A model for a solvent-free synthetic organic research laboratory: Click-mechanosynthesis and structural characterization of thioureas without bulk solvents

Article abstract of DOI:10.1039/c2gc35799b

The mechanochemical click coupling of isothiocyanates and amines has been used as a model reaction to demonstrate that the concept of a solvent-free research laboratory, which eliminates the use of bulk solvents for either chemical synthesis or structural characterization, is applicable to the synthesis of small organic molecules. Whereas the click coupling is achieved in high yields by simple manual grinding of reactants, the use of an electrical, digitally controllable laboratory mill provides a rapid, quantitative and general route to symmetrical and non-symmetrical aromatic or aromatic-aliphatic thioureas. The enhanced efficiency of electrical ball milling techniques, neat grinding or liquid-assisted grinding, over manual mortar-and-pestle synthesis is demonstrated in the synthesis of 49 different thiourea derivatives. Comparison of powder X-ray diffraction data of mechanochemical products with structural information found in the Cambridge Structural Database (CSD), or obtained herein through single crystal X-ray diffraction, indicates that the mechanochemically obtained thiourea derivatives are pure in a chemical sense, but can also demonstrate purity in a supramolecular sense, i.e. in all structurally explored cases the product consisted of a single polymorph. As an extension of our previous work on solvent-free synthesis of coordination polymers, it is now demonstrated that such polymorphic and chemical purity of selected thiourea derivatives, the latter being evidenced through quantitative reaction yields, can enable the direct solvent-free structural characterization of mechanochemical products through powder X-ray diffraction aided by solid-state NMR spectroscopy.

Full text of DOI:10.1039/c2gc35799b

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Volume 14 | Number 9 | September 2012 | Pages 2355–2648
ISSN 1463-9262
COVER ARTICLE
Friščić, Eckert-Maksić et al.
A model for a solvent-free synthetic organic research laboratory:
click-mechanosynthesis and structural characterization of thioureas
without bulk solvents
1463-9262(2012)14:9;1-M

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PAPER
A model for a solvent-free synthetic organic research laboratory:
click-mechanosynthesis and structural characterization of thioureas
without bulk solvents†
Vjekoslav Štrukil,a Marina D. Igrc,a László Fábián,b Mirjana Eckert-Maksić,*a Scott L. Childs,c
David G. Reid,d Melinda J. Duer,d Ivan Halasz,a Cristina Mottilloe and Tomislav Friščić*d,e
Received 24th May 2012, Accepted 24th July 2012
DOI: 10.1039/c2gc35799b
The mechanochemical click coupling of isothiocyanates and amines has been used as a model reaction to
demonstrate that the concept of a solvent-free research laboratory, which eliminates the use of bulk
solvents for either chemical synthesis or structural characterization, is applicable to the synthesis of small
organic molecules. Whereas the click coupling is achieved in high yields by simple manual grinding of
reactants, the use of an electrical, digitally controllable laboratory mill provides a rapid, quantitative and
general route to symmetrical and non-symmetrical aromatic or aromatic–aliphatic thioureas. The enhanced
efficiency of electrical ball milling techniques, neat grinding or liquid-assisted grinding, over manual
mortar-and-pestle synthesis is demonstrated in the synthesis of 49 different thiourea derivatives.
Comparison of powder X-ray diffraction data of mechanochemical products with structural information
found in the Cambridge Structural Database (CSD), or obtained herein through single crystal X-ray
diffraction, indicates that the mechanochemically obtained thiourea derivatives are pure in a chemical
sense, but can also demonstrate purity in a supramolecular sense, i.e. in all structurally explored cases the
product consisted of a single polymorph. As an extension of our previous work on solvent-free synthesis
of coordination polymers, it is now demonstrated that such polymorphic and chemical purity of selected
thiourea derivatives, the latter being evidenced through quantitative reaction yields, can enable the direct
solvent-free structural characterization of mechanochemical products through powder X-ray diffraction
aided by solid-state NMR spectroscopy.
particularly as a means to conduct solvent-free and low-energy
synthesis.3 This is evidenced by a rapidly growing number of
research areas where mechanochemistry has been successfully
applied for the improvement of reaction efficiency: supramolecu-
lar synthesis4 of hydrogen- or halogen-bonded materials,5
including pharmaceutical cocrystals6 and salts,7 photoreactive,
chromophoric or luminescent cocrystals,8 the synthesis of
coordination compounds, clusters and polymers,9 metallodrugs10
and porous metal–organic frameworks.11 However, the dominant
area of application of mechanosynthesis in a laboratory is
organic synthesis,12 including asymmetric catalysis.13 Significant
advances in the mechanosynthesis of organic compounds have
recently been achieved through the application of metal-based
catalysis,14 catalytic supramolecular templating15 and reversible
covalent bonding.16 A mechanochemical approach to click-
chemistry was first reported by the Stolle group, who demon-
strated solvent-free polymer synthesis using a 1,3-dipolar
Huisgen cycloaddition in a ball mill,17 and our group recently
demonstrated the mechanochemical thiourea click-coupling as a
highly-efficient route to thiourea organocatalysts.18
Introduction
Mechanochemical reactions,1 i.e. reactions initiated or sustained
through mechanical force, are becoming increasingly important
in the context of environmentally-friendly synthesis,2
aRuđer Bošković Institute, Bijenička cesta 54, Zagreb, Croatia.
