Application of lanthanoid catalysts for the synthesis of Michler's hydride

Article abstract of DOI:10.2174/157017809787892993

A series of lanthanoid (Ln³⁺) based Lewis acid catalysts were investigated as alternatives to other metal based catalysts for the formation of Michler's hydride, 4, 4′-methylenebis(N, N-dimethylaniline) (1). The lanthanoid based Lewis acid cata

Full text of DOI:10.2174/157017809787892993

Letters in Organic Chemistry, 2009, 6, 229-233
229
Application of Lanthanoid Catalysts for the Synthesis of Michler's
Hydride
Philip C. Andrews, Peter C. Junk, K. Peter Kemppinen, Kristina Konstas and Kellie L. Tuck*
Centre for Green Chemistry and the School of Chemistry, Monash University, Clayton 3800, Australia
Received November 12, 2008: Revised January 29, 2009: Accepted January 29, 2009
Abstract: A series of lanthanoid (Ln3+) based Lewis acid catalysts were investigated as alternatives to other metal based
catalysts for the formation of Michler's hydride, 4,4'-methylenebis(N,N-dimethylaniline) (1). The lanthanoid based Lewis
acid catalysts were superior to previously published catalysts resulting in formation of 4,4'-methylenebis(N,N-
dimethylaniline) (1) and N,N-dimethyl-4-(4-(methylamino)benzyl)aniline (2). If paraformaldehyde was added to the reac-
tion only 4,4'-methylenebis(N,N-dimethylaniline) (1) was formed.
Keywords: Lanthanoids, Lewis acids, catalysis, radicals, oxidation.
INTRODUCTION
process is the formation of Michler's hydride, 4,4'-
methylenebis(N,N-dimethylaniline) (1), an important inter-
mediate in the preparation of di- and triaryl dyes, e.g. mala-
chite green lactone and crystal violet [5,6]. It is most com-
monly synthesised in low yield by the acid catalysed con-
densation reaction of N,N-dimethylaniline with formalde-
hyde or paraformaldehyde (Scheme 1) [7].
Lewis acid catalysed reactions constitute one of the most
common procedures in organic chemistry, allowing a pleth-
ora of functional group transformations and C-C bond for-
mation. In this respect, inorganic and metal-organic salts
play a fundamental role. However, there can be significant
drawbacks associated with both the metal based compounds
and the reaction protocols [1]. Often the Lewis acid contains
a toxic metal (eg Sn, Hg) or is highly corrosive (eg BF3,
AlCl3). An anhydrous and oxygen free environment is often
The oxidation of N,N-dimethylaniline to 4,4'-methyl-
enebis(N,N-dimethylaniline) (1), in the absence of formalde-
hyde has been previously observed with a variety of transi-
Me
Me
N
Me
N
Me
N
O
H+ (cat)
Me
Me
+
H
H
1
Scheme 1. Classical acid promoted synthesis of Michler's hydride.
required and volatile organic solvents are predominantly
used for the reaction medium and for extraction. Recent pro-
gress therefore in the development and application of Lewis
acids which are highly active but tolerant of aqueous, protic
and aerobic conditions are timely, particularly in light of the
need to develop more sustainable methods [2]. Foremost
amongst these new catalysts are those based on lanthanoid
metals, since they are Lewis acidic while having low toxic-
ity. These have proved successful in promoting a wide vari-
ety of important organic transformations often displaying
unexpected selectivity and reactivity [3,4].
tion metal catalysts; CuCl2 [8], CuCl [9], Os3(CO)12 [10],
FeCl3 [11,12] and CoCl2 [9,13], in either acetonitrile [9,11-
13], methanol [8], or neat [10]. Natural kaolinite in aqueous
media has also been reported to be an effective catalyst for
this reaction [14].
In assessing the applicability of lanthanoid based Lewis
acid catalysts to this reaction, we now report their superiority
over current metal based catalysts in the formation of 1 from
N,N-dimethylaniline in air and without the need for the use
of formaldehyde (Scheme 2) [15]. Though higher yields are
obtained the synthesis of 1 is still accompanied by a mixture
of by-products, including N-(4-dimethyl-aminobenzyl)-N-
methylaniline 2 and N-methylaniline 3.
The success of lanthanoid salts in promoting Friedel-
Crafts type reactions has prompted us to consider their pos-
sible application and efficacy in aniline condensation reac-
tions. One particularly difficult and challenging industrial
RESULTS AND DISCUSSION
Purification of the reaction mixture by column chromato-
graphy (silica gel) conclusively identified the condensed
products. The major product, 4,4'-methylenebis(N,N-
*Address correspondence to this author at the School of Chemistry, Monash
University, Clayton 3800, Australia; Tel: +61 3 99054510; Fax: +61 3
99054597; E-mail: kellie.tuck@sci.monash.edu.au
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

