Introduction
Cinnamic acids compose a relatively large family of organic acids which appear to have antibacterial, antifungal and antiparasitical activities. They are also used in macromolecular synthesis as very important building blocks for various classes of polymers, having attractive properties, especially a high photoreactivity due to the presence, in the main or side chains, of the cinnamoyl group, well known as photoresponsive unit. Polymers containing cinnamoyl moieties are used in a wide range of applications in emerging fields such as advanced microelectronics [
1], photolithography [
2], non-linear-optical materials [
3], integrated circuit technology [
4] and photocurable coatings [
5].
For their use in perfume production, the food industry, pharmaceuticals, medicine and technical applications, cinnamic acids are synthesized on a commercial scale. A wide range of approaches are available, the most important being the Perkin reaction [
6], the Claisen condensation [
7], the Knoevenagel-Doebner condensation [
8] and the Heck reaction [
9]. Despite the great variety of wellknown and tried methods, the development of new general synthetic protocols for cinnamic acids is still an active field.
In this paper, we wish to report a protocol for a new direct route for cinnamic acid synthesis, starting from aromatic aldehydes and aliphatic carboxylic acids, in the presence of boron tribromide as reagent.
Results and Discussion
In a typical experimental procedure (the Perkin reaction) [
10], cinnamic acids can be prepared from aromatic aldehydes and aliphatic carboxylic anhydrides in the presence of bases, particularly with sodium or potassium salts of the carboxylic acids corresponding to the anhydrides used in reactions as reagents. Thus, potassium acetate was used for the reaction between acetic anhydride and benzaldehyde at 180 °C, for 8 hours, affording cinnamic acid in 70-72% yield. Using sodium acetate instead of potassium acetate, the yields are lower under the same conditions [
11]. It was also demonstrated that this reaction is not suitable when aliphatic aldehydes are employed [
12].
Our first investigations were focused on using aliphatic carboxylic acids instead of aliphatic carboxylic anhydrides, in order to offer an alternative to classic methods. Unfortunately, the conclusion was negative, the synthesis does not take place.
By stepwise investigations, we established that the aliphatic carboxylic acids can yield cinnamic acids only in the presence of boron tribromide, under certain conditions. We assume that the reaction evolves through a reactive intermediate, namely triacylborate, which is obtained, in a first stage of the synthesis, from the reaction between the aliphatic carboxylic acid and boron tribromide. Afterwards, it reacts with the aromatic aldehyde used in the system, resulting in cinnamic acid.
This hypothesis was confirmed by our experimental results obtained by reacting acetic acid and boron tribromide, whereupon triacetyl borate was produced
in situ, the product being identical to that prepared from boric acid and acetic anhydride according to the literature [
13]. The resultant triacetyl borate was subsequently reacted with
p-chlorobenzaldehyde, under similar conditions, giving the corresponding cinnamic acid in comparable (78%) yield. The main advantage of our method is the possibility of obtaining cinnamic acids directly in an one-pot synthesis, avoiding intermediary steps, namely the synthesis, isolation and purification of triacetyl borate. The presence of 4-DMAP and pyridine was needed for product formation to take place.
In this case, the high reactivity of triacyl borates can be explained by the presence of the methylene group of the aliphatic carboxylic acids, activated by the boron atom which is electronic deficient [
14]. Thus, we have experimentally established that aliphatic carboxylic acids
1 react with aromatic aldehydes
2 in the presence of boron tribromide as reagent and 4-DMAP and Py as bases, in the molar ratio 5.45:1:1.1: 0.5: 1.5, giving cinnamic acids
3, as presented in
Scheme 1.
Scheme 1.
Direct synthesis of cinnamic acids from aliphatic carboxylic acids and aromatic aldehydes in the presence of boron tribromide
Scheme 1.
