Recent advances of enzymatic reactions in ionic liquids: Part II

Recent advances of enzymatic reactions in ionic liquids: Part II

Journal Pre-proof Recent Advances of Enzymatic Reactions in Ionic Liquids: Part II Amal A.M. Elgharbawy, Muhammad Moniruzzaman, Masahiro Goto PII: S...

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Journal Pre-proof Recent Advances of Enzymatic Reactions in Ionic Liquids: Part II Amal A.M. Elgharbawy, Muhammad Moniruzzaman, Masahiro Goto

PII:

S1369-703X(19)30365-1

DOI:

https://doi.org/10.1016/j.bej.2019.107426

Reference:

BEJ 107426

To appear in:

Biochemical Engineering Journal

Received Date:

26 June 2019

Revised Date:

29 October 2019

Accepted Date:

4 November 2019

Please cite this article as: Elgharbawy AAM, Moniruzzaman M, Goto M, Recent Advances of Enzymatic Reactions in Ionic Liquids: Part II, Biochemical Engineering Journal (2019), doi: https://doi.org/10.1016/j.bej.2019.107426

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Recent Advances of Enzymatic Reactions in Ionic Liquids: Part II Amal A. M. Elgharbawya, Muhammad Moniruzzamanb,c* and Masahiro Gotod,e* a

International Institute for Halal Research and Training (INHART), International Islamic University Malaysia (IIUM), Kuala Lumpur, Malaysia b Chemical Engineering Department, Universiti Teknologi PETRONAS, 32610 Seri Iskandar, Malaysia c Centre of Research in Ionic Liquids (CORIL), Universiti Teknologi PETRONAS, Seri Iskandar, Malaysia d Center for Future Chemistry, Kyushu University, Fukuoka 819-0395, Japan e Department of Applied Chemistry, Graduate School of Engineering, Kyushu University, 744 Moto-oka, Fukuoka 819-0395, Japan

*Corresponding authors: [email protected] (M. Moniruzzaman), [email protected] (M. Goto).

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Graphical abstract

Highlights    

Overview of second and third generation ionic liquids (ILs) for enzymes ILs showed great enhancement of enzyme performance Novel materials have been developed to stabilize enzymes in ILs More studies are required to develop cost analysis for ILs bioprocesse

Abstract

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As a biocompatible and designer solvent, ionic liquids (ILs) are extensively used for enzymatic conversion of substrates, particularly those that are insoluble or sparingly soluble in water and common organic solvents. More than a decade ago, the first-generation ILs involved in enzymatic reactions generally comprised an imidazolium cation and noncoordinating anions, such as tetrafluoroborate and hexafluorophosphate. Recently, focus has shifted to more environmentally acceptable second- and third-generation ILs comprising enzyme compatible cations (e.g., cholinium salts) and anions, such as amines and amino acids. A wide range of such ILs have been derived from readily available renewable resources and used in biocatalytic reactions. Compared with first-generation ILs, the use of enzymes in second- and third-generation ILs provides better activity and stability, and they are also

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attractive from both an environmental and an economic viewpoint. In this review, we report

the recent advances of enzymatic reactions in second- and third-generation ILs. The intention of this review is not to cover first-generation ILs, but rather to update and overview the

potential approaches developed within the last ten years for enzymatic reactions in second-

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and third-generation ILs.

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Abbreviations (S)-CPMA [(C16BnIM)2C122+]

(S)-(4-chlorophenyl)-(pyridin-2-yl)methanol

[(C8)3BnN+] [(CH3)4N] [(EO)-3C-im] [bmim] [C12mim] [C16tma] [C18tma]

Benzyltrioctylammonium Tetramethylammonium 1-(2-(2-Methoxyethoxy)ethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-1-ium 1-butyl-3-methylimidazolium 1-dodecyl-3-methylimidazolium N,N,N,N-hexadecyltrimethylammonium N,N,N,N-octadecyltrimethylammonium

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N-methyl-N-propanolpyrrolidinium Ethylsulfate 1-ethanol-3-methylimidazolium

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[C1C3OHPyr] [C2H5SO4] [C2OHmim] [C4(C6im)2] [CH3SO3] [CH3SO4] [Cho] [deme] [dmapa] [dmim] [E2-MPy] [E3-MPy] [emim]

