Synthesis and conformational features of sym N,N′,N″- triarylguanidines

Article abstract of DOI:10.1007/s12039-010-0017-8

A one pot reaction involving sym N,N′-diarylthiourea and the respective arylamine in the presence of aq. KOH in nitrobenzene at ≥105°C afforded sym N,N′,N″-triarylguanidine in fair to good yield and the products have been characterized. Sym N,N′,N″-tri(4-tolyl)guanidine possesses (7) anti-anti conformation, sym N,N′,N″-tri(2-tolyl) guanidine (8) and sym N,N′,N″-tris(2,4-xylyl)guanidine (11) each possess anti-anti αβα conformation whereas sym N,N′,N″-tris(2-anisyl)guanidine possesses (9) syn-anti αββ conformation as determined by single crystal X-ray diffraction data. The observed conformations appear to result from a subtle balance between steric factor associated with the aryl substituent and multiple electronic factors namely n-π conjugation/negative hyperconjugation and non-covalent interactions in the crystal lattice. Indian Academy of Sciences.

Full text of DOI:10.1007/s12039-010-0017-8

J. Chem. Sci., Vol. 122, No. 2, March 2010, pp. 157–167. © Indian Academy of Sciences.
Synthesis and conformational features of
sym N,N′,N″-triarylguanidines
KANNIYAPPAN GOPI, BRIJESH RATHI and NATESAN THIRUPATHI*
Department of Chemistry, University of Delhi, Delhi 110 007
e-mail: tnat@chemistry.du.ac.in; thirupathi_n@yahoo.com
MS received 27 August 2009; revised 28 January 2010; accepted 5 February 2010
Abstract. A one pot reaction involving sym N,N′-diarylthiourea and the respective arylamine in the
presence of aq. KOH in nitrobenzene at ≥105°C afforded sym N,N′,N″-triarylguanidine in fair to good
yield and the products have been characterized. Sym N,N′,N″-tri(4-tolyl)guanidine possesses (7) anti–anti
conformation, sym N,N′,N″-tri(2-tolyl)guanidine (8) and sym N,N′,N″-tris(2,4-xylyl)guanidine (11) each
possess anti–anti αβα conformation whereas sym N,N′,N″-tris(2-anisyl)guanidine possesses (9) syn–anti
αββ conformation as determined by single crystal X-ray diffraction data. The observed conformations
appear to result from a subtle balance between steric factor associated with the aryl substituent and mul-
tiple electronic factors namely n–π conjugation/negative hyperconjugation and non-covalent interactions
in the crystal lattice.
Keywords. Sym N,N′,N″-triarylguanidines; organocatalysts; N-donor ligands; conformations; non-
covalent interactions; AM1 calculations.
1. Introduction
higher than that of the commercially available
10
N,N,N′,N′-tetramethylguanidine (pKa = 23⋅4).
Guanidine, (NH2)2C(=NH) (A) is a CN3 core con-
taining compound that possesses a central carbon
atom to which one imino group (NH) and two amino
groups (NH2) are covalently bonded. N−Substituted
guanidines have attracted attention recently due to
their multiple role as non-ionic bases, organocata-
N-Substituted guanidines can be prepared either
by guanylation (i.e. the conversion of an amine to a
guanidine, where the amine nitrogen is incorporated
into the newly formed guanidine functional group)
11
of amine with a guanylating reagent or guanid-
inylation (i.e. functionalization of a pre-existing
guanidine core). Sym N,N′,N″-tri-substituted gua-
1–6
lysts, and as N-donor ligands for metal ions. Sym
12
N,N′,N″-trisubstituted guanidines 1–3 were shown to
act as N-donor ligands in their monoanionic (guanid-
inate(1-), B) and dianionic (guanidinate(2-), C)
forms and in such forms the guanidinate backbone
nidines (1–6) were prepared by guanylation reaction
involving the primary amine and the respective sym
N,N′-di-substituted carbodiimide at elevated tem-
8,10b,13
peratures depending upon the substrate.
exhibits bridging bidentate and chelating bidenate
4–6
Guanylation of aryl amines with unsymmetrically
substituted N,N′-diarylcarbodiimides catalysed by
Bu4NF was shown to afford unsymmetrical guanidi-
coordination modes with various metal ions.
In
addition, sym N,N′,N″-triphenylguanidine (1) was
also shown to coordinate to the metal ions through
the imine nitrogen in its neutral form. Compounds 2
and 3 owing to their high basicity were shown to act
14
nes of the type D in moderate to good yield. How-
ever, guanylation of aryl amine with sym N,N′-
dialkylcarbodiimide catalysed by metal amides,
half-sandwich rare earth metal complexes, and Al-
ClMe2 at relatively mild reaction conditions were
shown to afford unsymmetrical guanidines of the
as non-ionic bases/superbases in organic transforma-
7–9
tions.
Recently, sym N,N′,N″-trialkylguanidines,
4–6 were shown as a highly basic compounds with
pKa values 24⋅92, 27⋅15, and, 24⋅74, respectively in
acetonitrile and the pKa value of 5 is ca 4 units
15
type E in high yield.
We have been interested in developing a one-pot
synthesis for sym N,N′,N″-triarylguanidines such as
7–12 in high yield with a view to investigate the
conformational features of this class of compounds
*For correspondence
157

158
Kanniyappan Gopi et al
and subsequently utilize these compounds as and C6H3Me2-2,6) were prepared from the corres-
organocatalysts and as N-donor ligands for metal ponding arylamine (430 mmol) and CS2 (660 mmol)
ions. The electron releasing Me/OMe substituents in in absolute ethanol (63⋅5 mL) in presence of KOH
7–12 were anticipated to exhibit a distinct reactivity (20 wt% with respect to CS2) following the literature
26
pattern with metal ions as compared with 1 and procedure reported for sym N,N′-diphenylthiourea
could serve as NMR spectroscopic handle during the and purified by crystallization from hot ethanol at
16−20
1 13
ambient temperature. H and C NMR spectra were
course of the reactions of 7–12 with metal ions.
