Scheme 3. Synthesis of Malonic Acid Half Oxyester 8 and
Alternative MAHOs and MAHTs Generated in This Study
Figure 1. Rates of H/D exchange for MAHOs and MAHTs.
extensive, i.e. 74ꢀ97%, deuteration, whereas MAHOs 9ꢀ11
exhibited much lower levels of H/D exchange, i.e. 14ꢀ38%.
The NMR data and comparisons of ease of deuterium
incorporations between MAHTs and MAHOs will be
significant when these compounds are employed as mech-
anistic probes. The ease of enolization in the MAHT series
was explored by DFT calculations. Using B3LYP12/
6-31G(d)13 with Gaussian 09,14 we first explored a series of
30 ester and 30 thioester conformations (e.g. transoid/cisoid)
and configurations (e.g. E/Z) in the parent phenol and
thiophenol esters. Using the B3LYP/6-31G(d) minima as
starting points the optimizations were repeated with the
M06-2X functional which has performed well in a bench-
marking study of 52 melatonin conformers.15 The geometries
and molecular orbitals of the MAHOs and MAHTs are
generally very similar. The main difference between the
MAHO and MAHT series is the presence of the additional
sulfur-centered orbital in the MAHTs which increases
delocalization of electron density from the sulfur atom
into the enol. Similar results were obtained when the study
was extended to a selection of representative solvents
(acetonitrile, dichloromethane, and methanol) and alter-
native functionals.
previously reported, i.e. 2-methyl-3-oxo-3-(phenylthio)-
propanoic-d2 acid and 2-(methyl-d3)-3-oxo-3-(phenylthio)-
propanoic acid.11 Because the unlabeled starting materials
were now readily available, we have been able to take
advantage of the relatively acidic methylene protons to
introduce deuterium labels directly by exploiting the ketoꢀ
enol tautomerization properties of the esters and thioesters.
The method is very straightforward and easy to perform. We
began work with the parent phenyl compounds 8 and 12
which were simply dissolved in d4-methanol and monitored
by 1H NMR, recording spectra after 4, 9, 19, and 29 min. As
seen from Figure 1 (blue traces: crosses, esters; dots, thioesters)
both compounds incorporated the deuterium label. The data,
however, reveal an important and unexpected difference
between oxy-8 and thio-12. The thioester showed significantly
2
higher levels of H-incorporation in the early stages of the
experiment. Thus after only 4 min, the H/D exchange for
thioester 12 was far more advanced than for oxyester 8, i.e.
72% and 18% respectively (Figure 1). Indeed after 9 min, 12
had incorporated 52% more deuterium than 8. The substi-
tuted aryl esters and thioesters from our synthetic work were
examined in comparable NMR experiments, which showed
(Figure 1; green, magenta, pink and brown traces) that more
rapid H/D exchange was consistently observed with MAHTs.
Indeed after only 9 min, MAHTs 2, 13, and 14 had undergone
Both MAHOs and MAHTs are easily prepared by the
method described here, and the rapid enolization of the
MAHT series measured by H/D exchange has important
mechanistic consequences in synthetic and bioorganic
chemistry. DFT calculations have examined this effect,
and it is ascribed to the presence of an additional sulfur-
centered frontier orbital which increases π-delocalization
between the heteroatom and the enol.
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Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.;
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Acknowledgment. The authors acknowledge the EPSRC,
UEA, and INTERREG IVA (IS:CE chem project 4061)
for financial support, the UEA high-performance cluster
“Grace” for computational resources, and the EPSRC Mass
Spectrometry Service for HRMS data.
Supporting Information Available. Experimental details,
spectral and analytical data for all reaction products, and
details of the DFT calculations. This material is available free
(15) Fogueri, U. M.; Kozuch, S.; Karton, A.; Martin, J. M. L J. Phys.
Chem. A 2013, 117, 2269–2277.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 15, 2013
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