E-mail: mmaksic@emma.irb.hr
bSchool of Pharmacy, University of East Anglia, Norwich Research
Park, Norwich, NR4 7TJ, UK. E-mail: L.Fabian@uea.ac.uk
cRenovo Research, 749 Moreland Avenue SE, Suite A201, Atlanta,
Georgia, USA. E-mail: schilds@renovoresearch.com
dDepartment of Chemistry, University of Cambridge, Lensfield Road,
CB2 1EW Cambridge, United Kingdom
eDepartment of Chemistry and FQRNT Centre for Green Chemistry and
Catalysis, McGill University, Montreal, H3A 0B8, Canada.
E-mail: tomislav.friscic@mcgill.ca; Fax: +1-514-398-3757;
Tel: +1-514-398-3959
†Electronic supplementary information (ESI) available: Details of exper-
iments and instrumental techniques, 1H and 13C solution NMR spectra
of mechanochemical products, selected 13C solid-state CP-MAS NMR
spectra, FTIR-ATR spectra, PXRD patterns and crystallographic data in
CIF format. (All crystallographic data, except for the 1e-SC and
1e-PXRD structures have been deposited with the Cambridge Structural
Database, CCDC deposition numbers 883638–883645). For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c2gc35799b
Whereas laboratory-scale mechanochemical synthesis is often
conducted by manual mortar-and-pestle techniques,19 the appli-
cation of a digitally controlled laboratory mill allows a higher
2462 | Green Chem., 2012, 14, 2462–2473
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level of reproducibility through clearly delineated reaction con-
ditions such as reaction time, impact force (which is readily
defined through selection of grinding ball weight and size) and
grinding intensity (which is defined by milling frequency).20 The
increasing popularity of mechanochemistry in recent synthetic
literature is related to the high energy- and solvent-efficiency of
milling reactivity compared to conventional laboratory tech-
niques (e.g. microwave-assisted solution synthesis)21 as well as
to the development of new modified mechanochemical methods,
such as liquid-assisted grinding (LAG)22–24 or ion- and liquid-
assisted grinding (ILAG).25
From the environmental point of view, these mechanochem-
ical techniques, when coupled with state-of-the-art methods of
solid-state analysis, could enable the development of a laboratory
research methodology that obviates the need for bulk solvent
throughout the entire synthesis and analysis sequence. The viabi-
lity of such a “solvent-free research laboratory” concept was
recently demonstrated in the synthesis of coordination polymers
based on simple and rigid organic ligands.26a From the synthetic
side, the ability of mechanochemical reactions to achieve quanti-
tative reaction yields is central to the development of solvent-
free research, as it provides an environmentally more acceptable
process and prevents the loss of reaction yield inherent to sol-
ution-based crystallization or chromatographic methods.18,27
From the analytical side, two instrumental techniques of out-
standing importance for solvent-free laboratory research are
structural characterization from laboratory powder X-ray diffrac-
tion (PXRD)28 data and solid-state NMR spectroscopy,29 both of
which offer the opportunity to avoid bulk solvents in post-syn-
thetic structural analysis, in particular for single crystal growth
and NMR sample preparation. Different groups have pointed to
the ability of mechanochemistry, when coupled with PXRD and
solid-state NMR, to enable solvent-free laboratory research in
the areas of metal–organic materials, specifically coordination
polymers,26 and hydrogen-bonded cocrystals, including model
pharmaceutical materials.30
We have now explored how the concepts of solvent-free
research26a,31 can be transferred into the arena of organic syn-
thesis, by focusing on the click-mechanochemical coupling of
amines and isothiocyanates leading to simple and rigid mole-
cules in the form of symmetrically and non-symmetrically N,N′-
disubstituted thioureas (Scheme 1).
Thioureas have been selected as target compounds due to their
importance and the simplicity of mechanochemical preparation.
The significance of thioureas lies in their pharmaceutically-
relevant physiological activity encompassing antibacterial,32
antimalarial,33 antiviral34 and antitumor35 behavior, as well as in
their organocatalytic activity36 and applications in anion sensing
and transport.37 The importance of thioureas as organocatalysts
is growing, with reported applications in enantioselective
Morita–Baylis–Hillman reactions, Michael additions, nitroaldol
condensations, acetalisations of aldehydes and ketones and
Friedel–Crafts alkylations.36 Consequently, a simple, efficient
and high-yielding procedure for the synthesis of thioureas is
desirable from both economic and environmental points of view.
The rapid and quantitative mechanosynthesis of chiral thiourea
organocatalysts using the mechanochemical amine–isothio-
cyanate click coupling was recently demonstrated on a gram
scale.18 Besides the efficient synthesis of important organocata-
lysts, this previous work also demonstrated that click mechano-
synthesis provides simple access to both mono- and bis-thioureas
based on sterically and electronically hindered diamines. The
superior control of product stoichiometry using click-mechano-
chemical synthesis resembled similar observations previously
made in the mechanosynthesis of coordination compounds26 and
cocrystal synthesis.38
The simplicity of the reaction, the potential importance of the
products in catalysis and anion binding studies, and their inher-
ently rigid structure make the amine–isothiocyanate coupling a
very suitable test reaction for exploring two important principles
of the proposed solvent-free research laboratory in organic syn-
thesis: avoiding bulk solvents in quantitative synthesis, and
structural characterization without the need to grow macroscopic
single crystals from bulk solvents.