Further, sym N,N′,N″-triarylguanidinium cations of recorded in CDCl3 using a spectrometer with field
7–12 could be a promising scaffold to stabilize reac- strengths 300 and 75⋅5 MHz, respectively. Chemical
tive anions of unusual structure given the extraordi- shifts are reported in ppm and were referenced to the
nary stability of guanidinium cations due to Y- solvent resonance as internal standards. TOF-Mass
21
aromaticity. One of the convenient routes envis- and EI-Mass spectra were obtained on a mass spec-
aged for 7–12 would be guanylation of aryl amine trometer with a mass range of 1000.
with the respective sym N,N′-diarylcarbodiimide as
13
previously reported for 1. Unfortunately, this route
is limited by sym N,N′-diarylcarbodiimides source.
(ArNH)2C=NAr (Ar = C6H4Me-4) (7)
Sym N,N′-diarylcarbodiimides necessary for 7–12
2.1 Synthesis of sym N,N′,N″-tri(4-tolyl)guanidine
are difficult to prepare because the reactions require
A 500 mL round bottom flask was charged with sym
N,N′-di(4-tolyl)thiourea (30⋅96 g, 120 mmol), 4-
additional reagents, toxic substances, catalysts and
sometimes involve more than two-step syntheses
toluidine (12⋅96 g, 120 mmol), 70 wt% aq. KOH so-
22−25
followed by rigorous purification procedure.
lution (27⋅60 g), and nitrobenzene (7⋅44 g). The con-
Some of the sym N,N′-diarylcarbodiimides are diffi-
cult to isolate from the reaction mixture due to solu-
tents of the RB flask were gradually heated up to
105°C and maintained at the same temp for 6 h,
bility issues. We describe here guanylation reactions
while being stirred with a mechanical stirrer. The
of arylamine with the easily accessible sym N,N′-
diarylthiourea in a single-step to afford 7–12 in good
yield and in large quantities. Further, the procedure
diluted with distilled water (100 mL) and the con-
reaction mixture was allowed to attain ambient tem-
perature to leave an orange residue. The residue was
reported here is convenient to perform. The newly
tents of the flask were set to stir with a mechanical
prepared sym N,N′,N″-triarylguanidines were charac-
terized by micro analytical data, spectroscopic
remaining residue was triturated with water
stirrer. Water soluble portion was decanted and the
methods and representative products characterized
(3 × 100 mL) to obtain a free flowing solid which
by X-ray diffraction data. The steric and electronic
was subsequently filtered and washed with distilled
factors responsible for the observed conformations
water (5 × 200 mL). The solid was transferred into a
of sym N,N′,N″-triarylguanidines were analysed.
RB flask (250 mL) that contained n-hexane
(2 × 150 mL) and the contents of the flask were set
to stir with a mechanical stirrer for 15 min and
2. Experimental
allowed to stand. n-Hexane soluble aliquot was dis-
Sym N,N′-diarylthiourea (ArNH)2CS (Ar = C6H4Me-4, carded and the insoluble solid was again dispersed
C6H4Me-2, C6H4(OMe)-2, C6H3Me2-3,5, C6H3Me2-2,4 in n-hexane (150 mL), stirred with a mechanical

Synthesis and conformational features of sym N,N′,N″-triarylguanidines
159
stirrer for 15 min and allowed to stand. The solid aq. KOH (14⋅00 g) and nitrobenzene (5⋅00 g) were
was filtered in small portions and washed charged into a 250 mL RB flask. The RB flask was
with n-hexane (4 × 200 mL), dried on a hot-plate at fitted with a mechanical stirrer and gradually heated
70°C for 6 h to furnish 7 in 83% yield (32⋅71 g, up to 105°C, while being stirred for 8 h. The reac-
99⋅30 mmol). The solid was dissolved in hot ethanol tion mixture was cooled to ambient temperature and
(250 mL) and left at room temperature for 12 h to diluted with water (150 mL). The organics were ex-
afford 7 (22⋅0 g) as colourless crystals. The mother tracted with chloroform (3 × 200 mL) and the ex-
liquor was concentrated on a rotary evaporator and tracts were dried over anhydrous Na2SO4 for an
left at room temperature for 12 h to afford second hour, filtered, concentrated under vacuum to obtain
crops of 7 (5⋅01 g). The aforementioned concen- an orange solid. The orange solid was dissolved in
tration and crystallization procedure was repeated to diethyl ether (150 mL) and stored at 10°C to afford a
obtain third crops of 7 (4⋅00 g). Total yield: 31⋅01 g colourless powder (17⋅00 g). Mother liquor was
(94⋅12 mmol), 78%; m.p. (DSC): 116⋅6°C (lit., m.p.: concentrated and stored at 10°C to secure colourless
27
118–123°C). IR (KBr): 3371, 3320 (NH), 1641 powder (2⋅50 g) and this purification procedure was
–1
1
(C=N) cm . H NMR: δ 2⋅29 (s, 9 H, CH3), 5⋅80 repeated to obtain more of 9 (1⋅50 g). Total yield:
13
(br, 2H, NH), 7⋅09 (br, 12H, ArH). C NMR: δ 20⋅8 80% (21⋅0 g, 55⋅64 mmol). Compound 9 (21⋅00 g)
(CH3), 121⋅7, 129⋅8, 132⋅5, 140⋅0, 145⋅5 (ArC and was dissolved in hot ethanol (150 mL) and stored at
+
C=N). TOF MS ES , m/z (%): 330⋅9995 (83) 10°C for several hours to furnish colourless crystals
+
+
[M + H] , 329⋅4692 (92) M , 223⋅6710 (45) of 9 in 71% yield (18⋅50 g, 49⋅01 mmol), (lit., yield:
+
+
28
[ArNCNAr + H] , 222⋅6423 (100) [ArNCNAr] . 25%). M.p. (DSC): 119⋅6°C. IR (nujol): 3407
–1
1
Anal. Calcd. for C22H23N3: C, 80⋅20; H, 7⋅04; N, (NH), 1655 (C=N) cm . H NMR: δ 3⋅80 (s, 9H,
12⋅75. Found C, 79⋅87; H, 6⋅97; N, 12⋅42.