230 Letters in Organic Chemistry, 2009, Vol. 6, No. 3
Andrews et al.
Me
Me
N
MeOH/O2
60 oC
LnCl3
(10% mmol)
+
Me
N
Me
N
Me
N
Me
H
N
Me
Me
Me
N
Me
1
2
3
Scheme 2. The preparation of 4,4'-methylenebis(N,N-dimethylaniline) (1), N,N-dimethyl-4-(4-(methylamino)benzyl)aniline (2) and N-
methylaniline (3).
Me
N
Me
N
Me
N
Me
N
NaBH4
MeOH
Me
Me
Me
Me
Cl
4
1
Scheme 3. Reduction of (4-N,N-dimethylaminophenyl)methenium chloride (4) with sodium borohydride to give 4,4'-methylenebis(N,N-
dimethylaniline) (1).
dimethylaniline) 1, was confirmed by 1H and 13C NMR spec-
troscopy and X-ray crystallography unit cell comparison
[16]. The minor product, N-(4-dimethylaminobenzyl)-N-
ligand. Previous reports of iron(III) chloride and iron(III)
complexes as catalysts, in the absence of formaldehyde, gave
yields of 6.5% of 1, 3.5% of 3 and 76% recovered starting
material [10,11]. For experimental comparison the FeCl3
reaction was repeated, giving yields comparable to that of
the lanthanoid chlorides, with very few byproducts observed
(entry 15). Copper(II) chloride had the opposite effect, giv-
ing a very low yield of the condensed products and large
quantities of the byproducts (entry 16). This is in agreement
with previous results which also used methanol [7], the
products were formed in low yields and a large proportion of
the byproducts were methyl crystal violet and crystal violet
with low yields of 1 and 2.
1
methylaniline 2, was also identified by H and 13C NMR
spectroscopy [17]. The byproduct N-methylaniline 3 was
1
identified by H NMR spectroscopic comparison with an
authentic sample. A deep-blue to purple coloured solution
is observed in most LnCl3 cases due to the formation of the
dye bis-(4-N,N-dimethylaminophenyl)methenium chloride 4,
(<2%) which was reduced with sodium borohydride to give
1 (Scheme 3) [18].
A comparison of Ln3+ with previously known Lewis acids
including triflates (OTf), FeCl3 and FeCl2 is reported in
(Table 1)†. The lanthanoid chlorides (entries 1-11) had simi-
lar levels of activity resulting in similar yields of the coupled
products 1 and 2 and in all cases 1 and 2 were formed in the
ratio of ~3:2. Interestingly, mischmetal chloride (entry 11),
which contains a mixture of lanthanoids, gave comparable
results to that of the pure lanthanoid chlorides. The lantha-
noid complexes (entries 12-14) gave poorer results than the
chlorides. It was expected that ytterbium triflate would give
a higher yield of products than the chlorides as lanthanoid
triflate complexes are usually much stronger Lewis acids due
to the greater electron withdrawing nature of the triflate
The effect of catalyst loading and solvent on the yield
and ratio of the coupled products (1 and 2) were investigated
using the most effective Lewis acid. The catalytic activity
initially increased almost linearly until 5 mol% after which it
plateaued (Fig. 1). As such, 5 mol% is considered to be the
best compromise between catalyst loading and activity. The
effects of a range of polar and non-polar solvents were ex-
amined (Table 2). The catalyst was insoluble in the majority
of the solvents examined and only dissolved in water,
methanol, ethanol and acetic acid. Methanol, ethanol and
acetic acid were the highest conversion solvents, whilst wa-
ter did not support the transformation at all. Even though
N,N-dimethylaniline is a liquid, the solvent free reaction
gave minimal product which is likely due to the catalyst in-
solubility. Consequently, a polar organic solvent, preferably
methanol, is required for the formation of the coupled prod-
ucts 1 and 2. From an environmental perspective, simple
alcohols (MeOH, EtOH) are preferred green solvents,
whereas acetonitrile, acetic acid or THF are not recom-
mended [19].
†To N,N-dimethylaniline (1.21 g, 0.01 mol) in methanol (20 mL) was added catalyst (5
mol %). The reaction mixture was heated to 60 ºC in air to give a deep blue to purple
coloured solution. After 24 h the solvent was removed under reduced pressure and 2M
NaOH(aq) (20 mL) was added. The mixture was extracted with Et2O (3 x 50 mL) and
the combined extracts evaporated under reduced pressure. The combined organic
extracts were not dried as the product reacted with drying agents (MgSO4 and Na2SO4)
to produce highly coloured purple compounds. If required column chromatography
(silica gel) with gradient conditions (hexane/ethyl acetate - ethyl acetate - ethyl ace-
tate/methanol) could be used to separate reaction products. Compound 1 can also be
purified by recrystallisation from methanol. If required, the catalyst can be recovered
from the aqueous layer.

Lanthanoid Catalysts for the Synthesis of Michler's Hydride
Letters in Organic Chemistry, 2009, Vol. 6, No. 3
231
Table 1. Effect of Catalyst on the Reactiona
Entry
Catalyst
1 + 2b (%)
Recovered Anilinesc (%)
By Products (%)
1
2
YCl3
LaCl3
CeCl3
NdCl3
SmCl3
EuCl3
GdCl3
TbCl3
HoCl3
ErCl3
44
20
23
31
29
29
26
30
32
27
30
8
42
65
47
57
59
59
61
48
59
61
56
56
82
53
75
51
8
6
3
8
4
6
5
8
6
8
7
10
7
8
9
8
10
11
12
13
14
15
16
6
MmCl3
6
[d]
La(CSA)3
Ce(SO4)2
0
17
19
20
9
0
[d]
Yb(OTf)3
FeCl3
2
0
CuCl2
26
aReaction conditions: 5 mol% of catalyst, MeOH, 60 °C, 24 h, yields based on 1H NMR analysis. b3:2 ratio of 4,4'-methylenebis(N,N-dimethylaniline) 1 and N,N-dimethyl-4-(4-
(methylamino)benzyl)aniline 2. cMixture of N,N-dimethylaniline and 3. dCSA = camphorsulfonic acid, OTf = trifluoromethanesulfonic acid, Mm = mischmetal.
~3:2 and a range of by-products were observed (in some
cases up to 16%, entry 5).
Blank reactions involving the aniline in methanol at 60
°C in air, gave no detectable amount of product confirming
that, in the absence of the catalyst, no reaction takes place.
Reports in the literature suggest that Lewis acid catalysed
oxidation reactions of N,N-dimethylaniline proceed via one-
electron oxidation or hydrogen abstraction of a methylene
proton give an amino radical [11]. To understand if lantha-
noid Lewis acids proceed through a similar reaction mecha-
nism, reactions involving the exclusion of air (degassed and
dried reagents) gave no reaction after heating to reflux for 12
h. In addition, a radical inhibitor BHT (2,6-di-tert-butyl-4-
methylphenol) was added to the reaction mixture performed
in air which suppressed the complete oxidation of N,N-
dimethylaniline. This result suggests that the oxidation of
Fig. (1). Reaction profile with different catalyst loadings.
N,N-dimethylaniline‡ using LnCl3 proceeds via an initial
In an effort to understand this oxidation reaction, N,N-
dimethylaniline was treated with a catalytic amount (5
mol%) of yttrium chloride under a range of reaction condi-
tions (Table 3). Under an atmosphere of either nitrogen or
carbon dioxide (entries 1 and 2) the reaction did not proceed
and only starting material was recovered. Reactions per-
formed in air solely gave products 1, 2 and unreacted aniline
(entries 3-6).
one-electron oxidation to give an aminium cation radical 5
(path a, Scheme 4), which may then undergo a hydrogen
abstraction (path b) to give the radical 6 followed by a fur-
ther one-electron oxidation to give an iminium cation 7 (path
c). Cation 7 can than undergo electrophilic aromatic substitu-
tion (EAS) to generate compound 2, which reacts further to
generate compound 3 and the benzylic cation 8. This subse-
quently reacts with another aniline molecule to yield 1§.
The overall yield of products did not significantly in-
crease with longer heating (entry 4) and this was postulated
to be due to the deactivation of the catalyst. Addition of a
further 5 mol% of the catalyst after 8 h (entry 5) increased
the overall yield of 1 and 2. This yield was also superior to
that obtained by the direct addition of 10 mol% of catalyst
(entry 6). In all cases 1 and 2 were formed in the ratio of
‡2,6-Di-tert-butyl-4-methylphenol (0.54 g, 2.47 mmol) and N,N-dimethylaniline (0.301
g, 2.47 mmol) were combined in methanol (20 mL) and YCl3 (10 mol%) was added.
The reaction mixture was heated to 60 ºC in air for 16 h. The solvent was removed
under reduced pressure and 2M NaOH(aq) (10 mL) was added. The mixture was ex-
tracted with Et2O (3 x 10 mL) and the combined fractions evaporated under reduced
pressure. The 1H NMR spectrum of the crude reaction mixture showed only starting
material.
§Small traces formaldehyde were found in the HNMR spectrum. However, the major
product is formed by the mechanism proposed in Scheme 4.
1

232 Letters in Organic Chemistry, 2009, Vol. 6, No. 3
Andrews et al.
Table 2. Effect of Solvent on the Reactiona
Entry
Solvent
1 + 2 (%)
Recovered anilinesb (%)
1
2
Water
Methanol
Ethanol
0
34
15
4
96
46
69
82
84
84
90
79
94
89
84
93
3
4
THF
5
Acetonitrile
Ethyl Acetate
Toluene
6
6
1
7
1
8
Acetic acid
Acetone
10
1
9
10
11
12
Chloroform
Solvent free
Nitromethane
2
2
3
aReaction conditions: 5 mol% YCl3, 60 °C, 24 h, yields based on 1H NMR analysis. bMixture of N,N-dimethylaniline and 3.
Table 3. Effect of Reaction Conditions on the Reaction and the Addition of Formaldehydea
Entry
Reaction Atmosphere
YCl3 Mol%
1 + 2 (%)
Recovered anilinesb (%)
1
N2
5
0
0
100
2
CO2
5
100
3
Air
5
34
46
4
Air
Air
5[c]
44
31
5
5+5[d]
50
28
6
Air
10
39
36
Entry
Formaldehyde
Formaldehyde (aq. 37% sol.)
p-Formaldehyde
YCl3 Mol%
1e (%)
Recovered anilinesb (%)
7
5
52
2
8
5
58
25
aReaction conditions: YCl3, MeOH, 60 °C, 24 h unless otherwise stated, yields based on 1H NMR analysis. bMixture of N,N-dimethylaniline and 3. c120 h. d5 mol% of catalyst fol-
lowed by an additional 5 mol% after 8 h. eYield after recrystallisation.
Me
Me
Me
Me
Me
CH2
Me
CH2
N
N
N
N
Path b
-H+
Path c
-e-
Path a
-e-
5
7
6
EAS
aniline
Me
Me
Me
H
Me
N
N
N
Me
1
+
N
Me
8
3
2
CH2
Scheme 4. Proposed formation of products via radical pathway.

Lanthanoid Catalysts for the Synthesis of Michler's Hydride
Letters in Organic Chemistry, 2009, Vol. 6, No. 3
233
[6]
[7]
Venkataraman, K. The Chemistry of Synthetic Dyes, Academic
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Identified by-products include N-methylaniline, crystal violet,
methyl crystal violet, bis(4-N,N-dimethylaminophenyl)methenium
chloride (dye).
The addition of an equivalence of formaldehyde or para
formaldehyde to the reaction mixture in methanol increases
the yield of 1 to 52 and 58% respectively (Table 3, entry 7
and 8). Under these conditions formaldehyde condenses with
N,N-dimethylaniline to form the benzylcarbonium ion which
reacts with another equivalent of N,N-dimethylaniline to give
1 [7]. This reaction gives small quantities of compound 4
which is removed upon recrystallisation from methanol.
[8]
[9]
[10]
In conclusion we have found an interesting lanthanoid
chloride induced oxidation of N,N-dimethylaniline in the
presence of oxygen, without the addition of toxic formalde-
hyde. This transformation is superior to those previously
published with the catalysts Os3(CO)12, FeCl3 and CoCl2, as
it does not require toxic reagents and uses methanol, an envi-
ronmentally preferred solvent [19]. It also gives superior
yields to that observed for CuCl2 catalysed reaction.
[11]
[12]
[13]
[14]
[15]
[16]
Values were within 1.5% of the literature X-ray unit cell values;
found a = 6.350 Å, b = 6.350 Å, c = 35.790 Å, ꢀ = ꢁ = ꢂ = 90°, V =
1443.1 Å3 T = 123 K, literature: a = 6.350 Å, b = 6.350 Å, c =
36.647 Å, ꢀ = ꢁ = ꢂ = 90°, V = 1477.7 Å3 T = 293 K; Nakai, H.;
Saito, T.; Yamakawa, M. Acta Cryst. Sec. C, 1988, 44, 2117.
ACKNOWLEDGEMENTS
We wish to thank the ARC and the ARC Centre of Green
Chemistry for their support. We would also like to thank Dr
Jonathan MacLellan for the X-ray crystallography unit cell
analysis.
[17]
1H NMR (400 MHz, CDCl3) ꢀ 2..82 (s, 3H, CH3), 2.90 (s, 6H,
CH3), 3.79 (s, 2H, CH2), 6.55-7.33 (m, 9H, ArH); 13C NMR (75
MHz, CDCl3) ꢀ 30.9, 39.9, 40.7, 112.5, 113.0, 129.5, 129.8, 130.3,
148.8, 149.0.
[18]
[19]
Lai, Y.-Y.; Lin, N.-T.; Wang, Y.; Luh, T.-Y. Tetrahedron, 2007,
63, 6051.
Capello, C.; Fisher, U.; Hungerbühler, K. Green Chem., 2007, 9,
927.
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