The solvent-free approach to the synthesis of thioureas was
first put forward by Kaupp, who investigated the synthesis of
non-symmetrical N-methyl-N′-arylthioureas through solvent-free
solid–solid and solid–gas reactions of amines with isothio-
cyanates.39 The reactions were conducted over a period of one
day, with occasional manual grinding in the case of a solid reac-
tant. Subsequently, Li and Wang described the solid-state
synthesis of several N,N′-diaryl thioureas from aromatic isothio-
cyanates and amines in a microwave oven and by manual grind-
ing.40 Steed’s group has reported the use of mechanochemical
grinding for the synthesis of a podand anion receptor through a
related reaction of coupling amines with isocyanates.41 The supra-
molecular solid-state chemistry of thioureas has recently become
of interest as a means for the structural interpretation of solution-
phase catalytic activity, as well as because of the recently intro-
duced use of thioureas as hydrogen-bonding templates for
directing the solid-state photodimerisation of olefins.42 Conse-
quently, thioureas represent a set of target molecules whose struc-
tural studies in the solid state43 could be particularly gratifying.
The current broad study demonstrates the generality of
mechanochemical thiourea synthesis, regardless of the physical
state of the reactants, their substituent-controlled reactivity or
steric hindrances. Specifically, we now report a successful quan-
titative synthesis of 49 symmetrical and non-symmetrical N,N′-
diaryl or N-aryl-N′-alkyl thiourea derivatives through mechano-
chemical amine–isothiocyanate coupling. The quantitative reac-
tion after mechanochemical treatment was evidenced through the
absence of the characteristic isothiocyanate 2200 cm−1 stretching
band in the Fourier-transform attenuated total reflection
(FTIR-ATR) spectra of products. Quantitative yields were also
verified by high-pressure liquid chromatography (HPLC) analy-
sis of selected samples. While high reaction efficiencies have
been obtained in simple manual grinding procedures, the labora-
tory mill enabled each synthesis to be conducted in quantitative
yield. The products of ball milling were all highly crystalline
solids, making them amenable to direct solvent-free structural
characterization by PXRD structure solution.
Scheme 1 The synthesis of N,N′-disubstituted thioureas through
primary amine–isothiocyanate coupling.
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Although the presence of a substituent at the para position in
both aromatic reactants was expected to provide insight into
possible substituent effects on mechanochemical reactivity, all
investigated reactions were found to proceed rapidly (within
10–20 minutes) to quantitative yield, with little or no observable
substituent effect. Since many of the reagents used in this study
are liquids at room temperature, the viability of the grinding syn-
thetic procedure was first explored by simply combining the
reagents in a mortar and conducting the reactions manually
using a pestle. The manual mechanical agitation of the reaction
mixtures resulted in a quantitative conversion of the starting
materials into the desired thiourea derivative in almost all cases
(Table 1).
Results and discussion
General reactivity of aromatic and aliphatic primary amines
The click-mechanochemical methodology was first tested on the
reaction of p-substituted aromatic isothiocyanates with differ-
ently p-substituted anilines as representatives of typical aromatic
amines (Table 1). As aliphatic amine reactants were explored iso-
propylamine, 3-dimethylaminopropylamine and benzylamine,
the latter being a representative of a reactant with benzylic char-
acter. All reactions were conducted using the 1 : 1 stoichiometric
ratio of the reactants, with the exception of reactions involving
isopropylamine. Due to its volatility which prevented efficient
handling, isopropylamine was always used in excess (Table 1).
The only exceptions were the coupling reactions involving the
most electron rich aromatic isothiocyanate, 4-methoxyphenyl
isothiocyanate (Table 1, entries 3, 4, 5 and 7), and some of the
reactions involving the electron poor amines, such as 4-chloro-
and 4-fluoroaniline (Table 1, entries 4, 5, 21 and 29). Such be-
haviour is consistent with the reduced electrophilic nature of the
isothiocyanate moiety in 4-methoxyphenyl isothiocyanate, and
the lowered nucleophilic character of 4-halogenated aniline.
However, in all quantitative yields were achieved by replacing
the manual methodology with 10 – 30 minutes milling in a labo-
ratory mechanical mill. Aliphatic amines are generally very good
nucleophiles and as such gave the corresponding thioureas 1f–
1h, 2f–2h, 3f–3h and 4f–4h in quantitative (i.e. 99% and higher)
yields.
Table 1 Reactions of aromatic isothiocyanates with aromatic, aliphatic
and benzylic (Bn) aminesa
Reactant physical
state (isothiocyanate/
amine)b
Yieldc
(manual,
milled)/%
Entry Product R1, R2
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
OMe, 4-OMe-Ph Liquid, solid
>99, >99
>99, >99
82, >99d
88, >99d
90e, >99d
