Unusual aryl migration in a mesomeric betaine in the solid and liquid state: Mechanistic insights into the SNAr reaction

Article abstract of DOI:10.1021/jo100350t

An intramolecular S_NAr mechanism has been identified in the unexpected aryl migration observed in a mesomeric betaine. The process changes drastically the optical and spectroscopic properties and should be a valuable model for related heteroaromatic systems.

Full text of DOI:10.1021/jo100350t

pubs.acs.org/joc
that this thionation does actually proceed via a domino
mechanism.5
Unusual Aryl Migration in a Mesomeric Betaine in
the Solid and Liquid State: Mechanistic Insights into
the SNAr Reaction†
‡
‡
David Cantillo,*,‡ Martı
n Avalos, Reyes Babiano,
ꢀ
´
‡ §
‡
ꢀ
ꢀ
Pedro Cintas, Jose L. Jimenez, Mark E. Light, and
Juan C. Palacios‡
‡
´
ꢀ
ꢀ
Departamento de Quımica Organica e Inorganica, QUOREX
Research Group, Facultad de Ciencias-UEX, Avda. de Elvas
s/n E-06071 Badajoz, Spain, and §Department of Chemistry,
University of Southampton, Highfield, Southampton SO17
1BJ, U.K.
In this conversion, mesomeric betaines 3 could also be
isolated when either an electron-donating isothiocyanate
was employed as dipolarophile (R2 = OCH3) or an elec-
tron-withdrawing group was linked to the imidazolinic
nitrogen of 2 (Ar = 4-NO2C6H4).
dcannie@unex.es
Here, we present the first aryl rearrangement occurring in
mesomeric betaines such as 3a (R1 = R2 = NO2) to give 2-(4-
nitrophenylthio)imidazo[2,1-a]pyrimidin-4-one system (4a)
(Scheme 1). The process took place spontaneously in both
the solid state and CHCl3 solution. In the absence of solvent,
this rearrangement was clearly visible to the naked eye as
orange crystals of 3a placed in a vacuum desiccator con-
verted gradually into colorless crystals of 4a. Complete
decoloration was observed after 2 weeks.
Received February 24, 2010
Figure 1 shows the gradual process in CDCl3 monitored
by 1H NMR (400 MHz). The protons of the sugar moiety in
compounds 3a and 4a showed similar chemical shifts and
identical coupling constants, thus demonstrating that both
the structure and conformation of the sugar fragment re-
mained unaffected during the rearrangement. However,
dispersion of signals corresponding to the 4-nitrophenyl
groups of 3a, caused by the hindered rotation of these
An intramolecular SNAr mechanism has been identified
in the unexpected aryl migration observed in a mesomeric
betaine. The process changes drastically the optical and
spectroscopic properties and should be a valuable model
for related heteroaromatic systems.
1
aromatic rings, disappeared in the H NMR spectrum of
4a showing the typical coupling pattern of two AA0XX0
systems. Also, as a result of this transposition, the carbon
resonances for C-2 and C-6a underwent significant upfield
shifts (Δδ = 14.7 and 5.6 ppm, respectively), while C-3 and
C-4 carbon atoms were deshielded to a lesser extent (Δδ =
1.8 and 4.3 ppm, respectively).
Mesomeric betaines along with the inherently aromatic
mesoionic rings, by virtue of their electronic delocalization
and luminescent properties, represent rising candidates for
optoelectronic applications which include nonlinear effects1
or the design of near-IR dyes.2
Among mesoionics, our group has extensively studied the
synthetic versatility of 1,3-thiazolium-4-olates,3 turning re-
cently to their 4-thiolate cousins as the presence of a bulkier
and polarizable exocyclic sulfur atom was predicted to cause
larger nonlinearities.4 We recently reported the synthesis
of imidazo[2,1-b]thiazolium-3-thiolate systems (1) from
the corresponding imidazo[2,1-b]thiazolium-3-olates (2) by
reaction with aryl isothiocyanates, proving unequivocally
The solid-state structure of 4a could be unambiguously
elucidated by single-crystal X-ray diffraction (Figure 2).
Crystal data6 revealed the favorable T-shaped arrangement
adopted by the two 4-nitrophenyl groups in agreement with
previous literature.7
This rearrangement can be interpreted as an intramolecu-
lar aromatic nucleophilic substitution (SNAr) in which the
thiolate group displaces the pyrimidinium ion of the nearest
4-nitrophenyl ring. Several factors appear to promote this
intramolecular process such as the activation exerted by the
nitro group, the good ability of the pyrimidinium ion as
leaving group, and the offset stacking disposition of both
†
ꢀ
ꢀ
Dedicated to Prof. Manuel Gomez Guillen.
ꢀ
(1) (a) Pilla, V.; De Araujo, C. B.; Lira, B. F.; Simas, A. M.; Millar, J.;
Athayde-Filho, P. F. Opt. Commun. 2006, 264, 225–228. (b) Prabhakar, C.;
Yesudas, K.; Bhanuprakash, K.; Rao, V. J.; Kumar, R. S. S.; Rao, D. N.
J. Phys. Chem. C 2008, 112, 13272–13280.
ꢀ
ꢀ
(5) Cantillo, D.; Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.;
Light, M. E.; Palacios, J. C. Org. Lett. 2008, 10, 1079-1082; J. Org. Chem.
2009, 74, 3698-3705.
(2) Langhals, H. Angew. Chem., Int. Ed. 2003, 42, 4286–4288.
ꢀ
(3) Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.; Palacios, J. C. Acc.
ꢀ
Chem. Res. 2005, 38, 460–468. and references cited therein.
(4) Sylla, M.; Giffard, M.; Mabon, G.; Cubillan, N.; Castellano, O.;
(6) Crystal data have been deposited with the Cambridge Crystallo-
graphic Data Centre (CCDC-764254) and can be obtained upon permission.
(7) Glowka, M. L.; Martynowski, D.; Kozfowska, K. J. Mol. Struct.
1999, 474, 81–89.
ꢀ
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Hernandez, J.; Soscun, H.; Phu, X. N. Chem. Phys. 2006, 330, 387–393.
4300 J. Org. Chem. 2010, 75, 4300–4303
Published on Web 05/19/2010
DOI: 10.1021/jo100350t
r
2010 American Chemical Society

