Insights on the mechanism for synthesis of methylenedianiline from aniline and formaldehyde through HPLC-MS and isotope tracer studies

Article abstract of DOI:10.1016/j.cclet.2012.10.001

The mechanism for synthesis of 4,4-methylenedianiline (MDA) via condensation reaction of aniline with formaldehyde has been studied extensively in this paper. The intermediate and by-products were isolated and identified. The combination of isotope labeli

Full text of DOI:10.1016/j.cclet.2012.10.001

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 1254–1258
www.elsevier.com/locate/cclet
Insights on the mechanism for synthesis of methylenedianiline from
aniline and formaldehyde through HPLC–MS and isotope tracer
studies
a
a
a
a
Chen Ye Wang a,b, Hui Quan Li a, , Li Guo Wang , Yan Cao , Hai Tao Liu , Yi Zhang
*
a Key Laboratory of Green Process and Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China
b Graduate School of Chinese Academy of Sciences, Beijing 100049, China
Received 29 May 2012
Available online 24 October 2012
Abstract
The mechanism for synthesis of 4,4-methylenedianiline (MDA) via condensation reaction of aniline with formaldehyde has
been studied extensively in this paper. The intermediate and by-products were isolated and identified. The combination of isotope
labeling and HPLC–MS characterizations disclosed that the reaction proceeded through an SN2 reaction mechanism. Moreover, the
effect of aniline/formaldehyde molar ratio on the formation of MDA was investigated. This work would be of significance to
understand the reaction mechanism deeply and provide valuable information for further improving the yield of desired product.
# 2012 Hui Quan Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 4,4-Methylenedianiline; Condensation reaction; Mechanism; HPLC–MS; Isotopic tracer
Methylenedianiline (MDA) has been widely used as starting material for the production of 4,4-methylene
diphenylene diisocyanate (MDI), which is an important precursor for the manufacture of polyurethanes. A variety of
methods have been reported for the synthesis of MDA [1–3]. Ongoing efforts were devoted to developing new
catalysts [4–6] or optimizing reaction conditions [7,8]. Industrially, MDA is obtained from the reaction of aniline with
formaldehyde in the presence of liquid acid catalysts. Nevertheless, few reports have dealt with the research on the
formation process of the intermediate and by-products. Therefore, it is necessary to use appropriate characterization
methods, thus giving insights on the mechanism for the MDA synthesis.
In this work, MDA was synthesized by the condensation reaction of aniline and formaldehyde in the presence of
HCl. The intermediate and major by-products were isolated and characterized, and DCl was used as a probe to study
the deuterium distribution in products. Using high performance liquid chromatography–electrospray tandem mass
spectrometry (HPLC–MS) analysis, the structures of products can be confirmed, and the related mechanism of MDA
synthesis from aniline and formaldehyde via multistep reactions is discussed. Additionally, the effect of aniline/
formaldehyde molar ratio on the formation MDA was also studied.
It should be mentioned that Kishore [9] proposed the condensation process consisting of a series of rearrangement
reactions in previous literature as shown in Scheme 1. Firstly, aniline first reacts with formaldehyde to provide
* Corresponding author.
E-mail address: hqli@home.ipe.ac.cn (H.Q. Li).
1001-8417/$ – see front matter # 2012 Hui Quan Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.10.001

C.Y. Wang et al. / Chinese Chemical Letters 23 (2012) 1254–1258
1255
H
H
N
H+
N
H2N
NH2
2 1
2 1A/F
acidic
A/F
neutral
neutral
aniline and formaldehyde
1 1
A/F
1 1A/F
acidic
=
]
H+
N
N
HN
H2C
CH2
NH
n
N
Scheme 1. Mechanism of HCl-catalyzed alternating condensation of aniline and formaldehyde.
N,N-methylene diphenylamine (aminal). Subsequently, the aminal formed reacts with HCl and produces MDA.
Finally, MDA would be partially converted to oligomers with functionalities of 3 and 4 (tri-MDA and tetra-MDA) in
the presence of acid catalyst.
The intermediate and by-products of tri-MDA and tetra-MDA formed during the reaction were labeled as 1, 2 and
3, respectively. Their configurations were first sketched by excluding other imagination structures based on the
molecular weights measured by MS1, as shown in Table 1.
Table 1
The molecular weights and structures of 1, 2 and 3.
Compounds
m/z (M+1)+
Molecule weights
198.12
Possible structures
Actual structures
1
199.12
1a
H
N
H
N
1a
2
304.18
303.18
2b
HN
HN
H2N
H2N
2a
NH2
NH2
2b
3
409.30
408.30
3b
NH2
H
N
H
N
H
N
3a
H N
2
NH
NH
NH
2
2
2
3b