>99, >99f
95, >99
OMe, 4-Me-Ph
OMe, Ph
OMe, 4-F-Ph
OMe, 4-Cl-Ph
OMe, i-Pr
Liquid, solid
Liquid, liquid
Liquid, liquid
Liquid, solid
Liquid, liquid
1g
1h
OMe, 3-(NMe2)-Pr Liquid, liquid
OMe, Bn
Liquid, liquid
Liquid, solid
Liquid, solid
Liquid, liquid
Liquid, liquid
Liquid, solid
Liquid, liquid
Liquid, liquid
Liquid, liquid
Liquid, solid
Liquid, solid
Liquid, liquid
Liquid, liquid
Liquid, solid
>99, >99
>99, >99
>99, >99
>99, >99
>99, >99
>99, >99d
>99, >99f
>99, >99
>99, >99
>99, >99
>99, >99
>99, >99
>99, >99
75, 97d,
9
2a(1c) H, 4-OMe-Ph
Reactions of sterically hindered amines and anilines
10
11
12
13
14
15
16
17
18
19
20
21
2b
2c
2d
2e
2f
2g
2h
H, 4-Me-Ph
H, Ph
H, 4-F-Ph
H, 4-Cl-Ph
H, i-Pr
H, 3-(NMe2)-Pr
H, Bn
The excellent yields of reactions involving 4-substituted aromatic
isothiocyanates with aliphatic amines and 4-substituted anilines
encouraged the exploration of the sensitivity of mechanochem-
ical coupling to steric hindrance. Reactants used for that purpose
were the more sterically hindered secondary amines piperidine,
morpholine and thiomorpholine (Scheme 2a), as well as 2,4- and
2,6-disubstituted anilines (Scheme 2b). In the case of secondary
aliphatic amines, the application of a laboratory mill led to the
formation of each aliphatic amine product in quantitative yield,
as established by HPLC (Table 2). The manual grinding reac-
tions involving cyclic secondary amines have not been con-
ducted due to potential complications related to the known
propensity of such molecules to react with atmospheric carbon
dioxide. However, the manual grinding and ball milling
3a(1d) F, 4-OMe-Ph
3b F, 4-Me-Ph
3c(2d) F, Ph
3d
3e
F, 4-F-Ph
F, 4-Cl-Ph
>99g
22
23
24
25
26
27
28
29
30
31
32
3f
F, i-Pr
F, 3-(NMe2)-Pr
F, Bn
NO2, 4-OMe-Ph
NO2, 4-Me-Ph
NO2, Ph
NO2, 4-F-Ph
NO2, 4-Cl-Ph
NO2, i-Pr
Liquid, liquid
Liquid, liquid
Liquid, liquid
Solid, solid
Solid, solid
Solid, liquid
Solid, liquid
Solid, solid
Solid, liquid
>99, >99f
>99, >99
>99, >99
>99, >99
>99, >99
>99, >99
>99, >99
98, >99d
>99, >99f
>99, >99
>99, >99
3g
3h
4a
4b
4c
4d
4e
4f
4g
4h
NO2, 3-(NMe2)-Pr Solid, liquid
NO2, Bn Solid, liquid
a The reaction time for manual grinding was typically 15–20 minutes
while ball milling was conducted for 10 minutes at 30 Hz using a single
stainless steel ball (12 mm diameter, m = 7.056 g). LAG experiments
were carried out using 50 μL of acetonitrile as the liquid phase. b At
25 °C. c Isolated yield. In reactions where 1H NMR indicated a
conversion lower than quantitative, the yield was calculated from the
corresponding NMR intensities of the product and unreacted
isothiocyanate or amine. d 15 minutes of neat ball milling. e 45 minutes
manual grinding. f Three-fold excess (six-fold for manual grinding and
five-fold for ball milling in the case of thiourea 4f) of isopropylamine
was used due to its high volatility (b.p. 32 °C). g 15 minutes of LAG.
Scheme 2 Synthesis of non-symmetrical (a) aromatic–aliphatic thio-
ureas starting from sterically hindered secondary amines and (b) aromatic
thioureas starting from sterically hindered primary aromatic amines.
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Table 2 Mechanochemical reactivity of the model 4-substituted
comparison of the PXRD pattern measured for the ground
product with the patterns simulated from the crystallographic
data available in the Cambridge Structural Database (CSD,
thioureas 1a (CCDC code WEFQEE), 2c (CCDC code
ZEYBIO) and 2j (CCDC code TABYUQ)) (Fig. 1).
aromatic isothiocyanates with cyclic secondary aminesa
Entry Product R1, X
Reactant physical stateb Yield/%
1
2
3
4
5
6
7
8
1i
4-OMe-Ph, CH2 Liquid, liquid
>99c
>99
>99
>99d
>99
>99e
>99d
>99
>99
>99d
>99
>99
1j
1k
2i
2j
2k
3i
3j
3k
4i
4j
4k
4-OMe-Ph, O
4-OMe-Ph, S
Ph, CH2
Ph, O
Ph, S
4-F-Ph, CH2
4-F-Ph, O
4-F-Ph, S
Liquid, liquid
Liquid, liquid
Liquid, liquid
Liquid, liquid
Liquid, liquid
Liquid, liquid
Liquid, liquid
Liquid, liquid
To further verify the polymorphic purity of the thiourea pro-
ducts, which is helpful when attempting structural characteriz-
ation from PXRD data, a selection of molecules was analyzed by
conventional single crystal X-ray diffraction. The preparation of
required single crystals was simplified by the quantitative yields
of mechanochemical reactions which allowed diffraction-quality
samples to be obtained by simple recrystallization of the ground
reaction mixtures from methanol. In this way, the crystal and
molecular structures have been determined for N,N′-bis(4-fluoro-
phenyl)thiourea (3d), N-(4-nitrophenyl)-N′-morpholinothiourea
(4j), N-(4-methoxyphenyl)-N′-piperidinothiourea (1i) and N-
phenyl-N′-thiomorpholinothiourea (2k) (Table 4). In all cases,
except 4j, the simulated PXRD pattern corresponded to the one
measured for the mechanochemical product.
9
10
11
12
4-NO2-Ph, CH2 Solid, liquid
4-NO2-Ph, O
4-NO2-Ph, S
Solid, liquid
Solid, liquid
a Ball milling was conducted for 10 minutes at 30 Hz by using a single
stainless steel ball (12 mm diameter, m = 7.056 g) and 40 μL of
acetonitrile as the liquid phase. b At 25 °C. c 15 minutes ball milling and
50 μL of acetonitrile. d Neat grinding. e 45 μL of acetonitrile.
