Regularities of the amino-Claisen rearrangement mechanism

Article abstract of DOI:10.1007/s11172-013-0010-8

The synthetic and kinetic regularities of the amino-Claisen rearrangement (ACR) were studied for the transformation of 2,5-dimethyl-N-(pent-3-en-2-yl) aniline. The ACR products are formed due to the conversion of a binary π-complex formed by the reaction of N-alkenylaniline hydrochloride with hydrochloride of the solvent (2,5-dimethylaniline).

Full text of DOI:10.1007/s11172-013-0010-8

Russian Chemical Bulletin, International Edition, Vol. 62, No. 1, pp. 83—87, January, 2013
83
Regularities of the aminoꢀClaisen rearrangement mechanism
I. B. Abdrakhmanov,a I. M. Borisov,b R. R. Ismagilov,a N. G. Nigmatullin,c R. N. Khusnitdinov,a and G. A. Tolstikovd†
aInstitute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences,
71 prosp. Oktyabrya, 450054 Ufa, Russian Federation.
Fax: +7 (347) 235 6660. Еꢀmail: chemhet@anrb.ru
bM. Akmulla Bashkir State Pedagogical University,
3a ul. Oktyabr´skoi Revolyutsii, 450008 Ufa, Russian Federation.
Fax: +7 (347) 272 5805. Еꢀmail: BorisovIM@yandex.ru
cBashkir State Agrarian University,
34 ul. 50 let Oktyabrya, 450001 Ufa, Russian Federation.
Fax: +7 (347) 228 0898. Еꢀmail: bgau@ufanet.ru
dN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry,
9 prosp. Akad. Lavrent´eva, 630090 Novosibirsk, Russian Federation.
Еꢀmail: Bensol@NJOCH.NS.ru
The synthetic and kinetic regularities of the aminoꢀClaisen rearrangement (ACR) were
studied for the transformation of 2,5ꢀdimethylꢀNꢀ(pentꢀ3ꢀenꢀ2ꢀyl)aniline. The ACR products
are formed due to the conversion of a binary ꢀcomplex formed by the reaction of Nꢀalkenylꢀ
aniline hydrochloride with hydrochloride of the solvent (2,5ꢀdimethylaniline).
Key words: Claisen rearrangement, mechanism, 2,5ꢀdimethylꢀNꢀ(pentꢀ3ꢀenꢀ2ꢀyl)aniline.
carried out on a Chromꢀ5 chromatograph with a flameꢀionizaꢀ
tion detector (column 1200×3 mm with 5% SEꢀ30 on Chromaꢀ
tone NꢀAWꢀHMDS) using helium as a carrier gas. The physicoꢀ
chemical and spectral characteristics of compounds 1a,b correꢀ
spond to those published earlier.1 Aniline (GOST 313ꢀ77), N,Nꢀdiꢀ
methylaniline (GOST 5855ꢀ78), and nitrobenzene (GOST 6350ꢀ56)
were purified by standard procedures.5
The kinetics of the aminoꢀClaisen rearrangement was studied
as follows. A mixture of 2,5ꢀdimethylꢀNꢀ(pentꢀ3ꢀenꢀ2ꢀyl)aniline
(1a) hydrochloride or 3,6ꢀdimethylꢀ2ꢀ(pentꢀ3ꢀenꢀ2ꢀyl)aniline
hydrochloride (2a) (22.6 g, 0.1 mol) and 100 mL of the correꢀ
sponding solvent, viz., 2,5ꢀdimethylaniline, aniline, or nitrobenꢀ
zene, was heated for 1—3 h at 150—190 С. The composition
and concentration of the products were determined by GLC.
The compounds in the mixture were identified by comparing the
retention times of the obtained samples and the corresponding
preꢀsynthesized individual substances.
The aminoꢀClaisen rearrangement (ACR) is an effiꢀ
cient method of orthoꢀalkenylation of arylamines.1,2 Reꢀ
gioselectivity, simplicity of the technological process, and
accessibility of the starting components and catalysts make
the ACR to be very attractive in the synthetic respect.
A wide range of unsaturated arylamines became accesꢀ
sible due to practical accomplishment of the ACR. Arylꢀ
amine derivatives possess a series of useful properties, in
particular, pesticidal, antioxidant, and anticorrosion acꢀ
tivity. In addition, since the sterically approached NH2
groups and the orthoꢀalkenyl substituent with the reactive
double bond are in the aromatic core of the ACR prodꢀ
ucts, they can be used in the synthesis of many nitrogenꢀ
containing heterocyclic compounds (indole, carbazole,
quinoline, quinazoline, and benzoxazine derivatives).
Although a considerable number of investigation is deꢀ
voted to the study of the ACR,2—4 the mechanism of the
aminoꢀClaisen rearrangement has not yet been interpretꢀ
ed unambiguously. Therefore, in this work, we studied the
kinetic regularities of the ACR of 2,5ꢀdimethylꢀNꢀ(pentꢀ
3ꢀenꢀ2ꢀyl)aniline in a medium of 2,5ꢀdimethylaniline.
Results and Discussion
Two possible mechanisms of the catalytic ACR, namely,
intraꢀ and intermolecular, are presently assumed in the
literature.1,2 The intramolecular mechanism is a oneꢀstage
concerted [3,3]ꢀsigmatropic rearrangement of the protoꢀ
nated form of arylamines with the pericyclic transiꢀ
tion state.3,4 The intermolecular mechanism includes
the elimination of the allyl carbocation (with the formaꢀ
tion of either a ꢀcomplex in the solvent cage, or a solvateꢀ
separated ionꢀmolecular pair) and its electrophilic attack
Experimental
The components of the reaction system were identified using
modern physicochemical methods of analysis. GLC analysis was
†
Deceased.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 0083—0087, January, 2013.
1066ꢀ5285/13/6201ꢀ83 © 2013 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 62, No. 1, January, 2013
Abdrakhmanov et al.
to the orthoꢀ or paraꢀposition of the aromatic core of
arylamine.
paraꢀisomer 3а neither in heptadecane nor in nitrobenzene
even at 250 С, but gives the cyclization product 2ꢀethylꢀ
3,4,7ꢀtrimethylindoline (4).
One of the most interesting objects for studying the
aminoꢀClaisen rearrangement is 2,5ꢀdimethylꢀNꢀ(pentꢀ
3ꢀenꢀ2ꢀyl)aniline (1а), whose uniqueness is an unusual
easiness of formation of both orthoꢀ (2а) and paraꢀisoꢀ
mers (3а).
These results unambiguously indicate that the ACR is
a complicated multistage process in which the solvent plays
a substantial role. This conclusion is brightly confirmed
by the results of an experiment with 2ꢀdeuteromethylꢀ5ꢀ
methylꢀNꢀ(pentꢀ3ꢀenꢀ2ꢀyl)aniline (5). The study of the
ACR of labeled Nꢀalkenylarylamine in 2,5ꢀdimethylaniline
showed that already at 30% conversion the starting subꢀ
strate 5 is transformed into compound 1а by 50% and
further into orthoꢀ and paraꢀisomers 2а and 3а containing
no isotope labels (Scheme 1).
Scheme 1
For 80% conversion, the transformation products of 5 are
compounds 1а, 2а, and 3а containing no deuterium atoms.
Since the solvent exerts different effects on the occurꢀ
rence of the ACR, the kinetic regularities of the isomerꢀ
ization of compound 1а were studied in a medium of
2,5ꢀdimethylaniline.
Kinetic regularities of the ACR of compound 1a in
a medium of 2,5ꢀdimethylaniline. The typical kinetic curves
of the ACR of hydrochloride 1а are shown in Fig. 1.
Figure 1 shows that the orthoꢀ and paraꢀisomers are
the major rearrangement products and at the initial reacꢀ
tion moment (before 10 min) they are accumulated with
1—3: R = Me (a), H (b)
The catalytic amino rearrangement of compound 1a
occurs in the presence of HCl in a 2,5ꢀdimethylaniline
solution at 150—200 С for 1—4 h. An analysis of the
reaction mixture revealed that the composition of the inꢀ
termediate and final ACR products depends on the nature
of the solvent used.
3,6ꢀDimethylꢀ2ꢀ(pentꢀ3ꢀenꢀ2ꢀyl)aniline (2а), 2,5ꢀdiꢀ
methylꢀ4ꢀ(pentꢀ3ꢀenꢀ2ꢀyl)aniline (3а), and 2ꢀethylꢀ3,4,7ꢀ
trimethylindoline (4) are formed due to the rearrangement
in 2,5ꢀdimethylaniline. In this conversion, orthoꢀisomer
2а acts as an intermediate product, while paraꢀisomer 3а
(70%) and dihydroindole 4 (3—5%) are the final products.
This was proved by the transformation of compound 2а
(isolated from the reaction mixture) into products 3а and
4 in the presence of НСl in 2,5ꢀdimethylaniline at 170 С.
The rearrangement of hydrochloride 1а in an aniline
medium also affords rearrangement products 2а and 3а.
However, up to 20% of products of the transfer of the
alkenyl group from molecule 1а to the aniline molecule to
form Nꢀ(pentꢀ3ꢀenꢀ2ꢀyl)aniline (1b) and 2ꢀ(pentꢀ3ꢀenꢀ
2ꢀyl)aniline (2b) were simultaneously observed in the reꢀ
action mixture. The presence of 2,5ꢀdimethylaniline in
the reaction mixture indicates that hydrochloride 1а lost
the alkenyl cation.
c/mol L–1
1.2
1.0
0.8
3a
0.6
0.4
0.2
2a
1a
20
40
60
80
100 t/min
Fig. 1. Kinetic curves for the consumption of 2,5ꢀdimethylꢀNꢀ
(pentꢀ3ꢀenꢀ2ꢀyl)aniline (1a) and accumulation of 3,6ꢀdimethylꢀ
2ꢀ(pentꢀ3ꢀenꢀ2ꢀyl)aniline (2a) and 2,5ꢀdimethylꢀ4ꢀ(pentꢀ3ꢀenꢀ2ꢀ
In nitrobenzene the rearrangement of 1а proceeds via
the intermediate formation of 2а and also completes by
the formation of 3а and 4. In the absence of a catalyst,
orthoꢀisomer 2а isolated from the reaction mixture forms
yl)aniline (3a). Reaction conditions: 170 С, [1а]0 = [HCI]0
=
= 1.07 mol L–1, 2,5ꢀdimethylaniline.

Mechanism of aminoꢀClaisen rearrangement
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 1, January, 2013
85
Scheme 2
the constant molar ratio 2а : 3a = 1.95 0.05. This prejuꢀ
dices the scheme of consecutive formation of 3a from 2a
at the initial reaction stage. Most likely, the orthoꢀ and
paraꢀisomers are accumulated in parallel in the initial peꢀ
riod of the reaction. However, after Nꢀisomer 1a was conꢀ
sumed, paraꢀisomer 3a continues to form with a simultaꢀ
neous decrease in the concentration of orthoꢀproduct 2a.
Therefore, 2а is gradually transformed into 3a at a deep
conversion of the initial reagent 1a. As can be seen from
Fig. 1, the concentration of paraꢀisomer 3a increases more
slowly than the concentration of orthoꢀisomer 2a decreasꢀ
es because of the partial occurrence of cyclization of 2а
with the formation of 4. Under all experimental condiꢀ
tions studied (variation of the temperature and concentraꢀ
tion of 1a and the catalyst), the kinetic curves of conꢀ
sumption of Nꢀisomer 1a are linear in the coordinates of
the firstꢀorder reaction equation, i.e., V0 = keff•[1a] (Fig. 2).
According to the accepted literature concepts, it should
be expected that the reaction order of consumption of 1a
with respect to the catalyst is also equal to unity. Howevꢀ
er, it turned out that the reaction orders with respect to the
catalyst for the consumption of 1a and accumulation of 2a
and 3a are equal to two (Fig. 3).
In presented Scheme 2, the key intermediate is binary
ꢀcomplex А, whose formation is equilibrium from the
protonated forms of the starting substrate and solvent
(reaction (3)). The interaction of the protonated amino
group of compound 1a with ꢀelectrons of the aromatic
ring of the protonated solvent partially disturbs the benꢀ
zene ring aromaticity, due to which the migration of the
alkenyl С5Н9 group is facilitated with the formation of the
orthoꢀ and paraꢀisomers. Taking into account steric hinꢀ
V0•103/mol L–1 s–1
5
1a
4
3
2a
2
1
3a
0
The second order with respect to НСl suggests that an
intermediate formed from protonated 1a and a protonated
solvent molecule (2,5ꢀdimethylaniline) appears in the reꢀ
action under study. Taking this into account, the regulariꢀ
ties of the aminoꢀClaisen rearrangement of compound 1a
in a solution of 2,5ꢀdimethylaniline can be described by
Scheme 2.
0.4
0.6
0.8
1.0
1.2 [N]0/mol L–1
Fig. 2. Initial rates of consumption of 2,5ꢀdimethylꢀNꢀ(pentꢀ3ꢀ
enꢀ2ꢀyl)aniline (1a) and accumulation of 3,6ꢀdimethylꢀ2ꢀ(pentꢀ
3ꢀenꢀ2ꢀyl)aniline (2a) and 2,5ꢀdimethylꢀ4ꢀ(pentꢀ3ꢀenꢀ2ꢀyl)ꢀ
aniline (3a) vs initial concentration of compound 1a ([N]0) in
the presence of HCl ([HCl] = 1.07 mol L–1).

86
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 1, January, 2013
Abdrakhmanov et al.
V0•103/mol L–1 s–1
Scheme 2) to the solvent molecule following the intramoꢀ
lecular mechanism, whereas compound 9 is probably
formed via reaction (9) (see Scheme 2) through the transiꢀ
tion state binding the orthoꢀ and paraꢀcarbon atoms of the
starting substrate (intramolecularly). The route of paraꢀ
isomer formation through stages (5) and (9) includes, in
fact, the double inversion of the alkenyl radical. Stages (7)
and (10) describe possible side reactions during the ACR.
Stage (4) explains the composition of the transalkylation
products of the deuterated Nꢀisomer in a 2,5ꢀdimethylaꢀ
niline medium (see Scheme 2).
According to Scheme 2, it can be assumed that the
rateꢀdetermining steps of the ACR are the stages of transꢀ
formation of complex А, i.e., stages (4)—(7). Therefore,
the rate of consumption of 2,5ꢀdimethylꢀNꢀ(pentꢀ3ꢀenꢀ
2ꢀyl)aniline (1a) (VN) will be represent the algebraic sum
of rates of stages (4), (5), (6), and (7)
7
6
5
4
3
2
1
0
1a
2a
3a
0.2 0.4 0.6 0.8 1.0 1.2 1.4 [N]0/mol L–1
Fig. 3. Initial rates of consumption of 2,5ꢀdimethylꢀNꢀ(pentꢀ3ꢀ
enꢀ2ꢀyl)aniline (1a) and accumulation of 3,6ꢀdimethylꢀ2ꢀ(pentꢀ
3ꢀenꢀ2ꢀyl)aniline (2a) and 2,5ꢀdimethylꢀ4ꢀ(pentꢀ3ꢀenꢀ2ꢀyl)ꢀ
aniline (3a) vs initial concentration of HCl ([1a] = 1.07 mol L–1).
VN = V5 + V6 + V7 – V4 = (k5 + k6 + k7 – k4)[A] =
= (k5 + k6 + k7)[A] – k4[A].
(11)
drances, it can be assumed that the orthoꢀisomer is formed
via the intramolecular mechanism through transition
state A due to С5Н9 group migration to the orthoꢀposition
of its own molecule via reaction (5). At stage (8) the
protonated form of the orthoꢀisomer undergoes isomerizaꢀ
tion in the reaction with the protonated form of the solꢀ
vent to form the binary ꢀcomplex, i.e., intermediate В. It
is most probable that the paraꢀisomer is formed upon the
migration of the С5Н9 substituent to the paraꢀposition of
the benzene ring of the solvent via reaction (6) (intermoꢀ
lecular mechanism). This isomer can also be formed inꢀ
tramolecularly from the orthoꢀisomer via reaction (9)
through transition state B. The inversion of the alkenyl
group should be observed in reactions (5) and (9). In fact,
it was established in a model experiment (Scheme 3) that
compounds 7—9 are the rearrangement products of 2,5ꢀdiꢀ
methylꢀNꢀ(5ꢀmethylhexꢀ3ꢀenꢀ2ꢀyl)aniline (6).
In Eq. (11) rate V4 was taken with minus, because at
stage (4) the starting Nꢀisomer is not consumed but is
formed. The concentration of complex А can be found
from the equilibrium condition of stage (3)
[A] = K3[Me2C6H3NH2+–C5H9][Me2C6H3–NH3+]. (12)
In turn, the concentrations of protonated forms of the
starting substrate and solvent are related by equilibria (1)
and (2) with the initial concentrations of the reactant,
solvent, and catalyst
[Me2C6H3—NH2+—C5H9] =
= K1[Me2C6H3—NHC5H9][H+],
(13)
[Me2C6H3—N+H3] =
= K2[Me2C6H3—NH2][H+].
The formation of the single orthoꢀisomer with inverted
alkenyl radical 7 indicates the intramolecular mechanism
of the rearrangement. On the contrary, the formation of
two paraꢀisomers 8 and 9 (with and without inversion of
the allyl radical) indicates two routes: product 8 is formed,
most likely, via reaction (6) by С5Н9 group migration (see
(14)
Equations (12) and (14) were obtained under the
assumption that the equilibrium of stages (1)—(3) is
not violated due to the consumption of the final products
of these stages in subsequent reactions. Taking into
Scheme 3

Mechanism of aminoꢀClaisen rearrangement
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 1, January, 2013
87
account Eqs (12)—(14), Eq. (11) is transformed into
the form
early on the temperature in the Arrhenius coordinates from
where the activation energies (E*) of the considered stages
were estimated.
VN = (k5 + k6 + k7)K1K2K3[Me2C6H3—NHC5H9]•
Stage
E*/kJ mol–1
•[Me2C6H3—NH2] [H+]2 – k4K1K2K3,
Consumption of 1a
Consumption of 2a
Consumption of 3a (initial stage)
116
114
80
where
[Me2C6H3NH—C5H9][Me2C6H3—NH2][H+]2
=
The paraꢀisomer is formed with a lower activation enꢀ
ergy compared to that of the orthoꢀisomer. It is most likely
that the intermolecular migration of the С5H9 allyl substiꢀ
tuent to the paraꢀposition of the solvent molecule at stage
(6) requires lower energy expenses compared to the inꢀ
tramolecular route of orthoꢀisomer formation at stage (5).
Thus, the complex study of the synthetic and kinetic
aspects of the acidꢀcatalyzed isomerization of 2,5ꢀdiꢀ
methylꢀNꢀ(pentꢀ3ꢀenꢀ2ꢀyl)aniline provides new concepts
on the mechanism of the aminoꢀClaisen rearrangement,
which includes the equilibrium stage of formation of the
binary ꢀcomplex from hydrochlorides of the starting
amine and solvent with its subsequent transformation into
the orthoꢀ and paraꢀisomers.
= const1[Me2C6H3NH—C5H9][Me2C6H3—NH2][H+]2 –
– const2[Me2C6H3—NHC5H9][Me2C6H3—NH2][H+]2. (15)
The rates of accumulation of the orthoꢀ (Vortho) and
paraꢀisomers (Vpara) with allowance for Eqs (12)—(14)
can be presented as follows:
Vortho = v5 = k5[A] = k5K1K2K3[Me2C6H3—NHC5H9]•
•[Me2C6H3—NH2][H+]2,
(16)
Vpara = v6 = k6[A]= k6k1k2k3[Me2C6H3—NHC5H9]•
•[Me2C6H3—NH2][H+]2.
(17)
According to Eqs (15)—(17), the reaction order with
respect to the catalyst is two and the partial reaction orꢀ
ders with respect to the starting substrate and solvent are
unity. The reaction rates depend on the rate constants of
the elementary steps in which the reactant is consumed
and the reaction products are formed and also depend on
the equilibrium constants of stages (1)—(3).
Equations (15)—(17) predict that the consumption
rates of the starting Nꢀisomer and the accumulation rates
of the orthoꢀ and paraꢀisomers at constant initial concenꢀ
trations of the starting substrate and solvent should inꢀ
crease nonꢀlinearly with an increase in the catalyst conꢀ
centration, which is experimentally observed (see Fig. 3).
The revealed kinetic regularities of the aminoꢀClaisen
rearrangement are retained in the whole temperature range
studied from 150 to 190 С.
References
1. I. B. Abdrakhmanov, Doct. (Chem.) Thesis, Institute of Orꢀ
ganic Chemistry, Ufa Scientific Center, Russian Academy
of Sciences, Ufa, 1989, 323 pp. (in Russian).
2. R. P. Lutz, Chem. Rev., 1984, 84, 205.
3. X. Peng, M. Dongfeng, Zh. Yunqing, Youji Hauxae [Chin. J.
Org. Chem.], 1986, 6, 226.
4. The Claisen Rearrangement: Methods and Applications, Eds
M. Hiersemann, U. Nubbemeyer, WileyꢀVCH Verlag, Weinꢀ
heim, 2007, 591 pp.
5. L. F. Tietze, Th. Eicher, Reaktionen und Synthesen im orgaꢀ
nischꢀchemischen Praktikum und Forschungslaboratorium,
Georg Thieme Verlag, Stuttgart, 1991, 649 S.
The initial rates of consumption of the Nꢀisomer and
Received November 27, 2012;
accumulation of the orthoꢀ and paraꢀisomers depend linꢀ
in revised form December 29, 2012