1,12-Di(3-hexadecylbenzimidazolium)dodecane

[hmim]

1,4-bis(3-hexylimidazolium-1-yl)butane Methanesulfonate Methylsulfate Choline (N,N-diethyl-N-methyl-N-(2-methoxyethyl)ammonium 3-(dimethylamino)-1-propylaminium 1,3-dimethylimidazolium 1-ethyl-2-methylpyridinium 1-ethyl-3-methylpyridinium ethylsulfate 1-ethyl-3-methylimidazolium 1-hexyl-3-methylimidazolium hexafluorophosphate

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1-hexyl-1-methylpyrrolidinium 2-(2-methoxyethoxy)ethylsulfate 3-methylimidazolium

[N221MEM] [omim]

N- ethyl-N-((2-methoxyethoxy)methyl)-N-methylethanaminium 1-octyl-3-methylimidazolium

[P6,6,6,14+] [TMA]OH [veim] Ala AOT

Trihexyl(tetradecyl)phosphonium Tetramethyl ammonium hydroxide (1-vinyl-3-ethylimidazolium bis(trifluoromethylsulfonyl)amide) Alanine Sodium bis(2-ethyl-1-hexyl)sulfosuccinate

BF4− Br− BCL

Tetrafluoroborate Bromide Burkholderia cepacia lipase

C16E10 CALB Cl− CMT CO CPMK CRL CTAB Cyt-c DAAO DBP DCA DEP DMA DMP DMSO DO FAME Fo HC

Decaethylene glycol hexadecyl ether Candida antarctica lipase B Chloride Chymotrypsin Carbon monoxide (4-chlorophenyl)-(pyridin-2-yl) methanone Candida rugosa lipase Cetyltrimethylammonium bromide Cytochrome C D-amino acid oxidase Dibutylphosphate Dicyanamide Diethylphosphate N,N-dimethylacetamide Dimethylphosphate Dimethyl sulfoxide (1,4-dioxane)-2-one Fatty acid methyl ester Formate Hydrocarbon

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NO3− Novozyme 435 OAc

5-hydroxymethylfurfural Ionic liquid Ionic liquid aqueous two-phase system Intrinsic activity Enzyme affinity Lignin peroxidase L-lactide Mucor miehei lipase Molecular weight Nicotinamide adenine dinucleotide

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HMF IL ILATPS Kcat Km LiP LLA MIML Mw NAD

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[hmpl] [MeOEtOEtOSO3] [mim]

Nitrate Lipase B from Candida antarctica immobilized on macroporous polyacrylic resin beads Acetate

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TX-100

Oleate Pseudomonas aeruginosa lipase Pseudomonas cepacia lipase Poly(ethylene glycol) Pentaethylenehexammonium acetate Pseudomonas fluorescens lipase Bishexafluorophosphate Poly-L-lactide P-nitrophenyl trimethylacetate Porcine pancreas lipase Rhizomucor miehei lipase Ring-opening polymerization Room-temperature ionic liquid Room-temperature solid-phase ionic liquid Surface-active lauroyl sarcosinate ionic liquid Supercritical Monolithic supported ionic-liquid-like phase 1,4-Dimethyl-triazacyclononane bis(trifluoromethylsulfonyl)amide Trifluoroacetate Trifluoromethanesulfonate Tetrahydrofuran 1,3,3-Tetramethylguandine acrylate Tosylate Unit enzyme activity Maximum velocity Water in ionic liquid Water in oil Water content expressed as the molar ratio of water to surfactant molecules Triton X-100

[P444PM]

tributyl(3‐ methoxypropyl)phosphonium

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Ole PAL PCL PEG PEHAA PEL PF6 PLLA PNTMA PPL RML ROP RTIL RTSPIL SALSIL sc SILLP TACN Tf2N TFA TfO THF TMGA TOS U Vmax w/IL w/o wo

[P444MEM][C16(PEG)10

tributyl ([2‐ methoxy]ethoxymethyl)phosphonium cetyl(PEG) 10

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Keywords: Ionic liquids; Immobilization; Enzyme stability; Biocatalysis; Biotransformation; Biofuels.

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1. Introduction

In 2010, the Biochemical Engineering Journal published our review paper on “Recent

Advances of Enzymatic Reactions in Ionic Liquids” [1]. At that time, application of ionic liquids (ILs) in biological applications, including enzymatic reactions, was limited. Most of the early studies reported enzymatic reactions in ILs involving an enzyme suspended in an IL prepared with a non-coordinating anion, such as 1-butyl-3-methylimidazolium 4

tetrafluoroborate ([bmim]BF4) and hexafluorophosphate ([bmim]PF6) [2–5]. However, like other applications of ILs, there has been increasing interest in the use of ILs for enzymatic reactions. Almost 31,500 articles have been published in the last ten years and research on enzymatic reactions in ILs is linearly increasing (Fig. 1). For the last few years, focus has shifted to more adequate and eco-friendly second (2nd)- and third (3rd)-generation ILs, which are more enzyme compatible than first (1st)-generation ILs [6]. More importantly, 2nd and 3rd-generation ILs can be derived from eco-friendly and comparatively inexpensive

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renewable resources.

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250 200 150 100 50

Number of Publications

5000 4500 4000 3500 3000 2500 2000 1500 1000 500 0

ScienceDirect

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Number of Publications

Scopus

0

2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

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Fig. 1. Numbers of articles published on enzymatic reactions in ILs from Scopus and ScienceDirect in the period 2010–2019 at 17 October 2019 with the keywords “ionic liquid” and “enzyme”.

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This review is intended to complement and update the 2010 review [1] up to the end of

the first three quarters of 2019, and it will mostly follow the same arrangement with some modification. We will not describe 1st-generation ILs and their properties because they are well known. We will also exclude comparison of the enzyme performance between ILs and organic solvents because this is well explained in our 2010 review [1] and other related papers [7–10]. ILs can be used in enzymatic reactions in various ways. The focus of this 5

review is ILs use as solvents and/or co-solvents. There are many papers on ILs that can be used as a reference for information that is not covered by the scope of this review. Some of them have highlighted particular applications, such as modification of enzymes with ILs, catalysis [11], ecotoxicity analysis [12], and cytotoxicity evaluation [13]. ILs have been acknowledged as reaction media for biotransformation. Very recently, T. Itoh [14] has published an excellent review highlighting various topics related to ILs and enzymatic reactions including “Enzymes Activated by Ionic Liquids for Organic Synthesis”.

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In the current review, particular attention is paid to development of enzymatic reactions in ILs, including esterification and transesterification, delignification of biomass [15], and enzymatic hydrolysis for production of biofuels, as well as novel immobilization and

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stabilization techniques, because there were only limited studies included in our 2010 review

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[1]. Significant progress has been made in this area in the last 10 years.

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2. Second (2nd)- and Third (3rd)-Generation ILs

Second-generation ILs have potential uses as functional materials, such as metal ion complexing agents, lubricants, and energetic materials. Because of their tunable physical and

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chemical properties, 2nd-generation ILs can provide a wide platform on which both the cation and anion properties can be individually designed and modified to enable new beneficial

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material production while preserving the main virtues of an IL. The 3rd generation of ILs have

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been used as active pharmaceutical ingredients (APIs) to generate ILs with biological activity [16–19]. The concept of task-specific ILs (3rd generation) was introduced by Davis [20] (Fig. 2).

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Fig. 2. Three generations of ILs. Reproduced by permission of The Royal Society of Chemistry [21]. Link to article.

Over the past few years, a number of reports of the use of 2nd-generation ILs in

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biocatalysis have shown that several enzymes show excellent activity and selectivity in ILs [9,10,22,23]. Enzymes also maintain exceptional operational and thermal stability in ILs.

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Therefore, we have seen significant progress in development of innovative ILs with improved green qualities. Recently, 3rd-generation ILs composed of readily available non-toxic and

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biodegradable ions, such as naturally existing bases and carboxylic acids, amino acids, and sugars, have started to emerge [24]. In contrast to 1st-generation ILs, 2nd-generation ILs are

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water and air stable. Commonly used cations in 2nd-generation ILs are alkylpyridinium, dialkylimidazolium, phosphonium, and ammonium, and the most common anions are halides,

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hexafluorophosphate, and tetrafluoroborate. These ILs have physical as well as chemical applications. Conversely, 3rd-generation ILs are of interest because they have ecological and

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biological applications [21]. The structures of some 2nd- and 3rd-generation ILs are given in Table 1.

Table 1. Some cations and anions used in 2nd- and 3rd-generation ILs and their structures. Cations 2nd Generation ILs

Anions

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Alkyl sulphate

1-ethyl-2-alkylpyridnium

X- (Halide) BF4- (Tetrafluoroborate) PF6- (Hexafluorophosphate) NO3- (Nitrate) (CN)2N- (Dicyanamide)

Phosphonium

Tosylate

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1-alkyl-3-methylimidazolium

Bis(trifluoromethane)sulfonamide

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Ammonium

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Sulfonium

Tetrachloroaluminate

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3rd Generation ILs (task-specific ILs)

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Docusate

Tetracycline

Diclofenac

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Cinnarizine

Choline

Lactate

Salicylate

Prilocaine

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Benzethonium

Ampicillin

Ibuprofen

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Ethambutol

Lidocaine

Tuammoniumheptane

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Penicillin G R-COO- (carboxylate)

Amino acid anion (e.g. glycine)

3. Enzyme Stabilization in ILs

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Enzymes are biocatalysts, and they greatly contribute to the current trends in industrial applications because they promote various processes. ILs are compatible with biological

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molecules because they are task specific. Therefore, enzymes show greater activity in ILs because of their adaptability [25]. For example, ILs can substitute n-heptane in the reaction

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catalyzed by Candida antarctica lipase B (CALB). The IL, namely [C7MIM][Tf2N],

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stabilizes the lipase because of the low nucleophilicity of the anion and the IL hydrophobicity [26]. Some studies have revealed that ILs are specific for protein stabilization, unfolding, and refolding. ILs are also regarded as biotransformation media for enzymatic processes. Based on the Anfinsen hypothesis, in the normal physiological state, the thermostable threedimensional structure of a native protein is determined by the total number of interatomic interactions, and consequently the sequence of amino acids [27]. Nishihara et al. [28]

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prepared three types of triazolium cetyl-PEG10 sulfate ILs and examined their activating effect on BCL. They reported that both the reaction rate and enantioselectivity are dependent on the cations of the coating ILs. When lipases were stored in an IL ([N221MEM][Tf2N]), an excellent stability was displayed by Tz1-PS, and it exhibited a notable activity after 2 years [28]. The same research group [29] has also reported four types of phosphonium cetyl(PEG)10 sulfate ILs, which were used as coating materials for BCL through the lyophilization process. They found that tributyl ([2‐methoxy]ethoxymethyl)phosphonium cetyl(PEG)10 sulfate

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([P444MEM][C16(PEG)10SO4]) worked best to coat lipase BCL to achieve high activity in transesterification of broad types of secondary alcohols using vinyl acetate as an acylating

reagent with perfect enantioselectivity (E > 200). Moreover, the coated BCL demonstrated

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recyclability up to five times in tributyl(3‐methoxypropyl)phosphonium

bis(trifluoromethylsulfonyl)amide ([P444PM][Tf2N]). Abe et al [30] used [P444MEM][NTf2]) and

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([N221MEM][NTf2]) as solvents with BCL with excellent enantioselectivity. They revealed that

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ammonium ILs influenced the lipase activity more strongly than phosphonium ILs. The thermal stability of some lipases and proteases has also been reported in many ILs [31]. Additionally, various enzymatic reactions have been performed in ILs, including hydrolysis,

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polymerization, and synthesis [32]. In some cases, exceptional yields in ILs have been reported [33]. However, some enzymes do not dissolve in ILs but remain suspended [1].

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Regardless, there are many options to tackle the issues of enzyme stability and insolubility in

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IL, such as IL functionalization, enzyme modification, using specific-task ILs, and using microemulsions (MEs) [34] and whole cells, and we will touch on these topics in the following sections.

3.1. Water-in-IL MEs

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The main challenge in using ILs with enzymes is that enzymes exhibit inadequate solubility in most ILs, which in return limits various biochemical reactions. Usually, a very small amount of water can be added to the reaction media to improve the solubility of enzymes in ILs. However, because of conformational change of the enzymes, they tend to show some level of inactivation. To increase the activity and solubility of enzymes in ILs, integrating water-in-IL (w/IL) MEs using appropriate surfactants and cosurfactants for stabilization is a promising method [35]. After initial development of w/IL MEs for enzymes

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by Moniruzzaman et al. [36], many w/IL MEs have been effectively applied to several enzyme-catalyzed processes (see Table 2).

