS) and the Science and
Engineering Research Board, Department of Science and Technology, New
Delhi (grant No. SR/S1/PC-42/2011).
Conclusion:
1
Fig.4.
800
MHz
H–15N-HSQC
(NH-coupled)
spectrum
of
molecule
2-fluoro-N’-(2fluorobenzoyl)benzohydrazide in solvent CDCl3; The molecular structure and the separations that give
magnitudes of scalar and through space couplings are identified by double headed arrows. The measured
coupling values are their signs derived from the relative slopes of displacement of cross sections
In conclusion we have synthesized the various derivatives of Imides and hydrazides
and detected the rare type of organic fluorine involved intramolecular hydrogen
bonding by utilizing several multidimensional and multinuclear solution state NMR
experiments. Through space coupling in different molecules varied between 2 to 14
Hz in several F-containing molecules, and are detected by 2D 1H–15N HSQC,
experiment. Variation in the detected couplings on altering the temperature provided
the conclusive evidence in favor of through space couplings. The DFT based
QTAIM and NCI calculations are used to corroborate the NMR experimental
results. We believe that the present studies might lead to better understanding of the
HB and open up opportunities in designing different foldamers and supramolecules
that are of chemical and biological importance.