The crystal structure of N,N′-bis(4-fluorophenyl)thiourea (3d,
Fig. 2a) was found to resemble that of the orthorhombic poly-
morph of the simple N,N′-bis(phenyl)thiourea (2c) (CCDC code
ZEYBIO), in which the molecules stack head-to-tail to form
zigzag tapes involving twin N–H⋯S contacts of 3.52 Å. The
N–H⋯S contacts can be interpreted as hydrogen-bonding
Table 3 Mechanochemical reactivity of 4-substituted aromatic
isothiocyanates towards sterically hindered 2,4- and 2,6-
dimethylanilinesa
Yieldc
Reactant
(manual,
Entry Product R1, R2, R3, R4
physical stateb milled)/%
1
2
3
4
5
6
7
8
1l
1m
2l
2m
3l
3m
4l
4-OMe-Ph, Me, Me, H Liquid, liquid
94d, >99e
4-OMe-Ph, Me, H, Me Liquid, liquid >99f
Ph, Me, Me, H
Ph, Me, H, Me
Liquid, liquid >99, >99g
Liquid, liquid >99
4-F-Ph, Me, Me, H
4-F-Ph, Me, H, Me
Liquid, liquid
Liquid, liquid >99
97, >99g
4-NO2-Ph, Me, Me, H Solid, liquid
4-NO2-Ph, Me, H, Me Solid, liquid
98, >99g
>99f
4m
a The reaction time for manual grinding was typically 15–20 minutes
while ball milling was conducted for 10 minutes at 30 Hz using a single
stainless steel ball (12 mm diameter, m = 7.056 g) and 50 μL of
acetonitrile as the liquid phase. b At 25 °C. c Isolated yield. For reactions
where 1H NMR indicated a conversion lower than quantitative, the yield
was calculated from the corresponding NMR intensities of the product
and unreacted isothiocyanate or amine. d 45 minutes of manual grinding.
e 40 minutes ball-milling. f 15 minutes ball-milling. g Neat grinding.
methodologies have been compared for the reactions of the steri-
cally hindered aliphatic i-propylamine, revealing that quantitative
yields are readily obtained by both approaches (Table 1, entries
6, 14, 22 and 30).
As evident from Table 3, excellent yields of non-symmetrical
thioureas have also been obtained in the case of sterically hin-
dered anilines. Again, the application of a laboratory mill
improved reaction yields to the quantitative level.
Single crystal structure determination: supramolecular
(polymorphic) purity of selected thiourea derivatives
The characterization of prepared thioureas using powder X-ray
diffraction suggested that, for all thioureas with available crystal
structures, the mechanochemical product consisted of a single
polymorphic form. Specifically, this was evident from the
Fig. 1 Comparison of measured (blue) and simulated (black) PXRD
patterns for selected mechanochemically prepared thioureas.
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Table 4 General and crystallographic parameters for mechanochemical thiourea products characterised by single crystal X-ray diffraction
Compound
1i
2k
3d
4j (form 1)
4j (form 2)
1e-SC
Formula
Mr
Crystal system
Space group
a (Å)
b (Å)
c (Å)
C13H18N2OS
250.35
Monoclinic
Cc
10.4930(2)
14.6391(4)
9.0779(2)
113.021(1)
1283.39(5)
180(2)
C11H14N2S2
238.36
Monoclinic
P21/c
11.5813(3)
9.3856(3)
10.8926(4)
101.21(3)
1161.4(2)
180(2)
C13H10F2N2S
264.29
Orthorhombic
Pnma
8.3457(1)
26.4224(2)
5.3071(6)
90
C11H13N3O3S
267.30
Monoclinic
P21/n
10.2252(2)
10.5172(3)
11.1949(2)
90.788(2)
1203.79(5)
180(2)
C11H13N3O3S1
267.30
Orthorhombic
Pca21
21.221(1)
8.0908(4)
28.647(2)
90
C14H13ClN2OS
292.77
Orthorhombic
Pbcm
5.6100(6)
7.9500(8)
32.010(3)
90
β (°)
V (Å3)
1170.3(1)
180(2)
4
4918.6(4)
291(2)
16
1427.6(3)
293(2)
4
T (K)
Z
4
4
4
μ(MoKα) (mm−1
)
0.238
0.427
0.284
0.273
0.268
0.406
Reflections measured
Independent reflections
Rint
R1 (I > 2σ(I))
wR2 (I > 2σ(I))
R1 (all data)
wR2 (all data)
S
Flack parameter
10 115
4498
0.0394
0.0441
0.1048
0.0655
0.1198
1.121
14 713
3390
8268
1882
11 967
4139
0.0300
0.0330
0.0957
0.0462
0.0980
1.021
—
35 514
9571
14 424
1693
0.0460
0.0472
0.0987
0.0773
0.1109
1.029
0.0346
0.0364
0.0856
0.0559
0.0924
1.065
0.1164
0.0471
0.0911
0.1498
0.1249
1.008
0.0451
0.0452
0.1106
0.0697
0.1210
1.086
0.10(7)
—
—
0.5(1)
—
interactions to a bifurcated sulfur acceptor. The N–H⋯S hydro-
gen bonds have been recognized as a characteristic part of the
solid-state assembly of thiourea molecules.43 The same zigzag
motif as observed in 3d is encountered in the majority of N,N′-
diarylthiourea crystal structures found in the Cambridge Struc-
tural database (CSD). The thiourea derivatives derived from sec-
ondary amines, N-phenyl-N′-thiomorpholinothiourea (2k), N-(4-
methoxyphenyl)-N′-piperidinothiourea (1i) and N-(4-nitrophe-
nyl)-N′-morpholinothiourea (4j), are not expected to form the
zigzag tape supramolecular motifs due to the presence of only
one N–H moiety per molecule. Indeed, in the herein determined
crystal structures of N-phenyl-N′-thiomorpholinothiourea (2k)
and N-(4-methoxyphenyl)-N′-piperidinothiourea (1i) the zigzag
tapes based on twin N–H⋯S interactions are replaced by chains
displaying only single N–H⋯S interactions (Fig. 2b,c). The
N⋯S separations in these two cases are shorter than observed in
zigzag tapes of diarylthioureas: 3.30 Å (for 2k, the N–H⋯S con-
tacts are also accompanied by short C–H⋯S contacts of 3.7 Å,
Fig. 2b) and 3.46 Å (for 1i, Fig. 2c).
considerable challenge even for conventional PXRD structure
solution procedures, we turned to a solution-based polymorph
screening.
