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Formation of the IMHB could account for the reduced
reactivity of mono-thioureas by imposing steric hindrance to
the approach of the isothiocyanate reactant. Presumably, a
combination of such molecular reactivity and the absence of
solubility-imposed limitations under mechanochemical conditions
enables the quantitative mono-functionalization of o-pda. Frontier
molecular orbital (FMO) analysis of mono-thiourea–isothiocyanate
pairs provided a suitable explanation for different reactivity of
mono-thioureas 1a–d compared to their urea analogues. The
analysis indicated that the most important interactions involve
the HOMOs (e.g. HOMO and HOMO-1) of mono-thioureas
and the LUMOs of isothiocyanates (Tables S6 and S7 in ESIz).
The HOMO analysis of 1a–d reveals much larger orbital
coefficients on sulfur compared to the nitrogen of the –NH2
group (illustrated for 1b, Fig. 1a). The relative sizes of the
molecular orbital coefficients on the chalcogen and amino
nitrogen atoms in the HOMO-1 of mono-thioureas and -ureas
are substantially different (Fig. S31 in ESIz). Ureas exhibited a
larger coefficient on the NH2 nitrogen atom (shown for 1e,
Fig. 1b) and, presumably, a greater propensity for isocyanate
addition.
9 V. Gotor, I. Alfonso and E. Garcı
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Click-mechanochemical thiourea coupling enabled the
quantitative and selective desymmetrisation of ortho- and
para-phenylenediamines. To the best of our knowledge, our
work is the first to demonstrate the controlled extension of a
molecular structure in a purely mechanochemical sequence
that combines competing bond-forming reactions: the thiourea
synthesis and the urea synthesis. The described reactivity avoids
the need to isolate intermediates and allows the building-up of
non-symmetrical molecules in >95% yield over two steps. Our
report complements previously reported multi-step mechano-
syntheses which exploit non-competing reactions or involve
purification steps.25
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, Chem. Commun., 2010, 46, 9191;
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We acknowledge the financial support of the Unity Through
Knowledge fund (project no. 63/10) and support of the
Ministry of Science, Education and Sport of Croatia (Project
No. 098-0982933-2920). McGill University, the FQRNT Centre
for Self-Assembled Chemical Structures and NSERC Discovery
Grant program are acknowledged for support (TF).
22 Milling 1e with p-chlorophenyl isothiocyanate for 30 min gave 2l in
65% yield, with quantitative conversion achieved after 3 hours of
milling. Under identical conditions p-methoxyphenyl isothiocyanate
and 1e did not react (most of the reagents remained unreacted).
23 To evaluate the effect of the thiourea substituent on reactivity,
Mulliken population analysis for the most stable conformer of
1a–d was carried out. The analysis did not reveal any significant
effect of the substituent on the charges on the NH2 nitrogen atom.
24 The cis-conformer 1d-cis displays an IMHB between the NH2
group and the sulphur atom (N–Hꢁ ꢁ ꢁS distance 3.360 A), but is
less stable than 1d-trans by 17.6 kJ molꢀ1 (see ESIz).
25 (a) V. P. Balema, J. W. Wiench, M. Pruski and V. K. Pecharsky,
Notes and references
y All compounds have been characterized by Fourier-transform infra-
1
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun.