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http://www.scirp.org/journal/ns Natural Science, 2017, Vol. 9, (No. 4), pp: 110-122

Microwave-Assisted Facile and Rapid Esterification of

Amino Acids I: Esterification of L-Leucine from Batch to

Flow Processes and Scale-Up

Ritsuko Nagahata, Takashi Nakamura, Yukie Mori, Kazuhiko Takeuchi

National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan

Correspondence to: Ritsuko Nagahata, nagahata-ritsuko@aist.go.jp;

Takashi Nakamura,

nakamura-mw@aist.go.jp

Keywords: Microwave-Assisted Esterification, Microwave Flow Reactor, Dielectric Properties, Amino Acid Ester,

L-leucine

Received: February 27, 2017 Accepted: April 27, 2017 Published: April 30, 2017

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

ABSTRACT

We herein report our studies into the effects of microwave irradiation on the sol-vent-free

esterification of L-leucine with alcohols. In the absence of solvent, micro-wave irradiation

accelerated the reaction compared to conventional oil bath heating. Measurement of the di-

electric properties under the reaction conditions revealed that the high dielectric loss factor

of the reaction mixture containing L-leucine, n-butanol, and a p-toluene sulfonic acid cata-

lyst could be attributed to the acceleration of the reaction. The depth of microwave pene-

tration into the reaction mixture as derived from the in-situ measurement of the dielectric

properties was ~13 mm, which suggested that a thinner reaction vessel was favorable for the

esterification of L-leucine. In addition to the batch reaction using a desktop microwave

reactor, two types of flow reaction were also performed using a desktop tubular reactor and

a semi-bench-scale tubular reactor. These flow reactions also exhibited high performances,

thus allowing the scale-up of this reaction system for industrial use.

1. INTRODUCTION

Microwaves are electromagnetic waves with frequencies ranging between 300 MHz and 30 GHz. They

are often employed in radars, wireless communication devices, and as heating tools in the form of micro-

wave ovens [1]. In recent years, microwave heating has also been widely used in laboratories as a high

throughput tool for preparative chemistry [2-7]. Indeed, a number of reports have been published dis-

cussing the application of microwave irradiation in organic synthesis for accelerating reaction rates and

improving product selectivity. However, to date, the majority of studies on microwave-assisted synthesis

have been carried out using desktop-scale reactors, despite various reports on the scale-up of microwave

syntheses for potential application on an industrial scale [8-11].

Open Access

https://doi.org/10.4236/ns.2017.94011 110 Natural Science

In the context of organic synthesis, amino acid esters are widely employed as inter-mediates for a

wide range of applications, such as medicinal chemistry [12], peptide synthesis [13], asymmetric synthesis

[14], dye-sensitized solar cells [15], and polymer chemistry [16]. To date, the principal method of amino

acid ester synthesis using alcohols has been the Fischer-Speier esterification procedure [17], in which an

amino acid and an alcohol are dehydrated in the presence of an acid catalyst, such as hydrogen chloride

[18], sulfuric acid [19], polyphosphoric acid [20], p-toluenesulfonic acid [21, 22], ion-exchange resins (e.g.,

Amberlyst® 15) [23], or trimethylchlorosilane [24]. However, as the amino group present in amino acids

can form an amide moiety through bonding with the carboxylic group of another molecule, the amino

group must be protected prior to esterification. This is typically carried out using an equimolar amount of

acid to produce the species shown in Eq. (1). Alternatively, an N-protected Boc-amino acid can be em-

ployed [25], which is prepared from the Bocanhydride rather than an acid. In terms of the esterification

reaction itself, amino acids can be esterified using a combination of methanol and thionyl chloride, where

the acid chloride reacts with methanol to form the ester [26]. This reaction proceeds smoothly at relatively

low temperatures (

., ~50˚C); however, it requires an excess of the toxic thionyl chloride reagent to drive

the reaction to completion. As such, safer and more efficient methods of amino acid esterification are re-

quired for application in industry.

As mentioned above, the Fischer-Speier esterification is the most common method for amino acid

ester synthesis using alcohols. However, this process generally requires large quantities of hazardous rea-

gents, is time consuming, and forms various hazardous by-products, which must subsequently be removed

via cumbersome post-processing methods. For example, during this reaction, a large volume of toluene is

required to produce an azeotrope with water. However, toluene is particularly toxic, and its release into the

atmosphere is the largest among the pollutant release and transfer register (PRTR) chemicals of a number

of countries. Therefore, a new synthetic method that does not require the use of toluene as a solvent is of

particular importance for industrial applications.

Due to the high polarity and the ionic character of amino acids (see Eq. (1)), micro-wave heating is

expected to be a favored technique for their esterification reactions. In-deed, the esterification of

N-protected amino acids via microwave synthesis has been reported in recent years [27-29]. Moreover,

Martinez-Palou’s group reported the esterification of unprotected amino acids with long-chain alcohols

using a small-scale micro-wave reactor in the context of combinatorial chemistry [30]. However, the ori-

gins of microwave effects on the amino acid esterification process have not yet been clarified, and to the

best of our knowledge, the scale-up of this reaction has also not been described yet.

Thus, we herein report our studies into the effects of microwave irradiation on the esterification of

amino acids with ethanol and n-butanol, using L-leucine as a representative amino acid. n-butanol was

selected as both a solvent and a reagent for a number of reasons. Firstly, the butyl ester of L-leucine is

widely utilized as an intermediate in the preparation of pharmaceutical products, such as valsartan, which

is employed in the treatment of high blood pressure and congestive heart failure [31]. In addition,

n-butanol can form an azeotrope with water, whose boiling point (117.7˚C) is close to that of toluene (

110.6˚C). Following optimization of the reaction with n-butanol, the batch and flow processes of this reac-

tion will be compared, with the overall aim of scaling-up the process for industrial-scale application.

https://doi.org/10.4236/ns.2017.94011 111 Natural Science

2. MATERIALS AND METHODS

Here, we first compared the efficiencies of microwave and conventional oil bath heating processes in

amino esterification of L-leucine using batch reactors. Then two types of microwave flow reactions were

examined using a desktop-scale tubular reactor and a semi-bench-scale tubular reactor in this reaction.

2.1. Materials

All reagents were purchased from Wako Pure Chemical Ind., Ltd. (Japan). L-Leucine (Leu, ≥99%)

and p-toluene sulfonic acid (PTS, ≥99%) were used with-out further purification. Ethanol (EtOH) (≥95%)

and n-butanol (BuOH, ≥99%) were distilled prior to use.

2.2. Analysis of the Reaction Products

The yield and the selectivity of the L-leucine esterification reaction were determined using 1H NMR

spectroscopy (Avance III 400M NMR spectrometer, Bruker, Germany). All spectra were recorded at 400

MHz. Deuterated chloroform (CDCl

, Wako Pure Chemical Ind., Ltd. Japan) and tetramethylsilane (TMS,

Wako Pure Chemical Ind., Ltd., Japan) were used as the solvent and internal standard for all NMR mea-

surements, respectively.

2.3. Measurement of Complex Dielectric Parameters

The dielectric properties of the various reagents were measured via a coaxial probe method using an

open-ended coaxial probe, as described elsewhere [32]. The measurement system consisted of a cus-

tom-built separable flask, a high-temperature dielectric probe (85070E, Agilent Technologies, USA) oper-

ating between −40 and 200˚C, and a vector network analyzer (8720ES, Agilent Technologies) operating

between 0.2 and 20 GHz. A PCMCIA-GPIB interface (National Instruments, USA) was employed to con-

nect the vector network analyzer to a PC equipped with data-collecting software (85,070, Agilent Tech-

nologies) capable of calculating complex dielectric properties using reflected signals (S11) from the vector

network analyzer. The flask was heated from the bottom and stirred using a stirring hotplate. Measure-

ments were carried out at various temperature intervals after stabilization for 1 min.

The system was calibrated prior to each measurement to compensate for small variations in the cable

position, the connections, the ambient temperature, and other factors capable of affecting system perfor-

mance. The testing probe was calibrated using a short circuit (a gold-plated precision shorting block in-

cluded in the 85070E probe kit), an open circuit (air), and a known load (deionized water, G18.2 MΩ, Mil-

li-Q, Millipore, at 25˚C).

2.4. Reaction Apparatus

2.4.1. Batch-Type Microwave Reactor

The batch-type microwave-assisted esterification of L-leucine was carried out using a multi-mode

microwave apparatus (Reactor model SMW-087, 2.45 GHz, maximum power output 770 W, Shikoku In-

strumentation Co., Ltd., Japan) equipped with a magnetic stirrer and three metal pipes (41 mm φ × 101

mm length) to act as a reflux condenser and a thermometer.

A mixture of L-leucine, alcohol, and acid catalyst were placed into a glass round-bottomed flask

equipped with a reflux condenser, a magnetic stirrer, and a fiber optic thermometer (AMOTH FL-2000,

Anritsu Meter Co., Ltd., Japan). The flask was then placed inside the cavity of the microwave reactor, and

was subjected to microwave irradiation at the reflux temperature. The reaction temperature was controlled

automat-ically using the fiber optic thermometer, and all reactions were carried out under atmospheric

pressure.

2.4.2. Desktop-Scale Microwave Tubular Reactor

The experimental setup employed for carrying out the flow reaction using a desk-top-scale micro-

https://doi.org/10.4236/ns.2017.94011 112 Natural Science

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