OCH3), 6⋅35 (br, 1H, NH), 6⋅70–7⋅10 (br m, 12H,
13
ArH), 8⋅50 (br, 1H, NH). C NMR: δ 55⋅5 (OCH3),
110⋅6 (br), 120⋅9 (br), 122⋅5 (br), 129⋅1 (br), 144⋅5,
2.2 Synthesis of sym N,N′,N″-tri(2-tolyl)guanidine
(ArNH)2C=NAr (Ar = C6H4Me-2) (8)
+
149⋅6 (ArC and C=N). TOF–MS ES , m/z (%):
+
+
380⋅7336 (78) [M + 3H] , 379⋅8248 (92) [M + 2H] ,
+
+
378⋅1553 (83) [M + H] , 254⋅9967 (91) [ArNCNAr] ,
242⋅1596 (100) [ArNCNAr–Me + 3H] . Anal.
Compound 8 was prepared and purified by a proce-
dure analogous to that mentioned previously for 7.
The quantity of starting materials is given below.
Sym N,N′-di(2-tolyl)thiourea (22⋅80 g, 88⋅90 mmol),
2-toluidine (9⋅52 g, 88⋅90 mmol), 70 wt% aq. KOH
(18⋅00 g) and nitrobenzene (6⋅00 g). Yield: 82%
(24⋅0 g, 72⋅85 mmol). Compound 8 was dissolved in
hot ethanol (150 mL) and stored at 10°C to furnish 8
+
Calcd. for C22H23N3O3: C, 70⋅00; H, 6⋅14; N, 11⋅13.
Found C, 69⋅60; H, 6⋅06; N, 10⋅75. The value of δC
55⋅5 ppm for OCH3 was independently confirmed
with the aid of two-dimensional HMQC NMR data
(see supporting information).
as colourless crystals in 75% yield (22⋅0 g,
66⋅78 mmol) (lit. yield: 60%).
133⋅3°C. IR (nujol): 3372 (NH), 1658 (C=N) cm .
2.4 Synthesis of sym N,N′,N″-tris(3,5-xylyl)
guanidine (ArNH)2C=NAr (Ar = C6H3Me2-3,5) (10)
17a
M.p. (DSC):
–1
1
H NMR: δ 2⋅19 (br, 9H, CH3), 5⋅60 (br, 2H, NH), The RB flask was charged with sym N,N′-bis(3,5-
13
7⋅00 (br, 3 H, ArH), 7⋅18 (br m, 9H, ArH).
C
xylyl)thiourea (10⋅00 g, 35⋅10 mmol), 3,5-xylidine
NMR: δ 17⋅8 (CH3), 121⋅5 (br), 122⋅5 (br), 126⋅8, (4⋅25 g, 35⋅10 mmol), 100 wt% aq. KOH (4⋅33 g)
+
129⋅0, 130⋅6, 144⋅7 (ArC and C=N). MS EI , m/z and nitrobenzene (10⋅00 g) and fitted with a me-
+
+
(%): 329⋅3 (82) [M ], 314⋅2 (33) [M–Me] , 222⋅2 chanical stirrer. The contents of the flask were
+
+
(75) [ArNCNAr] , 107⋅1 (100) [ArNH2] . Anal. slowly heated up to 105°C, while being stirred at the
Calcd. for C22H23N3: C, 80⋅20; H, 7⋅04; N, 12⋅75. same temperature for 15 h. The reaction mixture was
Found C, 80⋅31; H, 6⋅98; N, 12⋅71.
cooled to ambient temperature and diluted with
distilled water (400 mL). The organics from the
above solution were extracted with chloroform
(3 × 300 mL) and the extract was subsequently dried
over anhydrous Na2SO4. The volatiles from the ex-
2.3 Synthesis of sym N,N′,N″-tris(2-anisyl)
guanidine (ArNH)2C=NAr [Ar = C6H4(OMe)-2] (9)
Sym N,N′-bis(2-anisyl)thiourea (20⋅00 g, 69⋅30 tract were removed under vacuum to obtain a brown
mmol), 2-anisidine (8⋅40 g, 74⋅40 mmol), 70 wt% solid. The solid was dissolved in n-hexane (150 mL)

160
Kanniyappan Gopi et al
and left at ambient temperature for several hours to aq. KOH (12⋅02 g) and nitrobenzene (10⋅00 g) were
furnish 10 as crystals in 73% yield (9⋅50 g, charged into a 250 mL RB flask and the flask was
25⋅57 mmol). Compound 10 was dissolved in hot fitted with a water condenser. The contents in the
ethanol (150 mL) and stored at 10°C to furnish 10 as flask were gradually heated up to 138°C and main-
colourless crystals (5⋅00 g). Mother liquor was con- tained at the same temperature for 24 h, while being
centrated and stored at 10°C to secure more of 10 stirred. The reaction mixture was cooled to ambient
(2⋅00 g) and this purification procedure was repeated temperature and diluted with water (200 mL). The
to obtain more of 10 (1⋅0 g). Total yield: 61% organics from the above solution were extracted
(8⋅00 g, 21⋅53 mmol). M.p. (DSC): 184⋅7°C. IR with chloroform (3 × 200 mL) and dried over anhy-
–1
1
(KBr): 3387 (NH), 1648 (C=N) cm . H NMR: δ drous Na2SO4. The volatiles from the extract were
2⋅27 (s, 18H, CH3), 5⋅80 (br, 2H, NH), 6⋅67, 6⋅84 removed under vacuum to furnish an orange residue.