The water content plays an important role in enzymatic reactions in MEs. Weng et al.

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[35] investigated p-nitrophenyl butyrate hydrolysis in a [bmim]PF6-based ME (50 °C)

catalyzed by Candida rugosa lipase (CRL). They demonstrated that the microenvironment

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around the lipase in a traditional ME can be regulated by altering the molar ratio of water to

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surfactant (W0). Addition of a very small amount of water to the IL-based ME resulted in formation of a network of hydrogen bonds between the water molecules and cations (i.e., imidazolium). They explained that the hydrogen-bonded network links the IL and surfactant,

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which improves the IL-based ME stability. Simultaneously, the water solubility can provide an aqueous interface film for hydrolytic reactions. This can be explained by the high water

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content in the micelle resulting in separation of the micelle system into two phases, which

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leads to enzyme inactivation [35]. The study showed that formation of an IL ME required a certain amount of water. However, the molar ratio of water would vary depending on the surfactant type and IL used. In contrast to ionic surfactants, newly introduced non-ionic surfactants, such as polyoxymethylene alkyl ether (CnEm), exhibit high biodegradability and low toxicity. Yu et al. [37] suggested that these nonionic surfactants usually have a minor effect on enzymes.

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ILs have been used not only as solvents, but also as surfactants. For instance, Calderón et al. [38] recently reported that surfactants derived from imidazolium tetrafluoroborate may improve the hydrolysis efficiency of p-nitrophenyl trimethylacetate catalyzed by αchymotrypsin. They used the water/[bmim]BF4 system with [C12mim]BF4 as a surfactant. They presumed that the influence of the IL goes beyond simply changing the surfactant/water interaction. They suggested that ILs can modify the substrate partitioning between the aqueous and micellar media, which leads to an increase in the aqueous concentration of the

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substrate [38]. Novel fatty-amino-acid-based IL surfactants using lauroyl sarcosinate anions have been reported by Mustahil et al. [39]. The synthesized surface-active lauroyl sarcosinate ionic liquids (SALSILs) with morpholinium and piperidinium cations exhibited 100%

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biodegradation after 28 days of the test period. They believed that the SALSILs could

successfully substitute conventional surfactants in a wide variety of applications, including

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food, cosmetics, and pharmaceutical applications [39]. Choline–fatty-acid-based ILs have

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also been investigated as biocompatible surfactants. Among the tested candidates, [Cho]Ole showed the best stability and lowest toxicity towards mammalian cell line NIH 3T3 [40]. It is noteworthy that water/IL MEs are not only applicable to stabilize enzymes, but they

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also facilitate biomass dissolution. Sharma et al. [35] used the [bmim]Cl PEG-8000 IL surfactant to enhance dissolution of sugarcane bagasse using cellulase and xylanase produced

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in house from Aspergillus assiutensis VS34. The pretreatment was performed at 90 °C for 2

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h, followed by saccharification with the two enzymes at 50 °C for 3 h, which maintained the activity at ≥90% and gave 0.117 g g−1 of ethanol.

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Surfactant AOT+ TX100

Solvent [bmim]PF6

Substrate/ main product 4-nitrophenyl butyrate (pNPB)+H2O → p-nitrophenol+ butyric acid

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Enzymes C. rugosa lipase

Reaction conditions 30 °C, 2-3 h, W0= 18, pH 8.0 AOT/ TX-100 = (1:2) 30 °C, 2-3 h, W0= 8, pH 7.4 AOT/ TX-100 = (1:2)

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Table 2. Enzyme-catalyzed reactions in w/IL MEs.

vinyl acetate+ benzyl alcohol→ benzyl acetate Candida rugosa lipase

Tween 20

[bmim]PF6

3

Candida rugosa lipase

Tween 20

[bmim]PF6

4

Trametes versicolor laccase Trametes versicolor laccase α-chymotrypsin

C16E10

[omim] Tf2N + nhexanol (0.5%)

o-Phenylenediamine +H2O2→ 2,3-di-amino phenazine

AOT+ TX100 (1:2)

[bmim]PF6

[C12mim]BF4

[bmim]BF4

[35]

[42]