Recrystallisation of the mechanochemical product from ethyl
acetate provided single crystals that exhibited a crystallographic
unit cell identical to the one indicated by PXRD pattern index-
ing. Structure determination revealed that the space group is
non-centrosymmetric (Pca21) with four independent molecules
in the asymmetric unit (Z′ = 4) held by the expected N–H⋯S
hydrogen bonds. The molecules in this solid-state structure of 4j
(polymorph 2) form two crystallographically distinct hydrogen-
bonded chains. Each chain consists of two alternating crystallo-
graphically distinct molecules of 4j, accounting for the observed
Z′ = 4 (Fig. 3). Although crystal structure determination for this
material was not attempted from powder diffraction data, it was
pleasing to observe that the PXRD indexing procedure initially
yielded the correct unit cell size and crystallographic parameters.
In contrast, the solid-state structure of 4j did not exhibit short
N–H⋯S interactions. Instead, the molecules are associated into
zigzag chains through N–H⋯O hydrogen bonds (2.96 Å)
between the N–H groups of each thiourea moiety and the
oxygen atom of the morpholine ring in neighbouring molecules
(Fig. 2d). The formation of N–H⋯O rather than N–H⋯S hydro-
gen-bonding motifs in 4j is surprising as the crystal structure of
2j, which contains a phenyl and a morpholine substituent
(CCDC code TABYUQ),44 exhibits only N–H⋯S interactions
analogous to those in 1i and 2j. Moreover, as the PXRD pattern
simulated for the crystal structure of 4j was evidently different
from the pattern of the mechanochemically obtained product, we
attempted a PXRD structure determination procedure. The
PXRD pattern indexing procedure suggested the mechanochem-
ical product with a large unit cell (a = 21.224 Å, b = 8.104 Å,
c = 28.655 Å, V = 4928.9 Å3) corresponding to the orthorhombic
system with Z = 16 and implying four different molecules in the
asymmetric unit. As such a structural problem would represent a
Structural characterization from PXRD data
The apparent crystallinity and purity of mechanochemically
obtained thioureas in a chemical, as well as a supramolecular
sense (i.e. the appearance of the product in one dominant poly-
morphic crystalline form) are key for crystal structure determi-
nation from PXRD data. Whereas the polymorphic purity of
mechanochemically prepared thioureas was indicated by pre-
vious and current single crystal X-ray crystallography studies,
PXRD analysis revealed that roughly 40% of them (22 com-
pounds) display diffraction patterns of sufficient quality for
structural characterization. The criterion for pattern quality was a
typical diffraction peak width at half maximum of 0.4° or less,
based on previous experience.26a,30 Consequently, crystal struc-
ture determination was attempted on a selection of five mechano-
chemically prepared thiourea derivatives: N-(4-methoxyphenyl)-
N′-phenylthiourea (1c), N-(4-chlorophenyl)-N′-(4-methoxyphe-
nyl)thiourea
(1e),
N-(4-nitrophenyl)-N′-(4-methylphenyl)
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Fig. 3 The assembly of four crystallographically independent types of
4j molecules in the crystal structure of the 4j polymorph 2. The crystal-
lographically distinct molecules are colour coded, and N–H⋯S hydro-
gen bonds are shown as yellow dotted lines.
explained concept of a solvent-free laboratory,26a structure deter-
mination was limited to measurements conducted on a laboratory
instrument in the simple flat-plate data collection mode. The
structure indexing procedure was conducted using either
DICVOL04 or DIVOL0645 within the DASH46,47 package dis-
tributed by the Cambridge Crystallographic Data Centre
(CCDC). Indexing provided satisfactory unit cell parameters for
all datasets and structure solution was pursued using the simu-
lated annealing techniques in DASH.
Crystal structure solution provided plausible preliminary solu-
tions for compounds 1c, 4b, 3f and 2m. However, numerous
attempts at solving the structure of N-(4-chlorophenyl)-N′-(4-
methoxyphenyl)thiourea 1e did not yield a reasonable solution,
most likely due to problems of preferred orientation when using
flat-plate scans. The visual inspection, as well as the indexing of
the PXRD pattern indicated that 1e should be isostructural to the
previously reported symmetrical N,N′-bis(4-methoxyphenyl)-
thiourea (1a) (CCDC code WEFQEE).48 This enabled an
alternative approach to elucidating the crystal structure of 1e, by
applying a suitable space group to the unit cell previously
reported for bis(4-methoxyphenyl)thiourea. The isostructurality
and the reduction in molecular symmetry on going from N,N′-
bis-(4-methoxyphenyl)thiourea (1a) to N-(4-chlorophenyl)-N′-(4-
methoxyphenyl)thiourea (1e) implied that the most suitable
choices of the space group would involve either a disordered
structure with the full retention of space group symmetry, or a
fully ordered structure with a reduced space group symmetry.
This dilemma was resolved with the aid of solid-state magic
angle spinning (MAS) cross-polarization (CP) 13C NMR spec-
troscopy. The 13C CP-MAS solid-state NMR spectrum of 1e
(Fig. 4) strongly indicated only one molecule per asymmetric unit
(i.e. Z′ = 1). The NMR signal for the carbon atom of the methoxy
group was particularly sharp, which clearly indicated only one
crystallographically independent type of molecule. This indicated
space groups P21212, P212121 and Pna21 as potential candidates.
Fig. 2 Assembly of molecules via N–H⋯S hydrogen bonds in the
crystal structures of compounds: (a) N,N′-bis(4-fluorophenyl)thiourea
(3d); (b) N-phenyl-N′-thiomorpholinothiourea (2k); (c) N-(4-methoxy-
phenyl)-N′-piperidinothiourea (1i) and (d) polymorph 1 of N-(4-nitro-
phenyl)-N′-morpholinothiourea (4j). The N–H⋯S hydrogen bonds are
shown as yellow dotted lines.
thiourea (4b), N-(4-fluorophenyl)-N′-(isopropyl)thiourea (3f)
and N-phenyl-N′-(2,6-dimethylphenyl)thiourea (2m). In order to
conduct solvent-free structural analysis in a typical laboratory
environment, which would be in accordance with the previously
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The preliminary crystal structures for 1c, 4b, 3f, 1e and 2m
were reasonable both in terms of the molecular geometry as well
as in terms of supramolecular interactions. The preliminary struc-
tures displayed either the characteristic thiourea N–H⋯S motif
of hydrogen bonds bifurcated on the sulfur acceptor (for 1c, 4b
hydrogen bonds. The choice of Pna21 led to stacks composed of
molecules oriented in parallel, whereas for the P21212 and
P212121 space groups the molecules were aligned in an alternat-
ing, antiparallel fashion.
The initial structure solution for 3f, however, indicated the
existence of two crystallographically independent molecules in
the unit cell (Z′ = 2). Whereas crystal structures with Z′ > 1 are
well known, their occurrence is generally considered unusual.
Similarly to the case of 1e, we employed solid-state CP-MAS
13C NMR spectroscopy to verify the correctness of the crystallo-
graphic determination. All recorded solid-state CP-MAS NMR
spectra, including that of 3f, exhibited a slightly broad singlet for
the thiourea carbon atom, consistent with Z′ = 1 and the presence
of two quadrupolar nitrogen nuclei. The signals for 4-methyl
and 4-methoxy groups, where present in the molecular structure,
were sharp singlets. For compound 3f, the solid-state NMR spec-
trum (Fig. 4) revealed three sharp signals in the region character-
istic for aliphatic groups, which strongly suggested only one
crystallographically independent isopropyl group in the crystal
structure and, therefore, Z′ = 1. Consequently, we concluded that
the structure of 3f obtained from PXRD data was erroneous. The
initial structural models for four (1c, 1e, 2m and 4b) out of five
molecules were considered suitable for Rietveld refinement. The
refinement was conducted using the Topas software49 and, by
using rigid body restraints for the phenyl rings, provided reliable
and reasonable crystal structures for compounds 1c, 2m and 4b
(Table 5, Fig. 5 and 6).
2
and 3f) or the formation of a known R2 (8) hydrogen bonded
motif composed of N–H⋯S interactions (for 2m). The three
potential space group choices for 1e all yielded the crystal struc-
ture composed of molecular stacks held by bifurcated N–H⋯S
For compound 1e, the careful Rietveld refinement indicated that
the P21212 model was superior to the P212121 or the Pna21 one.
However, in order to verify the correctness of the P21212 structure,
we resorted to single crystal structure determination. Whereas the
single crystal growth experiments consistently provided very thin
plates, those grown from a methanol–acetone solution were found
suitable for single crystal X-ray diffraction. Structure deter-
mination procedure revealed a unit cell identical to that expected
from powder diffraction experiments. However, the space group
was determined as Pbcm, identical to that of the symmetrical
N,N′-bis(4-methoxyphenyl)thiourea (1a) structure WEFQEE.48
This highly symmetrical space group requires the molecule of 1e
to be disordered over a mirror plane, which is inconsistent with
the order inferred by solid-state 13C CP-MAS NMR.
Fig. 4 Solid-state 13C CP-MAS NMR spectra for the compounds 3f
(top) and 1e (bottom).
Table 5 Crystallographic parameters for the crystal structures of thioureas 1c, 1e, 2n and 4b determined from PXRD data
Compound reference
1e-PXRD
14H13Cl1N2O1S1
292.79
Orthorhombic
7.9168(4)
31.787(2)
5.5767(3)
90
1403.4(1)
293
P21212
4
2m
1c
4b
Chemical formula
Formula mass
Crystal system
a (Å)
b (Å)
c (Å)
C
C15H16N2S1
256.37
C14H14N2O1S1
258.34
C14H13N3O2S1
287.34
Orthorhombic
14.5044(9)
13.6232(9)
7.1408(3)
90
1411.0(1)
293
Pna21
Monoclinic
12.6721(3)
9.7973(3)
12.1009(3)
115.223(1)
1359.12(6)
293
P21/n
4
1.25
Monoclinic
28.494(2)
5.5557(3)
8.1430(4)
90.748(4)
1289.0(1)
293
P21/c
4
1.33
β (°)
Unit cell volume (Å3)
Temperature (K)
Space group
Z
4
1.35
ρcalc (g cm−3
)
1.39
Rp
Rwp
X
0.0367
0.0501
0.559
0.0293
0.0406
0.571
0.0395
0.0522
0.975
0.040
0.053
0.732
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Fig. 5 Rietveld fits of experimental (blue line) and simulated (red line)
PXRD patterns and for compounds: (a) 1c, (b) 4b and (c) 2m. The
difference between experimental and calculated patterns is shown in
grey.