13
(br, 9H, ArH). C NMR: δ 21⋅3 (CH3), 119⋅1 (br), The residue was washed with ethanol (80 mL) and
124⋅4 (br), 138⋅8 (br), 144⋅0 (br), 144⋅7 (ArC and filtered to secure 12 as a colourless solid in 69%
+
C=N). TOF−MS ES , m/z (%): 373⋅0528 (39) yield (9⋅00 g, 24⋅22 mmol). The sample was further
+
+
[M + H] , 372⋅0259 (100) [M ]. Anal. Calcd. for purified by crystallization from hot ethyl acetate at
C25H29N3: C, 80⋅82; H, 7⋅86; N, 11⋅31. Found C, ambient temperature. Yield after crystallization:
29,30
80⋅41; H, 7⋅81; N, 11⋅36.
65% (8⋅50 g, 22⋅88 mmol).
M.p. (DSC):
1
243⋅4°C. H NMR: δ 2⋅33, 2⋅39 (br, 18H, CH3),
4⋅76, 5⋅01 (each s, 2H, NH), 6⋅82 (br, 1H, ArH),
7⋅04 (br, 8H, ArH). C NMR: δ 18⋅7 (CH3), 121⋅9,
126⋅8, 128⋅1 (br), 128⋅6, 130⋅9, 134⋅7, 135⋅7, 136⋅6,
137⋅7, 145⋅3, 146⋅5 (ArC and C=N). IR (KBr): 3377
(NH), 1639 (C=N) cm . TOF–MS ES , m/z (%):
2.5 Synthesis of sym N,N′,N″-tris(2,4-xylyl)
guanidine (ArNH)2C=NAr (Ar = C6H3Me2-2,4) (11)
13
Compound 11 was prepared and purified by a pro-
cedure analogous to that described previously for 10
with the reaction period being 10 h. The quantity of
starting materials is given below. Sym N,N′−bis(2,4-
xylyl)thiourea (20⋅00 g, 70⋅30 mmol), 2,4-xylidine
(8⋅51 g, 70⋅30 mmol), 100 wt% aq. KOH (15⋅79 g),
and nitrobenzene (10⋅00 g). Yield: 77% (20⋅00 g,
53⋅83 mmol). The sample was further purified by
crystallization from n-hexane at ambient tempera-
ture for several hours to furnish 11 in 69% yield
(18⋅00 g, 48⋅44 mmol). Crystals suitable for single
crystal X-ray diffraction data were grown from
n-heptane at ambient temperature over the period of
–1
+
+
+
373⋅1153 (18) [M + H] , 372⋅1628 (50) [M] ,
+
+
371⋅6063 (93) [M–H] , 370⋅5751 (100) [M−2H] .
Anal. Calcd. for C25H29N3: C, 80⋅82; H, 7⋅86; N,
11⋅31. Found C, 80⋅63; H, 7⋅90; N, 11⋅22. The val-
ues of δH 4⋅76 and 5⋅01 ppm for NH protons and the
value of δC 18⋅7 ppm for CH3 were independently
confirmed with the aid of two-dimensional HMQC
NMR data (see supporting information).
2.7 Crystal structure determinations
several hours. M.p. (DSC): 100⋅8°C. IR (nujol): Suitable crystals of 1, 7–9, 11 and 12 for X-ray dif-
–1
1
3396 (NH), 1659 (C=N) cm . H NMR: δ 2⋅16 (br, fraction study were carefully selected after examina-
9H, CH3), 2⋅27 (s, 9 H, CH3), 5⋅40 (br, 2H, NH), tion under an optical microscope and mounted on
13
6⋅95, 6⋅98 (br, 9H, ArH). C NMR: δ 17⋅7, 20⋅7 the goniometer head with a paraffin oil coating. The
(CH3), 122⋅2 (br), 127⋅3, 128⋅9, 129x4 (br), 131⋅2 unit cell parameters and intensity data were col-
+
(br), 145⋅5 (ArC and C=N). TOF MS ES , m/z (%): lected at room temperature using a Bruker SMART
+
+
374⋅66 (48) [M + 2H] , 373⋅14 (55) [M + H] , APEX CCD diffractometer equipped with a fine
+
+
372⋅10 (100) M , 344⋅14 (24) [(M−2Me) + 2H] , focus Mo-Kα X-ray source (50 kV, 40 mA). The
+
251⋅07 (22) [ArNCNAr + H] . Anal. Calcd. for data acquisition was done using SMART software,
C25H29N3: C, 80⋅82; H, 7⋅86; N, 11⋅31. Found C, and SAINT software was used for data reduction.
31
80⋅73; H, 7⋅85; N, 11⋅28.
The empirical absorption corrections were made
32
using the SADABS program. The structure was
33
solved and refined using the SHELXL-97 program.
