Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 535–536.
Published online in Wiley InterScience
JLCR
Short Research Article
1
Origin of the large isotope-induced shift in the H-NMR of
ortho-2H-labelled anilidesy
JOHN R. JONES1, WILLIAM J. S. LOCKLEY1,*, RICHARD J. LEWIS2 and DAVID J. WILKINSON2
1 Department of Chemistry, University of Surrey, Guildford GU2 7XH, UK
2 AstraZeneca R&D Charnwood, Bakewell Rd, Loughborough, Leics LE11 5RH, UK
Received 26 July 2006; Revised 15 December 2006; Accepted 22 December 2006
Keywords: anilide; N-arylamide; deuterium; isotope shift; conformation
Introduction
Results and discussion
Isotope effects associated with the introduction of
deuterium into a molecule are conveniently investi-
gated using both 1H- and 13C-NMR.1 We recently
reported an isotopic shift for the remaining ortho proton
of ortho-2H anilides2 which was very large, 16 ppb
upfield in CDCl3 at 298 K.
The effect of temperature on conformational prefer-
ences can be calculated5 and the results compared
with the experimental data from variable temperature
NMR studies to provide estimates of the relative
populations of the two conformers together with the
enthalpy and entropy variation between them (Table 1).
In all cases DS for the process approximated to zero
(and hence was assumed to be zero for modelling
purposes) whilst DH was of the order of ꢀ133 J/mol for
a non-polar solvent, toluene, to ꢀ53 J/mol for a polar
solvent, acetonitrile. Hence, the data clearly suggest
that the position of equilibrium is enthalpy driven.
Moreover, the decrease in DH with increasing solvent
polarity argues strongly for an electronic rather than
steric origin. The effect may reflect different dipole–
dipole,6,7 non-bonding-orbital2d or H-bonding2b inter-
actions Though similar effects have previously been
advanced as explanations8 for anomalous isotopic
shifts, to our knowledge this is the first direct experi-
mental evidence for an electronically mediated con-
R
R
HN
O
H
HN
O
D
D
H
2
1
The deshielding effect of the carbonyl group on the
o-proton of anilides affords sensitive probe for
a
conformation about the N–Ar bond and such chemical
shifts have been used to investigate the conformations
of mono-ortho(2a–c) and mono-meta(2d)-substituted ani-
lides, hence we ascribed the origin of the effect to a
small preference for conformer 2 over conformer 1.3
The results of variable temperature NMR studies of one
such system, ortho-2H acetanilide,4 in three solvents
are now reported.
formational effect arising from
substitution.
a single D-atom
Table
1 Thermodynamic parameters and populations of
conformer 2 for [2-2H] acetanilide, in three NMR solvents at
298 K
Solvent
DH (J/mol)
DS (J/
K mol)
Population of
conformer 2
(% at 298 K)
*Correspondence to: William J. S. Lockley, Department of Chemistry,
University of Surrey, Guildford GU2 7XH, UK.
[2H]Toluene
[2H]Dichloro-
methane
ꢀ118 to ꢀ147
ꢀ66 to ꢀ83
ca. 0
ca. 0
51.2–51.5
50.7–50.8
E-mail: w.lockley@surrey.ac.uk
yProceedings of the Ninth International Symposium on the Synthesis
and Applications of Isotopically Labelled Compounds, Edinburgh,
16–20 July 2006.
[2H]Acetonitrile
ꢀ47 to ꢀ59
ca. 0
50.5–50.6
Copyright # 2007 John Wiley & Sons, Ltd.