On the formation of imines in water-a comparison

Article abstract of DOI:10.1016/j.tetlet.2009.05.117

The reaction of aniline with aryl aldehydes in water has been investigated in the past, but contradictory results have been published. While only small amounts of imines 3 were detected by NMR analysis, isolation afforded high imine yields. A reinvestigat

Full text of DOI:10.1016/j.tetlet.2009.05.117

Tetrahedron Letters 50 (2009) 4663–4665
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On the formation of imines in water—a comparison
*
Vittorio Saggiomo, Ulrich Lüning
Otto-Diels-Institut für Organische Chemie, Christian-Albrechts-Universität zu Kiel, Olshausenstr. 40, D-24098 Kiel, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of aniline with aryl aldehydes in water has been investigated in the past, but contradictory
results have been published. While only small amounts of imines 3 were detected by NMR analysis, iso-
lation afforded high imine yields. A reinvestigation of the reaction of benzaldehyde (1a) and salicylalde-
hyde (1b) with aniline (2) revealed two important factors which explain the putative contradiction: (i)
NMR only reveals the fraction of products which is soluble in water, and (ii) imines 3 form during or after
workup.
Received 13 March 2009
Accepted 29 May 2009
Available online 6 June 2009
Keywords:
Imines
Solvent-free reactions
Schiff bases
Water
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
amounts of imines can be detected in water. Among many other
substrates, they investigated the reaction of benzaldehyde (1a) or
The reaction of primary amines with carbonyl compounds to
give imines—also called Schiff bases or azomethines—is a reaction
which is well known.1 In nature it serves to interconvert amino
salicylaldehyde (1b) with aniline (2) (Fig. 1).
In contrast to these results, Tashiro and co-workers8 reported
excellent yields of imines 3 when they reacted aldehyde 1a or 1b
with aniline (2) in water—a remarkable putative contradiction.
Due to the high relevance for DCC, we reproduced these experi-
ments in our laboratory to understand this discrepancy (see Table
1).
acids and
a-ketoacids into one another with the help of vitamin
B6 (pyridoxamine–pyridoxal as coenzyme in transaminases2), but
it has also been widely used in organic chemistry for numerous
purposes since the 1800s. Due to its reversibility, the formation
of imines has gained increasing interest in recent years as it is
one of the reactions widely used in dynamic combinatorial chem-
istry.3 When an imine is formed from an aldehyde and a primary
amine, one molecule of water is liberated per molecule of imine.
Consequently, the formation of imines is facilitated when water
is removed from the reaction mixture. In many experimental pro-
cedures, water-removing techniques or reagents are employed.4
The synthetic chemist therefore hesitates to have water present
when he tries to synthesize an imine, although water would be
the environmentally most benign solvent.5
First, the NMR experiment of Lehn’s group (A1)7 was repeated
in our laboratory. The literature experiment was carried out using
a molar ratio of aldehyde 1a to amine 2 of 1:3. A 16.5 mM solution
of aldehyde 1a in D2O at pD 7.5 gave 5.4% of imine 3a. This yield
had been determined by simply integrating the signals for alde-
hyde 1a and imine 3a in D2O.
When repeating this experiment, we did not use a buffer to
allow for a comparison to the Tashiro experiments.8 With a molar
2. Results and discussion
R
NH2
In dynamic combinatorial chemistry (DCC), water which is pro-
duced by an imine formation will stay in the reaction mixture, and
the question arises to which extent water can be tolerated. Litera-
ture studies reveal surprising answers. While we discovered that in
a specific dynamic combinatorial library, water can even be used as
the solvent,6 other researchers have found less promising results. A
recent study of Lehn and co-workers7 shows that only small
- H2O
+ H2O
+
N
R
CHO
2
1a R = H
1b R = OH
3a R = H
3b R = OH
* Corresponding author. Fax: +49 431 880 1558.
E-mail address: luening@oc.uni-kiel.de (U. Lüning).
Figure 1. The reaction of aldehydes 1 with an amine such as aniline (2) to give
imines 3 is a reversible process.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.117