2.6 Synthesis of sym N,N′,N″-tris(2,6-xylyl)
guanidine (ArNH)2C=NAr (Ar = C6H3Me2-2,6) (12)
Hydrogen atoms were fixed in idealized positions
and refined in a riding model. The X-ray crystallo-
Sym N,N′−bis(2,6-xylyl)thiourea (10⋅00 g, 35⋅10 graphic parameters and the details of data collection
mmol), 2,6-xylidine (4⋅26 g, 35⋅10 mmol), 100 wt% and structure refinement are presented in table S1

Synthesis and conformational features of sym N,N′,N″-triarylguanidines
161
(see supporting information). The crystallographic produced largely insoluble material. Thus, the
data for 1 and 12 are reported in the supporting aforementioned reaction was carried out in the
information to better analyse the non-covalent inter- presence of 100 wt% aq. KOH in nitrobenzene at
actions though crystal structure data of 134 and very 138°C for 24 h to afford a mixture from which 12
recently that of 1230 are reported in the literature. was isolated as colourless crystalline material in
CCDC-723582 (1), CCDC-723583 (7), CCDC- 69% yield. Conceivably, 12 can also be prepared
723584 (8), CCDC-723585 (9), CCDC-723586 (11), from the reaction involving ArNCNAr, and ArNHLi
38
and CCDC-723587 (12) contain the supplementary (Ar = 2,6-Me2C6H3) as previously reported for 13.
crystallographic data for this paper. Copies of these However, the method reported here for 12 does not
39–41
data can be obtained free of charge from the Cam- require ArNCNAr, a reagent hard to prepare
and
bridge Crystallographic Data Centre (www.ccdc. hence less cumbersome and more convenient to
cam.ac.uk/data_request/cif).
perform. The probable mechanism of formation of
sym N,N′,N″-triarylguanidine from the reaction of sym
N,N′-diarylthiourea and the respective arylamine in
the presence of a base is believed to proceed through a
tetrahedral intermediate that could collapse to form
the product as outlined in scheme 1.
3. Results and discussion
3.1 Synthesis
The reaction of sym N,N′-di(2-tolyl)thiourea with
four fold excess of KO2 in acetonitrile was shown to
afford 8 in 60% yield along with trace amount of
3.2 Spectroscopic studies
17a
27,35,36
sym N,N′-di(2-tolyl)urea. Compounds 7,
928
The TOF-mass spectrum of 7 revealed peaks at
+
and 1230 are known in the literature but details perti-
nent to their synthesis and complete characterization
have not been described clearly. The one pot reac-
tion involving sym N,N′-diphenylthiourea and ani-
line in the presence of 35 wt% aq. NaOH reported
for 137 appeared to be the most convenient procedure
for 7−12 because this procedure does not require
sym N,N′-diarylcarbodiimide and hence the number
of steps is reduced. We decided to prepare 7−12 in a
single-step from the reaction involving sym N,N′-
diarylthiourea and the corresponding arylamine fol-
lowing the procedure reported for 1 given the possi-
ble role of 7−12 as N-donor ligands for metal ions,
and as organocatalysts. The patent procedure re-
ported for 1 did not work for 7–12 and hence we
substantially modified the patent procedure and the
results obtained in our hands are listed in table 1.
The reactions of sym N,N′−diarylthiourea with the
respective arylamine in the presence of aq. KOH of
varying strengths in nitrobenzene afforded 7−11 in
good yield. Compounds 7 and 8 were isolated as
colourless solid by simple work procedure (see ex-
perimental). Compounds 9–11 were isolated as col-
ourless solid after removal of nitrobenzene by
vacuum distillation. Using this procedure, 7–11 can
be isolated on multigram scale conveniently.
m/z = 329⋅4692 and 330⋅9995 assignable for M , and
[M + H] , respectively whereas that of 9 revealed
+
peaks at m/z =378⋅1553, 379⋅8248, and 380⋅7336
which are assigned for [M + H] , [M + 2H] , and
+
[M + 3H] , respectively. The highly intense peaks
+
observed for [M + H] ion of 7 and 9 are attributed
to the formation of a stable guanidinium cation of
+
the type [FH] . The EI-mass spectrum of 8 revealed
a peak at m/z = 329⋅3 assignable for M . Compounds
10–12 revealed peaks at m/z = 372⋅0259, 372⋅10,
and 372⋅1628, respectively assignable for M of the
respective guanidine moiety.
+
+
+
+
Compound 7 revealed two IR bands at 3371, and
3320 cm assignable for ν (NH) and a single band at
–1
–1
1641 cm assignable for ν (C=N) as analogously
–1
reported for 1 (ν (NH): 3387 and 3373 cm , and
–1 42
ν (C=N): 1629 cm ) whereas the IR spectrum of
8–12 each revealed a single ν (NH) band at 3372,
3407, 3387, 3396, and 3377 cm and a single ν(C=N)
–1
The reaction of bulkier (ArNH)2CS with ArNH2
(Ar = 2,6-Me2C6H3) under the condition identical to
that adopted for 10 and 11 produced 12 in low yield
and the same reaction carried out at 150 °C
–1
band at 1658, 1655, 1648, 1659, and 1639 cm ,
respectively. Two ν (NH) bands observed for 1 and
7 compared with one ν (NH) band observed for 8–12

162
Kanniyappan Gopi et al
Table 1. Syntheses of sym N,N′,N″-triarylguanidines (7–12).
Strength of aq KOH
Ar
(wt%), time (h)
Compound
Yield (%)
83
4-MeC6H4
70, 6
70, 6
7
8
9
10
11
12
a
2-MeC6H4
82
b
2-(OMe)C6H4
3,5-Me2C6H3
2,4-Me2C6H3
2,6-Me2C6H3
70, 8
80
100, 15
100, 10
73
77
69
c
100, 24
a
17a b
28 c
Lit., yield: 25%; Temp: 138°C
Lit., yield: 60%;
Scheme 1. Probable mechanism of formation of sym N,N′,N″-triarylguanidines.
may be attributed to an intermolecular medium 13 can have four extreme C−N rotameric conforma-
strength N–H⋅⋅⋅N hydrogen bonding present in the tions namely, syn–syn, syn–anti, anti–syn, and
formerly mentioned compounds as will be discussed anti−anti with τCNC=N torsion angles of 0⋅0−0⋅0, 0⋅0–
in the following section.