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C.Y. Wang et al. / Chinese Chemical Letters 23 (2012) 1254–1258
NH2
H2N
H2N
NH2
NH2
NH2
+
H2N
NH2
NH2
NH2
NH2
H2N
NH2
NH2
+
Scheme 2. Proposed cleavage pathways of tri-MDA and tetra-MDA by HPLC–MS.
The intermediate 1 could be confirmed by this method. However, it is not enough to confirm the by-products 2 and 3
due to the existing of isomers. The fragments in the MS2 were therefore used for this purpose.
The proposed pathways of tri-MDA and tetra-MDA were analyzed by HPLC–MS and shown in Scheme 2. The
formation of the fragment ion at m/z 211.16 was ascribed to the structure of 2b, because 2a could not generate a free
radical with such m/z value. Thus, by-product 2 was testified to be 2b. Similarly, by-product 3 was testified as 3b due to
the formation of the fragment ion at m/z 316.26, which is impossibly produced from 3a.
Based on the structures of products confirmed, the mechanism on the formation of MDA, as well as intermediate
and by-products could be represented in Scheme 3. The reaction might occur through the nucleophilic addition of
adjacent phenyl groups to the cationic carbon atom of formaldehyde. This is the fastest step in this reaction, and can be
occurred at room temperature without any acid catalyst. As it is well accepted that free carbonium ions are difficult to
stabilize, it suggests that the substrate undergoes an SN2 type nucleophilic substitution reaction. When the
O
H
NH
NH
NH2
NH
OH
+
H
H
H
NH2
H+
H+
H2N
+
NH
NH
NH2 NH
+
NH
N
H2
NH2
H2N
H2N
NH
NH2
+
NH
NH
+ H+
a)
H2
H
N
N
-H -aniline
N
H
NH2
H2N
NH2
H2N
NH2
H2N
NH2
H2
H
N
N
H
N
-H -aniline
NH2
NH2
NH2
H2N
H2N
NH2
NH2
H2N
NH2
NH2
H+
+
H2N
NH
NH
H2N
NH2
NH
b)
+
H+
NH2
NH
H2 N
NH 2
H2N
NH2
H2N
NH2
NH2
Scheme 3. Possible mechanism of HCl-catalyzed condensation of aniline and formaldehyde. (a) Proposed mechanism for chain reaction. (b) Further
transformation of MDA to downstream derivates might occur under appropriate conditions.

C.Y. Wang et al. / Chinese Chemical Letters 23 (2012) 1254–1258
1257
DHN
NHD
NH 2
O
NH2
+
H
H+
DCl
DHN
DHN
NHD
NHD
2
1
NH2
NH2
3
Scheme 4. Expected deuterium enrichment in the reaction of aniline, formaldehyde and DCl.
intermediate is interacted with a Brønsted acid site of the catalyst, the positive partial charge on the C-atom between
two benzene rings makes it susceptible to a nucleophilic attack by the free electron pair of the amino function or the
phenyl ring of aniline.
The protonation of the secondary amine function is readily achieved by acid catalysis as revealed in Scheme 3(a).
This reaction mechanism also provides an explanation for the formation of tri-MDA and tetra-MDA. Tri-MDA and
tetra-MDA are stable end products of this reaction, and they are both the products of the nucleophilic attack between
MDA or tri-MDAwith aminal molecule. A similar mechanism has been suggested by theoretical speculation as shown
in Scheme 3(b).
If the nucleophilic attack occurred on the nitrogen of MDA instead of phenyl ring, MDA-aminal would be formed.
Because it contains a methylene bridged biphenyl unit like MDA as well as the secondary amine, it was labeled as
MDA-aminal. The molecule is still reactive and can be further converted to tri-MDA due to this secondary amino
function.
The desired product of MDA and by-products of tri-MDA and tetra-MDA formed by the reaction were indentified
by HPLC–MS. By ion selective mass spectra calibration, the mass peaks at m/z 200, 305 and 410 could be assigned to
MDA, tri-MDA and tetra-MDA based on the analysis of corresponding molecular mass, respectively. The results
indicated that the distribution of deuterium was the same as the structures in Scheme 4. With respect to the analysis for
the reaction, it can be concluded that the mechanism of aniline and formaldehyde complied via the pathway of
Scheme 3(a).
In this reaction, aniline serves as reactant and solvent. Fig. 1 revealed the dependence of MDA yield on aniline/
formaldehyde molar ratio. When aniline/formaldehyde was lower than 2, aminal was easily formed via the reaction of
aniline and formaldehyde due to the higher concentration of formaldehyde. According to the mechanism discussed
above, tri-MDA and tetra-MDA of polycondensation reactions are easily formed when the aminal concentration is
high. The concentration of formaldehyde in the reaction system became lower with the increase of aniline/
formaldehyde molar ratio, resulting in too low concentration of condensation reagent to conduct further
polymerization. The molar ratio of aniline/formaldehyde at 3 is suitable for obtaining higher MDA yield.
The formation of intermediate and by-products in the condensation reaction of aniline with formaldehyde over HCl
catalyst was studied in this work. When DCl was used as probe, there was H/D exchange during the production of
MDA and its by-products. HPLC–MS was used to character the distribution of D. Importantly, based on these results,
100
80
60
MDA
tri-MDA
tetra-MDA
40
20
0
0
1
2
3
4
5
6
7
8
9
Molar ratio of aniline/formaldehyde
Fig. 1. The effect of molar ratio of aniline/formaldehyde on the formation of MDA and by-products (T = 100 8C, t = 90 min, HCl/aniline = 1.5).

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C.Y. Wang et al. / Chinese Chemical Letters 23 (2012) 1254–1258
the condensation reaction is proposed to be occurred through SN2 reaction mechanism. The results revealed that the
amount of aminal can evidently influence the formation of tri-MDA and tetra-MDA. The experimental results also
precisely illustrated this point.
Acknowledgment
This work was supported by the Knowledge Innovation Program of the Chinese Academy of Sciences
(No. KGCX2-YW-215).
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