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V. Saggiomo, U. Lüning / Tetrahedron Letters 50 (2009) 4663–4665
Table 1
Reaction conditions, analysis conditions, and product ratios for the imine formation between aldehydes 1a–b and aniline (2)
Experiment
Aldehyde
Reaction condition
Analysis
Ratio 1:3
A1
A2
A3
B1
B2
B3
1a
1a
1a
1b
1b
1b
D2O
H2O
NMR
96:4
5:95
5:95
88:12
3:97a
3:97b
NMR after workup and vacuum
NMR
NMR
NMR after workup and vacuum
NMR
No solvent, vacuum
D2O
H2O
No solvent, vacuum
a
Yield after recrystallization: 85%.
Yield after recrystallization: 83%.
b
ratio of aldehyde 1a to amine 2 of 1:1 at 10 mM for each starting
material in D2O, it became obvious that both starting materials
which are liquids were not soluble in deuterated water, and the
resulting mixture was non-homogeneous. Also pure aldehyde 1a
and pure amine 2 form two layers with water, showing that the
solubility of these compounds is low in water. Neither heating of
the NMR tube nor application of ultrasound resulted in the forma-
tion of a single layer. Either the solution remained biphasic or it be-
came emulsion like. When a 1H NMR was recorded, it resulted in
the same ratio of imine 3a to aldehyde 1a as reported by Lehn.7
It must be noted that when analyzing the water layer alone by
recording its NMR spectrum, only a small amount of the starting
material was analyzed. The major part of the material is in the
other layer and the NMR does not analyze it. The experiment
was repeated with 3 equiv of aniline (2) without any improvement
of the solubility or the percentage of imine 3a dissolved in water.
When calcium chloride (CaCl2) or hydrochloric acid (HCl) was
added to the emulsion, everything dissolved completely and the
solution finally was clear. However the Lewis acid and the
Brønsted acid simply solubilized aldehyde 1a and amine 2 but their
addition had no effect on the formation of imine 3a, whose concen-
tration remained low. No imine could be detected when HCl was
used, and when CaCl2 was used the amount of imine 3a was less
than 5%.
A second imine-forming experiment has also been investigated
in both references in water:7,8 the reaction between salicylalde-
hyde (1b) and aniline (2). Also in this case, the yields reported
for the formation of imine 3b in water are completely different.
In the NMR experiment of Lehn et al.,7 the reported yield of imine
3b was only 14% while in the experiment of Tashiro et al.,8 the
same imine 3b was obtained in 87% yield. Suspecting the same ef-
fects during the reaction and workup as in experiments A1–A3 [1a
with aniline (2)], this reaction was also carried out in the three dif-
ferent ways as described above.
NMR experiment B1 was carried out under the same conditions
as experiment A1, and it did not show drastic changes in the ratio
of final imine 3b to aldehyde 1b compared to the ratio reported by
Lehn.7 Although salicylaldehyde (1b) is a little bit more soluble in
water than benzaldehyde (1a), the solution once more was bipha-
sic, and, as in experiment A1, neither heating nor sonication im-
proved the solubility of the starting materials. Experiment B2
was repeated in the same way as experiment A2 was carried out.
In this particular case, after workup, when the crude oil was sub-
jected to vacuum, only a small amount of solid appeared. But after
12 h in vacuo, the product was almost completely solid. Recrystal-
lization from n-hexane gave pure imine 3b as yellow needles in
85% yield.
In the last experiment (B3),10 salicylaldehyde (1b) and aniline
(2) were simply mixed together in a ratio of 1:1, and then the reac-
tion was evacuated for 12 h. The result was the same as in exper-
iment B2. After recrystallization from n-hexane, 83% of the final
imine 3b was recovered. Thus this experiment also shows that
water as a solvent does not play any role during the formation of
the imine. The liquid aldehyde and the liquid amine react with
each other to give the respective imine 3b in the absence of
solvent.
In contrast, Tashiro and co-workers were able to isolate imines
3 in good yields. The authors used a 0.6 M solution of aldehyde 1a
and amine 2. The starting materials 1a and 2 were stirred in water
vigorously for 3 h. Then, the products were extracted with dichlo-
romethane, dried, and analyzed by NMR. The yield of imine 3a was
found to be 97%.8
When this reaction was repeated (A2), again the low solubility
of the starting materials in water could be observed. Vigorous stir-
ring only provoked the reaction mixture to become emulsion like.
Analogous to the reference, the reaction was stopped after 3 h, and
the reaction mixture was extracted with dichloromethane, dried
over MgSO4, and the solvent was evaporated in vacuo. In order to
record the NMR and to remove the remaining solvent traces, the
vessel containing the oily product was evacuated using an oil
pump. A few seconds after the vacuum was established, the oily
product solidified and heat was developed. This was the first clue
that the imine-forming reaction takes place when the two starting
components are in concentrated contact with each other after the
workup. Water does not play any role in the reaction as the starting
aldehyde 1a and amine 2 as well as the final product are only
slightly soluble in water. Then after the workup, when the two re-
agents are concentrated, they react. The oil pump vacuum simply
helps in the formation of imine 3a by removing the water formed
in the imine condensation.
3. Conclusion
The scope of this work was to elucidate the contradictory re-
sults presented in two different and recent papers. Both papers
contain reproducible experiments and their goal is not focused
on the synthesis of a single imine but on (a) a general imine syn-
thesis in the presence of water8 and (b) the relationship between
the structure and stability of imine formation in aqueous solution.7
However, when the same starting materials were used (1a, 1b, and
2), drastically varying yields were found for the respective imines
3a and 3b.
The putative contradiction in the two sets of experiments lies in
the fact that the reaction only presumably takes place in water and
that the ‘water results’ are compared. But on the contrary, the reac-
tion takes place best in the absence of solvent.
To prove the latter hypothesis, aldehyde 1a and amine 2 were
mixed without any solvent in experiment A3.9 After a few seconds,
a solid formed and the reaction was exothermic. The crude product
was kept in vacuo for 10 min. Subsequent NMR analysis afforded
the same yield as experiment A2 (95%).
The solubilities of the starting materials, and those of the final
products, play an extremely important role in the dynamical com-
binatorial chemistry. Even if the starting building blocks are well
soluble in water but the final product is not, this can drive a reac-
tion to the latter product, into a thermodynamic trap. In order to