1
180⋅0, 180⋅0–0⋅0 and 180⋅0–180⋅0°, respectively as
H NMR spectra of 7, 8, and 10 revealed a broad illustrated in scheme 2. The number of conformer
peak at δH = 2⋅29, 2⋅19, and 2⋅27 ppm for CH3 pro- increases to a minimum of sixteen if the aryl sub-
tons whereas the H NMR spectrum of 9 revealed a stituents are unsymmetrically substituted as those
1
downfield shifted peak at δH = 3.80 ppm; two present in 8, 9 and 11 as listed in table 2. In solu-
singlets were observed at δ H = 2⋅16 and 2⋅27 ppm tion, the conformers shown in scheme 2 and table 2
for 11 which are assignable for o- and p-CH3 pro- may equilibrate among themselves due to (i) rapid
tons of the aryl moieties. In addition, compounds 7, N–Ar bond rotation if the aryl substituents are less
8, 10, and 11 exhibited a broad peak in the range bulky and (ii)
a
relatively fast prototropic
43
δH = 5⋅40–5⋅80 ppm whereas 12 exhibited two up- amine−imine tautomerism arising from shift of the
field shifted singlets at δ H = 4⋅76 and 5⋅01 ppm for NH protons across the C=N bond as shown in
the NH protons. Compound 9 exhibited a broad peak scheme 3. Compounds 9 and 12, analogous to 1338
at δH = 6⋅35 ppm and a significantly down field appear to retain syn–anti conformation in solution as
shifted broad peak at δH = 8⋅50 ppm for the NH pro- inferred from two separate signals observed for the
13
tons. The C NMR spectra of 7, 8, 10, and 12 NH protons. A broad peak observed for the NH pro-
revealed a singlet at δ C = 20⋅8, 17⋅8, 21⋅3, and tons of 7, 8, 10 and 11 in conjunction with a highly
1
13
18⋅7 ppm for CH3 carbon while 9 exhibited a down- symmetrical H and C NMR spectra suggest
field shifted singlet at δ C = 55⋅5 ppm for OCH3 car- that there exist perhaps both prototropic amine–
bon. On the other hand, two distinct singlets are imine tautomerism as well as N–Ar bond rotation
observed at δ C = 17⋅7 and 20⋅7 ppm for 11 which due to less bulky aryl moieties in these compounds
are ascribed to the o- and p-CH3 carbon of the aryl on a time scale faster than NMR time scale
7
–1
rings. Sym N,N′,N″-triarylguanidines 1, 7, 10, 12 and (3 × 10 s ).

Synthesis and conformational features of sym N,N′,N″-triarylguanidines
163
Scheme 2. Possible conformations of 1, 7, and 10−13.
Table 2. Various possible tautomers of 8, 9, and 11a.
syn–syn ααα
syn–syn ααβ
syn–syn αβα
syn–syn αββ
syn–anti ααα
syn–anti ααβ
syn–anti αβα
syn–anti αββ
anti–syn ααα
anti–syn ααβ
anti–syn αβα
anti–syn αββ
anti–anti ααα
anti–anti ααβ
anti–anti αβα
anti–anti αββ
aα and β indicate upward and downward orientation of o-substituent on the aryl ring
with respect to the CN3 plane. The nomenclature begins from the aryl substituent
attached to the imine nitrogen in a clock-wise direction
45
(molecules 1 and 2)], and 1 (1⋅363(3) Å). The sali-
44
ent structural parameters of A,
A2⋅C5H8N4
A⋅C5H8N4,
and related sym N,N′,N″-triaryl-
45
guanidines are collected in table 4. The parameter
ΔCN defined in table 4 was used to measure the
extent of delocalization of the lone pair on the
amino nitrogen with the C=N bond of amidines (n–π
Scheme 3. Prototropic amine-imine tautomerism in sym
N,N′,N″-triarylguanidines.
46
conjugation). ΔCN value range from 0 Å in fully de-
localized system up to 0⋅10 Å in a fully localized
system retaining C–N and C=N groups. We intro-
duce an additional parameter ΔCN′ in table 4 to better
understand the bonding situation in sym N,N′,N″-
triarylguanidines. The ΔCN 0⋅077(4) Å value in 7 is
shorter than the ΔCN′ 0⋅106(4) Å value. The amino
nitrogen in 7 are planar (ΣN = 360°) that contrasts
with the significantly pyramidilised amino nitrogens
3.3 Structural investigations
3.3a Crystal structures: Compounds 7–9 were
crystallized from ethanol and 11 was crystallized
from n-heptane at ambient temperature and single
crystals were subjected to X-ray diffraction studies.
The ORTEP representations of 7–9 and 11 are de-
picted in figure. 1. Selected bond distances and bond
angles are listed in table 3. Compound 7 possesses
anti–anti conformation as indicated by τCNC=N values
(–146⋅7(2) and –128⋅1(2)°) that contrast with
syn−syn conformation revealed by 1 (τCNC=N 12⋅4(4)
and 37⋅2(4)°). 4-Toluidine is more basic than aniline
(pKa = 5⋅08 vs 4⋅87) and this trend could possibly be
maintained in 1 and 7. Such difference in basicity
and different types of non-covalent interactions in
the crystal lattice could probably dictate the confor-
mations of 1 and 7. The C1–N3 distance, 1⋅391(3) Å
in 7 is slightly longer than the analogous distance
found in guanidine, A [1⋅3663(10) Å (molecule 1),
44
45
in A, A⋅C5H8N4, A2⋅C5H8N4. The aforementioned
structural variation may be explained by invoking (i)
n–π conjugation or negative hyperconjugative inter-
action involving the lone pair on the amino nitrogen
47
with C=N π∗ orbital, (ii) the interaction of the lone
pair on the amino nitrogen with the antibonding
48,49
orbital of the aryl substituent
and intermolecular
N–H⋅⋅⋅N hydrogen bonding (see below).
Sym N,N′,N″-tri(2-tolyl)guanidine (8) possesses
anti–anti αβα conformation as inferred from the
τCNC=N values (134⋅4(3) and 145⋅4(3)°) and from
the orientation of o-Me substituents with respect to
the planar CN3 unit (see table 2). In contrast, sym
N,N′,N″-tris(2-anisyl)guanidine (9) possesses syn–
anti αββ conformation as revealed by τCNC=N values
(–11⋅6(5) and 154⋅0(3)°) as well as from the orienta-
44
and 1⋅3635(9) Å (molecule 2)], co-crystals of
A⋅C5H8N4 (1⋅366(2) Å) and A2⋅C5H8N4 [1⋅359(3) Å

164
Kanniyappan Gopi et al
Figure 1. The ORTEP representations of 7–9 and 11 at 30% probability level. NH hydro-
gen atoms drawn as circles of arbitrary size and the remaining hydrogen omitted for clarity.
tion of o-OMe substituents with respect to the planar 8 (ΔCN 0⋅095(6) Å) but higher than that observed for
CN3 unit. Thus, a subtle variation of the substituents 7 (ΔCN 0⋅077(4) Å) probably owing to the steric hin-
in the o-position of the aryl moiety results in differ- drance associated with the o-Me substituent in 8 and
ent conformation namely, anti–anti αβα for 8 versus 11. Compounds 12 and 13 were shown to possess
syn–anti αββ for 9. The values of ΔCN 0⋅100(6) and syn–anti conformation as revealed by τCNC=N values
ΔCN′ 0⋅111(6) Å in 9 are significantly higher than [τCNC=N: 1⋅0(2) and 178⋅5(1)° (12); –11⋅0(2) and
30,38
those observed for 1 (ΔCN 0⋅086(5), and ΔCN′ 172⋅5(2)° (13)].
0⋅078(4) Å) and these values are the highest among
sym N,N′,N″-triarylguanidines studied.
3.3b AM1 Calculations: In order to gain an
Sym N,N′,N″-tris(2,4-xylyl)guanidine (11) pos- insight regarding conformational features of sym
sesses anti–anti αβα conformation as inferred from N,N′,N″-triarylguanidines, we carried out semi-
τCNC=N values (130⋅8(2) and 148⋅9(1)°) as well as empirical AM1 energy calculations for syn–syn,
from the orientation of o-Me substituents as analo- syn–anti, anti–syn, and anti–anti conformations for
gously found in o-tolyl derivative, 8. The ΔCN value, 7 and the optimized energies for these conformers
0⋅091(3) Å in 11 is comparable to that observed for are 6⋅52, 0⋅00, 2⋅46 and 5⋅75 kcal/mol, respectively.

Synthesis and conformational features of sym N,N′,N″-triarylguanidines
Table 3. Selected bond distances (Å) and bond angles (deg) for 7–9, and 11.
165
7
8
9
11
C1–N1
C1–N2
C1–N3
C2–N1
C9–N2
C16–N3
1⋅285(3)
1⋅362(3)
1⋅391(3)
1⋅427(3)
1⋅411(3)
1⋅421(3)
C1–N1
C1–N2
C1–N3
C2–N1
C16–N3
C9–N2
1⋅377(4)
1⋅282(4)
1⋅380(4)
1⋅421(4)
1⋅432(4)
1⋅432(4)
C1–N1
C1–N2
C1–N3
C2–N1
C9–N2
C16–N3
1⋅372(4)
1⋅272(4)
1⋅384(4)
1⋅408(4)
1⋅413(4)
1⋅400(4)
C1–N1
C1–N2
C1–N3
C2–N1
C10–N2
C18–N3
1⋅384(2)
1⋅367(2)
1⋅276(2)
1⋅416(2)
1⋅427(2)
1⋅428(2)
N1–C1–N2
N1–C1–N3
N2–C1–N3
C1–N1–C2
C1–N2–C9
C1–N2–H2
C9–N2–H2
C1–N3–C1
C1–N3–H3
119⋅1(2)
124⋅4(2)
116⋅5(2)
119⋅8(2)
127⋅3(2)
116⋅3(2)
116⋅4(2)
123⋅9(2)
118⋅0(2)
N1–C1–N2
N1–C1–N3
N2–C1–N3
C1–N1–C2
C1–N1–H1
C2–N1–H1
C1–N2–C9
119⋅8(3)
115⋅2(3)
125⋅0(3)
120⋅9(3)
119⋅5(3)
119⋅5(3)
119⋅8(3)
123⋅2(3)
N1–C1–N2
N1–C1–N3
N2–C1–N3
C1–N1–C2
C1–N1–H1
C2–N1–H1
C1–N2–C9
121⋅1(3)
113⋅8(3)
125⋅0(3)
126⋅6(3)
116⋅7(3)
116⋅7(3)
120⋅2(3)
129⋅0(3)
115⋅5(3)
N1–C1–N2 116⋅5(2)
N1–C1–N3 123⋅2(2)
N2–C1–N3 120⋅3(2)
C1–N1–C2
126⋅8(2)
C1–N1–H1 116⋅6(2)
C2–N1–H1 116⋅6(2)
C1–N2–C10 121⋅9(2)
C1–N2–H2 119⋅1(2)
C10–N2–H2 119⋅1(2)
C1–N3–C18 119⋅4(2)
C1–N3–C16
C1–N3–C16
C1–N3–H3A
C1–N3–H3A 118⋅4(3)
C16–N3–H3A 118⋅4(3)
C16–N3–H3A 118⋅0(2)
C16–N3–H3A 115⋅5(3)
Table 4. Salient structural parameters of guanidine and its derivatives.