It is possible that the inconsistency between single crystal
X-ray diffraction and solid-state NMR is a result of single crys-
tals being composed of micro-scale domains of different orien-
tation. Whereas the structure of each individual domain would
be organized so as to provide a sharp NMR signal, the different
orientations of the domains lead to a pseudo-centrosymmetric
average structure being observed using single crystal X-ray dif-
fraction. Although single crystal structure determination provided
only an averaged distribution of the phenyl ring substituents in
the crystal structure of 1e, the inspection of the overall molecular
packing allowed verification of the model structures based on
powder diffraction. The projections of the structure along the
crystallographic (010) and (001) directions clearly revealed cor-
respondence to the structure obtained by powder X-ray structure
determination in the P21212 space group. Consequently, single
crystal analysis indicates the validity of the structure indicated by
Rietveld refinement. As a further confirmation of the non-centro-
symmetric structure deduced by combination of PXRD structure
determination and solid-state NMR, we compared the PXRD
pattern simulated for the structure of 1e obtained by single
crystal diffraction to the measured one. Following Rietveld
refinement, the fit of the structure in the Pbcm space group was
considerably worse than that obtained for the structure in the
P21212 space group (see ESI†).
Fig. 6 Fragments of crystal structures determined from PXRD data
along with molecular diagrams for (a) 1c, (b) 4b, (c) 2m and (d) 1e.
Self-assembly of simple bis(aryl)thioureas in the solid-state
The structures of 1c, 1e, 2m and 4b determined from PXRD
data provide insight into the supramolecular chemistry of simple
bis(aryl)thioureas in the solid state. According to the recent
edition of the CSD, the crystal structures of pure symmetrical
and non-symmetrical bis(aryl)thioureas have been poorly
studied, with 12 and 7 chemically distinct examples recorded in
the database, respectively.48,50,51 The four PXRD structures pro-
vided herein illustrate three different types of self-assembly
motifs based on N–H⋯S hydrogen bonds (Fig. 6): corrugated
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chains of molecules aligned head-to-head (parallel molecular
dipoles) in 1c; corrugated chains of head-to-tail aligned mo-
lecules (antiparallel molecular dipoles) in 1e and 4b; and discrete
2
dimers based on the R2 (8) supramolecular synthon in 2m. The
comparison of PXRD patterns for all bis(aryl)thioureas syn-
thesized herein (Fig. 7) reveals that these structures could be
representative of two families of solid-state structures adopted by
symmetrical as well as non-symmetrical p-substituted bis(aryl)
thioureas. We propose that these structural families, designated
I and II, are based on the corrugated chains of molecules held by
bifurcated N–H⋯S hydrogen bonds observed in structures 1c, 1e
and 4b and in previously reported structures of symmetrical bis
(aryl)thioureas. In the structural family I these supramolecular
chains are juxtaposed so as to form parallel stacks (Fig. 8).
Such supramolecular architecture gives rise to a characteristic
(200) reflection at the Bragg angle range 5–7° in the PXRD
Fig. 8 Arrangement of molecules in two structural families of p-phenyl
substituted thioureas, viewed along the N–H⋯S hydrogen-bonded chains:
(a) structural family I and (b) structural family II.
pattern which corresponds to the width of the supramolecular
stack. The (200) reflection also corresponds to the lattice separ-
ation between sulfur atoms in neighboring hydrogen-bonded
stacks, which explains the pronounced intensity of this
reflection.
The structural family II is characterised by a characteristic
(110) reflection at the Bragg angle range 8–10° in the PXRD
pattern. The (110) plane again corresponds to the separation
between strongly scattering sulfur atoms in nearest-neighbour
hydrogen-bonded molecular stacks which are now arranged in a
herringbone pattern with an angle of 44° between neighbouring
stacks (Fig. 8). The inspection of PXRD patterns for bis(aryl)-
thioureas containing 2,4-dimethylphenyl or 2,6-dimethylphenyl
moieties does not reveal such a clear division into structural
families (Fig. 9). This could be the result of the formation of dis-
2
crete R2 (8) hydrogen-bonded dimers, as the ones observed for
2m, instead of infinite hydrogen-bonded stacks. Presumably, the
three-dimensional crystallographic arrangement of discrete mole-
cular dimers would be more sensitive to changes to molecular
structure than the assembly of one-dimensional hydrogen-
bonded chains.
Fig. 7 Comparison of PXRD patterns for the simple p-substituted
N,N′-diaryl(thioureas) prepared by click-mechanochemical coupling.
Inspection of the patterns indicates that most compounds belong to the
structural family I, while 2b and 4b–4e form the structural family II.
The PXRD pattern of 4a does not belong to either of the structural
families.
Conclusions
Mechanochemical milling was used to conduct quantitative syn-
thesis of 49 different monothioureas based on variously substi-
tuted aromatic, aliphatic, heterocyclic, primary, as well as
2470 | Green Chem., 2012, 14, 2462–2473
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098-0982933-2920). McGill University, the FQRNT Centre for
Self-Assembled Chemical Structures, the NSERC Discovery
Grant program, Canada Foundation for Innovation Leaders
Opportunity Fund, and the FQRNT Nouveaux Chercheurs
program are acknowledged for support.
Notes and references
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X-ray powder diffraction data. Structural characterization was
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dimensional 13C solid-state NMR measurements.52
Structural and spectroscopic characterization of thioureas
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small rigid organic molecules. Whereas this current study is
limited to simple organic reactivity at a proof-of-principle level,
we hope it will encourage the further development of solvent-
free research procedures in more complex synthetic systems.‡
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