V. Saggiomo, U. Lüning / Tetrahedron Letters 50 (2009) 4663–4665
4665
Cousins, G. R. L.; Sanders, J. K. M.; Stoddart, J. F.. Angew. Chem. 2002, 114, 938–
993; . Angew. Chem., Int. Ed. 2002, 41, 898–952; (d) Storm, O.; Lüning, U. Chem.
Eur. J. 2002, 8, 793–798.
have a good and reproducible distribution of products in a library,
all the components should be soluble and, by this, be free to inter-
act with one another.
4. (a) Carey, F. C.; Sundberg, R. J. Advanced Organic Chemistry, 4th ed.; Springer:
New York, 2006. p. 460; (b) Gattermann, L. Die Praxis des organischen Chemiker
(Gattermann; Wieland), neu bearb. von Wieland, T.; Sucrow, W. de Gruyter, 43.
Aufl., Berlin, New York, 1982.
Acknowledgment
5. (a) Horvath, I. T.; Anastas, P. T. Chem. Rev. 2007, 107, 2167–2168; (b) Li, C.-J.;
Chan, T.-H. Comprehensive Organic Reactions in Aqueous Media, 2nd ed.; Wiley:
New York, 2007; (c) Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie
Academic & Professional: London, 1998.
6. Saggiomo, V.; Lüning, U. Eur. J. Org. Chem. 2008, 25, 4329–4333.
7. Godoy-Alcantar, C.; Yatsimirsky, A. K.; Lehn, J.-M. J. Phys. Org. Chem. 2005, 18,
979–985.
We are grateful for the support provided by the Marie Curie Re-
search Training Network MRTN-CT-2006-035614 Dynamic Combi-
natorial Chemistry (DCC).
References and notes
8. Simion, A.; Simion, C.; Kanda, T.; Nagashima, S.; Mitoma, Y.; Yamada, T.;
Mimura, K.; Tashiro, M. J. Chem. Soc., Perkin Trans. 1 2001, 2071–2078.
9. Experiment A3: 1.0 mL (10 mmol) of benzaldehyde (1a) and 910
lL (10 mmol)
1. (a) Patai, S. The Chemistry of the Carbon–Nitrogen Double Bond; Wiley: London,
1970; (b) Patai, S. The Chemistry of the Amino Group; Wiley: London, 1968; (c)
Patai, S. The Chemistry of the Carbonyl Group; Wiley: London, 1966; (d) Layer, R.
W. Chem. Rev. 1963, 63, 489–510; (e) Goering, B. K. Ph.D. Dissertation, Cornell
University, 1995.
2. Aminotransferases and transaminases form enzyme class 2.6.1. For the
mechanisms of transaminases via imines see: (a) Meister, A. Biochemistry of
the amino acids; Academic Press: New York, 1957; (b) Frey, P. A.; Hegeman, A.
D. Enzymatic reaction mechanisms; Oxford University Press, 2007. p. 148ff; For a
recent review, see (c) Toney, M. D. Arch. Biochem. Biophys. 2005, 433, 279–287.
3. (a) Corbett, P. T.; Leclaire, J.; Vial, L.; West, K. R.; Wietor, J.-L.; Sanders, J. K. M.;
Otto, S. Chem. Rev. 2006, 106, 3652–3711; (b) Meyer, C. D.; Joiner, C. S.;
Stoddart, J. F. Chem. Soc. Rev. 2007, 36, 1705–1723; (c) Rowan, S. J.; Cantrill, S. J.;
of aniline (2) were mixed in a 5 mL flask. The crude oil was left under vacuum
(4 Â 10À4 mbar) for 10 min, until all the oil became solid. Then, 10 mg of the
crude product11 was analyzed by 1H NMR. Ratio imine 3a/aldehyde 1a: 95:5.
10. Experiment B3: 966 lL (10.0 mmol) of salicylaldehyde (1b) and 911 lL
(10.0 mmol) of aniline (2) were mixed, and the reaction mixture was left
under vacuum (4 Â 10À4 mbar) for 12 h. Then, 10 mg of the crude product was
analyzed by 1H NMR. Ratio imine 3b/aldehyde 1b: 97:3. Recrystallization from
n-hexane gave the final product11 in 83% yield.
11. N-Benzylideneaniline (3a): SDBS No.: 2145, CAS No.: 538.51.2;
o-(phenyliminomethyl)phenol (3b): SDBS No.: 7178, CAS No.: 779-84-0.