Δ
CN = y–x; ΔCN′ = z–x
Angle sums around the
amino nitrogen (deg)
Compound
Δ
CN (Å)
ΔCN′ (Å)
Aa
Molecule 1
0⋅0616(9)
0⋅0733(9)
0⋅060(2)
0⋅0661(10)
0⋅0611(9)
0⋅071(2)
347, 356
345, 350
351, 356
Molecule 2
b
A⋅C5H8N4
A2⋅C5H8N4
Molecule 1
b
0⋅047(4)
0⋅060(4)
0⋅086(5)
0⋅077(4)
0⋅095(6)
0⋅100(6)
0⋅091(3)
0⋅083(6)
0⋅041(3)
0⋅056(4)
0⋅059(4)
0⋅078(4)
0⋅106(4)
0⋅098(6)
0⋅111(6)
0⋅108(3)
0⋅090(6)
0⋅032(3)
359, 350
348, 353
359, 355
360, 360
360, 360
360, 360
360, 360
360, 360
358, 355
Molecule 2
1
7
8
9
11
12
13c
a
44 b
Temp: 270 K, Ref. 45; Ref. 38
c
Hence, syn–anti conformation appears to be the stabilization due to the N–H⋅⋅⋅N and C–H⋅⋅⋅π interac-
most stable conformer of 7. However, compound 7 tions (see supporting information). It has been dem-
revealed anti–anti conformation in the solid-state. onstrated that organic compounds with flexible
The energy penalty of 5⋅75 kcal/mol associated with torsion angles are prone to exhibit conformational
50
7 is perhaps partly compensated by crystal structure polymorphism. The solid–state conformation of 7

166
Kanniyappan Gopi et al
organocatalysts, (ed) T Ishikawa (Weinheim: Wiley-
VCH) Chapter 4, pp 93–136
is probably kinetic in origin. Additional experiment
1
such as variable temperature H NMR and DFT/ab
3. Coles M P 2009 Chem. Commun. 3659
4. Edelmann F T 2008 Adv. Organomet. Chem. 57 183
5. Coles M P 2006 Dalton Trans 985
6. Bailey P J and Pace S 2001 Coord. Chem. Rev. 214
91
initio calculations would probably yield better in-
formation regarding the conformational features of
sym N,N′,N″-triarylguanidines.
7. Schuchardt U, Sercheli R and Vargas R M 1998 J.
Braz. Chem. Soc. 9 199
4. Conclusions
8. Costa M, Chiusoli G P, Taffurelli D and Dalmonego
G 1998 J. Chem. Soc. Perkin Trans. 1 1541
9. Sercheli R, Ferreira A L B, Guerreiro M C, Vargas R
M, Sheldon R A and Schuchardt U 1997 Tetrahedron
Lett. 38 1325
10. (a) Eckert-Maksić M, Glasovac Z, Trošelj P, Kütt A,
Rodima T, Koppel I and Koppel I A 2008 Eur. J.
Org. Chem. 5176; (b) Glasovac Z, Kovacevic B,
Mestrovic E and Eckert-Maksić M 2005 Tetrahedron
Lett. 46 8733
11. Katritzky A R and Rogovoy B V 2005 Arkivoc 4 49
12. Powell D A, Ramsden P D and Batey R A 2003 J.
Org. Chem. 68 2300
13. Bailey P J, Mitchell L A and Parsons S 1996 J. Chem.
Soc. Dalton Trans. 2839
A one pot synthesis was developed for sym N,N′,N″-
triarylguanidines in moderate to good yield without
recourse to the isolation of sym N,N′-diaryl-
carbodiimide, one of the commonly used and diffi-
cult to isolate guanylating reagents. We believe that
the present method is beneficial especially when sym
N,N′,N″-triarylguanidines are required in large
amounts. The observed conformations of sym
N,N′,N″-triarylguanidines appears to be dictated by
multiple factors, i.e. steric factor associated with the
aryl rings and electronic factors that maximizes the
conjugative interaction involving the lone pair on
the amino nitrogen with C=N* orbital (negative
hyper conjugation) or the antibonding orbitals of the
aryl ring. The energy associated with non-covalent
interactions are low (i.e. <5 kcal/mol) nonetheless
these forces when act together could also play a sig-
nificant role in deciding the shape/conformation of
sym N,N′,N″-triarylguanidines.
14. Molina P, Aller E and Lorenzo A 2003 Synlett. 714
15. (a) Du Z, Li W, Zhu X, Xu F and Shen Q 2008 J.
Org. Chem. 73 8966; (b) Zhang W-X and Hou Z 2008
Org. Biomol. Chem. 6 1720; (c) Rowley C N, Ong T-
G, Priem J, Woo T K and Richeson D S 2008 Inorg.
Chem. 47 9660
16. Sym
N,N′,N″-triarylguanidines
(ArNH)21C9 =NAr
C6H4NO2-4, and
17
18
(Ar = C6H4Cl-4,
C6H4Cl-3,
20
C6F5 ) are known but presently we are focused only
on 7–12 for the reasons mentioned in the introduction
17. (a) Kim Y H and Yon G H 1983 J Chem. Soc. Chem.
Commun. 715; (b) Molina P, Alajarín M and Saez J
1983 Synth. Commun. 13 67
Acknowledgements
The authors acknowledge the Department of Science
and Technology, New Delhi (SR/S1/IC-22/2004)
and University of Delhi for financial support. Dr M
Nethaji, Department of Inorganic and Physical
Chemistry, Indian Institute of Science, Bangalore
is gratefully acknowledged for his assistance in
solving the crystal structures reported in this manu-
script. Pierre Charless Hirson is acknowledged
for his experimental assistance in isolating com-
pound 10.
18. Macholdt–Erdniss J 1958 Chem. Ber. 91 1992
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Supplementary information
The supplementary information can be obtained/
viewed on www.cdcc.comac.uk/data_request/cif.
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Tatchell A R 1989 in Vogel’s textbook of practical
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