Cantillo et al.
JOCNote
SCHEME 1. N/S-Aryl Rearrangement in Mesomeric Betaines 3
π-deficient N-aryl groups, the latter favoring the frontal
approach of the 4-nitrophenyl group to the neighboring
sulfur atom. In order to understand the way in which 3a is
transformed into 4a, we have carried out a computational
study on the relative migratory aptitude of the N-aryl group
in compounds 3a and 3b (R1 = NO2; R2 = OCH3) in the gas
phase at the B3LYP/6-31G(d)8 level using the Gaussian03
package.9 Figure 3 collects the relative electronic energies of
all optimized stationary states involved in both the experi-
mental 3af4a and the hypothetical 3bf4b rearrangements.
During the search of the stationary states involved in these
processes, concerted transition structures TS3af4a and
TS3bf4b could be located, and their relative energies
(ΔΔEq = 9.0 kcal/mol) account for the evolution of 3a into
4a and why, under the same reaction conditions, the trans-
formation of 3b into 4b does not occur. Moreover, when 3b
was heated at reflux in toluene for 6 h or in CHCl3 at 100 °C
(sealed vessel) for 2 h, aryl migration could not be observed
either.
FIGURE 1. Transformation of betaine 3a into its isomer 4a in
CDCl3. Compound 3a (a) just dissolved, (b) after 2 h, (c) after 24 h.
FIGURE 2. ORTEP drawing of the crystal structure of 4a.
However, there was still a missing link between structure
and migratory ability in those betaines. To shed light into
steric and electronic factors and looking for a predictive
picture as well, a comparative study on a series of structural
parameters (bond lengths and angles, and bond orders) in
nine betaines resulting from the different R1 and R2 combi-
nations (R1 and R2 = H, OCH3, NO2) (see the Supporting
Information) as well as the energy of the corresponding
frontier orbitals was undertaken (Table 1).
An analysis of these data rules out geometry parameters as
responsible of the different behavior. In stark contrast,
inspection of the frontier orbitals reveals that the nature of
R2 profoundly affects both the energy and symmetry of the
virtual orbitals. Thus, the UMOs for betaines 3a, 3d, and 3g,
possessing the appropriate symmetry to interact with the
OMO located at the sulfur atom, have a gap of ∼2.7 eV.
FIGURE 3. Energetics of the 3af4a and 3bf4b rearrangements.
TABLE 1. Energy Differences (in eV) of the Orbitals Involved in
Rearrangement at the B3LYP/6-31G(d) Level
ΔE (OMO-
exptl result
(yield, %)b
compd
R1
R2
UMO)a
3a
3b
3c
3d
3e
3f
3g
3h
3i
NO2
NO2
NO2
H
H
H
OCH3
OCH3
OCH3
NO2
OCH3
H
NO2
OCH3
H
NO2
OCH3
H
2.79
4.82
4.82
2.74
5.04
4.80
2.74
4.87
4.78
reaction (78)
no reaction
no reaction
not tested
no reaction
not tested
not tested
(8) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652. (b) Lee, C.;
Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789.
(9) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci,
B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Ragha-
vachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;
Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komar-
omi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision C.02;
Gaussian, Inc.: Wallingford, CT, 2004.
no reaction
not tested
a[a] HOMO-1 and [b] LUMO for 3d and 3g; LUMOþ1 for 3a;
LUMOþ6 for 3i; LUMOþ7 for 3b, 3c, and 3f; LUMOþ8 for 3h;
LUMOþ9 for 3e. bSee ref 5.
Compounds 3d and 3g could not be obtained experimentally.
In the remaining derivatives, the UMOs with adequate sym-
metry for overlapping differ by at least 4.8 eV. In fact,
compounds 3b, 3c, 3e, and 3h5 did not undergo aryl migration.
J. Org. Chem. Vol. 75, No. 12, 2010 4301

Cantillo et al.
JOCNote
FIGURE 5. Significant bond lengths and bond orders (in brackets)
for TS3af4a (B3LYP/6-31G(d) level).
FIGURE 4. (a) HOMO-1 of 3a, (b) LUMOþ1 of 3a (B3LYP/6-
31G(d) level).
TABLE 2. Significant Geometry Parameters for the Stationary Points
Involved in the Rearrangements of 3a and 3b (B3LYP/6-31G(d) Level)
C-N
(A)
C-S
(A)
exptl result
(yield, %)
R2
structure
N-C-S
NO2
3a
1.45
1.76
2.88
1.45
1.87
2.85
3.01
2.14
1.79
3.04
2.29
1.79
63.4
77.1
65.8
62.4
72.9
66.4
reaction (78)
TS3af4a
4a
3b
TS3bf4b
4b
OMe
no reaction
Figure 4 shows the orbitals involved in the rearrangement
of 3a (Table 2) and Figure 5 the most significant bond lengths
FIGURE 6. (a) PES corresponding to the transformation of 3a into
4a, calculated at the ONIOM[B3LYP/6-31G(d):PM3] level with full
optimization of each structure. (b) Three-dimensional representa-
tion of the Chebyshev polynomial that fits to the PES data with
superposition of its first derivative plots. Red and blue lines
correspond to zones where the derivative values with respect to X
(C-N bond) and Y (C-S bond), respectively, are close to zero.
and bond orders for TS3af4a
.
As a final and intriguing mechanistic question, assuming a
formal nucleophilic displacement, we also wondered whether
an alternative stepwise mechanism through a Meisenheimer-
type intermediate did exist. To provide a clear-cut response,
we decided to construct the potential energy surface (PES)
for this reaction. Since the calculation is now computationally
expensive, this was carried out using the hybrid ONIOM-
[B3LYP/6-31G(d):PM3] method.10,11 A total of 176 (16 ꢀ 11)
optimized structures were required to create the PES stemming
from the sequential lengthening (0.1 A) of both the N-C (a)
and S-C (b) bonds (Figure 6a). Following the procedure
previously described for us,12 we have created a new hyper
surface with a three-dimensional representation essentially
identical (r > 0.9999) where we have superimposed the con-
tour maps of isovalue lines (Figure 6b) to establish the real
location of each stationary point on the PES.
Calculations of first derivatives with respect to either X or
Y coordinates and their graphical plots gave rise to isovalue
lines. Incorporation of these lines into the PES defined a
single saddle point coincident with TS3af4a (Figure 7) and
discarded an alternative stepwise mechanism through a
Meisenheimer-type intermediate. These results have further
been confirmed by the IRC calculation for this transition
structure at the B3LYP/6-31G(d) level (see the Supporting
Information).
FIGURE 7. ONIOM[B3LYP/6-31G(d):PM3]-optimized structure
for TS3af4a (C---N bond length, 1.78 A; C---S bond length, 2.14 A).
Ball and sticks represent the partial system treated at the B3LYP/6-
31G(d) level, whereas the wire-shaped structure corresponds to the
molecular fragment assessed at the PM3 level.
nucleophilic aromatic substitution in a wide range of aromatic
substrates. The transformation described here is consistent
with the ab initio study of reactions of benzenediazonium ion
with water.13 Thus, our results agree with a direct SNAr
reaction with a rather loose transition state analogous to the
saddle structures of front-side nucleophilic replacement at
saturated centers.
That this aryl migration proceeds via a rather concerted
pathway may add further understanding to mechanism of
In conclusion, this note discusses an unexpected aryl mi-
gration occurring through a concerted mechanism and may
(10) Maseras, F.; Morokuma, K. J. Comput. Chem. 1995, 16, 1170–1179.
(11) Froese, R. D. J.; Morokuma, K. In The Encyclopedia of Computa-
tional Chemistry; Schleyer, P. v. R., Allinger, N. L., Clark, T., Gasteiger, J.,
Kollman, P. A., Schaefer,H. F., III; Schreiner, P. R., Eds.; John Wiley:
Chichester, 1998; pp 1245-1257.
ꢀ
ꢀ
(12) Cantillo, D.; Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.;
(13) (a) Wu, Z.; Glaser, R. J. Am. Chem. Soc. 2004, 126, 10632–10639.
(b) Ussing, B. R.; Singleton, D. A. J. Am. Chem. Soc. 2005, 127, 2888–2899.
Light, M. E.; Palacios, J. C. J. Org. Chem. 2009, 74, 7644–7650.
4302 J. Org. Chem. Vol. 75, No. 12, 2010