Direct synthesis of cinnamic acids from aliphatic carboxylic acids and aromatic aldehydes in the presence of boron tribromide
A study on the reaction parameters, such as reagent stoichiometry, base, solvent, temperature, reaction time, aldehyde reactivity, etc. was carried out. With regards to the stoichiometry, the best molar ratio between
1 and
2 is 5.45:1, due to the fact that the triacyl borate synthesis is performed in an excess of aliphatic carboxylic acid (see Experimental Section). The molar ratio between
2 and boron tribromide is 1:1.1 and this resulys in good yields for the reaction. In the case of
2 and the bases 4-DMAP and Py, the molar ratio is 1:0.5:1.5 because the reaction gives higher yields under basic conditions (see
Scheme 2).
Regarding the choice of the base, taking into account literature data [
15] and our own previously reported experimental results [
16,
17], we concluded that 4-DMAP and Py is the most effective mixture of bases for this synthesis, compared to other basic media we tested.
Another conclusion of our study is that without a suitable solvent, this reaction is difficult to perform. Under these circumstances, we tested several solvents such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), N-methylpyrrolidone (NMP) and hexamethylphosphortriamide (HMPTA) (see
Table 1). We have selected NMP as the solent of choice because it proved to be a good solvent for all products involved in synthesis, it is stable under the reaction conditions and has a convenient
boiling point (202°C).
Table 1.
Influence of solvent on yield in final product a
Table 1.
Influence of solvent on yield in final product a
Experiment. | Solvent | Temperature (°C) | Yield (%) b |
---|
1 | DMSO | 160-170 | 35 |
2 | DMF | 140-150 | 27 |
3 | HMPTA | 160-170 | 21 |
4 | NMP | 180-190 | 80 |
As for the reaction time and temperature, the syntheses necessitated high temperatures (reflux at 180-190°C) for 9-12 hours. (
Table 2). At lower temperatures, the yields decreased. For example, the yield for the product
3a decreased from 80%, when the reaction was conducted at reflux for 9 h, to 47% when the reaction is performed at 145-150°C for 9 h.
Table 2.
Cinnamic acids prepared by direct synthesis with boron tribromide
Table 2.
Cinnamic acids prepared by direct synthesis with boron tribromide
Cinnamic acids a | Yield b (%) | Reaction time (hours) | M.p. c (°C) | Literature m.p. (°C) |
---|
3a | 80 | 9 | 248-250 | 249-250 [18] |
3b | 78 | 9 | 176-177 | 175-177 [18] |
3c | 65 | 12 | 131-133 | 132-133 [19] |
3d | 53 | 12 | 173-175 | 173-175 [19] |
3e | 81 | 9 | 195-197 | 196-197 [21] |
3f | 72 | 10 | 105-107 | 106-107 [20] |
3g | 76 | 10 | 195-197 | 196-197 [20] |
As presented in
Table 2, we obtained cinnamic acids
3a-g in yields which ranged from 53 to 81%, depending on the reaction conditions and structure of the aldehydes
2. The cinnamic acid
3d was obtained in the lowest yield due to the presence of the methoxy (–OCH
3) group which has an electron donating effect. The cinnamic acids with electron withdrawing groups were obtained in good yields.
Scheme 2.
Mechanism of cinnamic acids synthesis from aliphatic carboxylic acids and aromatic aldehydes in the presence of boron tribromide
Scheme 2.
Mechanism of cinnamic acids synthesis from aliphatic carboxylic acids and aromatic aldehydes in the presence of boron tribromide
It is noticeable that, despite the fact that triacyl borate has three acyl groups, only one of them is reactive under these conditions. Our experimental data have proven that the yield of the main product decreases when the molar amount of BBr
3 is lower than the molar ratio given previously. On the basis of our own investigations, as well as on the basis of literature data [
15], the mechanism shown in
Scheme 2 can be proposed for this new direct synthesis.
The mechanism evolves in stages, as follows: first, the aliphatic carboxylic acid
1 reacts with boron tribromide and produces a stable intermediate
A, the triacyl borate, which behaves chemically as a mixed anhydride [
22]. This borate, in the presence of 4-DMAP, generates the reactive intermediate
B which reacts with the aromatic aldehydes
2 by the known mechanism, yielding the cinnamic acids
3. The detailed mechanism of this reaction will be discussed in a separate communication.