Cantillo et al.
JOCNote
stimulatethe search for this shortof pathways in aromatic and
heteroaromatic systems.
(m, 1H, H-50), 4.95 (d, J 6.4 Hz, 1H, H-20), 4.49 (dd, 1H, J 2.0
Hz, J 12.0 Hz, H-60), 4.21 (dd, 1H, J 2.8 Hz, J 9.6 Hz, H-40), 4.10
(dd, 1H, J 12.0 Hz, J 5.6 Hz, H-600), 2.11 (s, 3H), 2.00 (s, 3H),
1.94 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.3, 169.7, 168.1,
163.3, 157.7, 149.5, 148.3, 143.9, 142.0, 138.5, 136.6, 131.4,
130.5, 128.8, 128.5, 124.3, 123.7, 118.8, 116.5, 90.1, 77.6, 71.6,
66.6, 63.4, 63.0, 20.7, 20.6, 20.5; IR (KBr, cm-1) 1743, 1675,
1579, 1526, 1502, 1423, 1347, 1225, 1109, 1046. Anal. Calcd for
C34H29N5O12S: C, 55.81; H, 3.99; N, 9.57; S, 4.38. Found: C,
55.67; H, 4.13; N, 9.52, S, 4.31.
Experimental Section
Synthetic procedure and spectroscopic data for 1,6-bis(4-
nitrophenyl)-4-oxo-3-phenyl-(30,50,60-tri-O-acetyl-1,2-dideoxy-R-
D-glucofurano)[10,20:4,5]-5aH,5bH-imidazo[2,1-a]pyrimidin-5-
ilium-2-thiolate (3a) are given in the Supporting Information of
ref 5a.
6-(4-Nitrophenyl)-2-(4-nitrophenylthio)-3-phenyl-(30,50,60-tri-
O-acetyl-1,2-dideoxy-r-D-glucofurano)[10,20:4,5]-5aH,5bH-imidazo-
[1,2-a]pyrimidin-4-one (4a). A solution of 3a (200 mg) in chloroform
(10 mL) was kept at room temperature and monitored by TLC
(benzene-acetonitrile 3:1; Rf3a, 0.3; Rf4a, 0.55) until the disap-
pearance of 3a was observed (∼24 h). The solution was evapo-
rated, and the residue was crystallized from ethanol (143 mg,
72%): colorless crystals; mp 231-232 °C; [R]D þ7, [R]578 þ8,
[R]546 þ15, [R]436 þ122 (c 0.5, chloroform); 1H NMR (400 MHz,
CDCl3) δ 8.27 (d, 2H, J 8.8 Hz), 7.91 (d, 2H, J 9.2 Hz), 7.73 (d,
2H, J 8.8 Hz), 7.53 (d, 2H, J 9.2 Hz), 7.49-7.41 (m, 5H), 6.35
(d, 1H, J 6.4 Hz, H-10), 6.14 (d, 1H, J 2.8 Hz, H-30), 5.30-5.26
Acknowledgment. This work was supported by the Minis-
ꢀ
terio de Educacion y Ciencia and FEDER (CTQ2007-66641)
and the JuntadeExtremadura (PRI07A016 and PRI08A032).
ꢀ
D.C. thanks the Spanish Ministerio de Educacion y Ciencia
for a fellowship.
Supporting Information Available: Copies of NMR spectra,
molecular-modeling coordinates, X-ray data (CIF), and addi-
tional tables and graphs. This material is available free of charge
via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 12, 2010 4303