Kcat/Km= 412.8 mM-1 min−1

[37]

o-Phenylenediamine +H2O2→ 2,3-di-amino phenazine

35 °C, 2-3 h, W0= 18 AOT/ TX-100 = (1:2)

[43]

p-nitrophenyl trimethylacetate→ acetate+ p-nitrophenolate

25 ºC, pH 7.00, W0= 10

Kcat/Km= 50.0 mM-1 min−1 Laccase was dissolved in the w/IL microemulsion. Kcat/Km= 12.5 mM-1 min−1

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Conversion rate: 87.9% Reused: 7 cycles

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50 °C, pH 6.0, W0= 6, 3h

Benzyl alcohol conversion to benzyl acetate: 94% at 6 h. p-nitrophenyl butyrate yield: 81.4%

Reference [41]

50 °C, pH 7.4, W0= 5.4, enzyme loading 10 wt%, molar ratio of phytosterols/lauric acid 1:2, 24 h 38.5 °C, W0= 16, pH 5.00

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4-nitrophenyl butyrate (pNPB)+H2O → p-nitrophenol+ butyric acid Phytosterols+lauric acid→ phytosterol esters+ H2O

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Findings Kcat/Km= 9.65 mM-1 min−1

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[38]

3.2. Enzyme Immobilization and Modification The enzyme insolubility and low tolerance in ILs have led to development of various commercially available immobilized enzymes, such as Novozyme 435 (CALB), which is the most common and widely applied lipase. There are many other examples, including Lipozyme (RML), lipase immobilized in Sol-Gel-AK from Candida rugosa, and Proteinase K immobilized on Eupergit C from Tritirachium album. Immobilization on solid supports is usually performed by cross-linking, physical or

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covalent bonding, or encapsulation [44]. However, traditional solid supports are not always

the carriers of choice. ILs act as agents for enzyme immobilization to enhance their activity.

Significant improvement in the lipase activity has been achieved by coating the enzyme with

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room-temperature solid-phase ionic liquids (RTSPILs) [45]. A hydrophobic RTSPIL is solid

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below or near room temperature, which may act as a carrier for the enzyme through physical adsorption [11].

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Miao et al. [46] synthesized Fe3O4 nanoparticles by chemical co-precipitation using [bmim]BF4 and treatment with 3-amino-propyltriethoxysilane (APTES-Fe3O4). The

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nanoparticles were used as a support for lipase (Candida antarctica) immobilization, in which the lipase exhibited reasonable dispersion in a rapeseed oil and methanol mixture with

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easy recovery using a magnetic field [46]. Similarly, porcine pancreatic lipase (PPL) has been immobilized on IL-modified (imidazolium-based IL) magnetic chitosan nanocomposites. The

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enzyme notably retained 91.5% of its initial activity after 10 repeated cycles [47]. The modification process is shown in Fig. 3.

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Fig. 3. Magnetic chitosan nanocomposites modified with [bmim]BF4 and their application to immobilization of

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PPL. Reprinted with permission from [47].

Chemically modified PPL with several functionalized ILs possessed improved catalytic

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activity in water-miscible ILs. The PPL modified with [HOOCbmim]Cl IL exhibited a 2-fold

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increase in the activity in 0.3 M [mmim]CH3SO4 than in aqueous medium. It has also been shown that PPL modified with [HOOCbmim]Cl shows 6-fold higher stability at 60 °C [48].

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Zhao et al. [49] prepared ether-functionalized ILs with formate or acetate anions that can dissolve a variety of substances and are also compatible with lipase. These ILs dissolved oils

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at 50 °C and the lipases retained their high activity even in high concentrations (up to 50% v/v) of methanol. The catalytic activity of an extracellular cellulase produced by the marine

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bacterium Pseudoalteromonas sp. was investigated in six different ILs. The enzyme showed remarkable stability in [emim]Br, [emim]OAc, [emim]CH3SO3, [bmpl][OTF], [bmim]Cl, and [bmim][OTF] with the activity ranging from 92.67% to 115%. The cellulase showed potential for saccharification of algal biomass in a single step process. In Table 3, we summarize the recent advances in immobilization and modification of enzymes and their performance in ILs after modification. 15

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6

7

8

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Trametes versicolor Laccase

[bmim]BF4 [bmim]CH3SO4 [bmim]BF4

Covalent binding: Immobilization on aminosilane modified superparamagnetic Fe3O4 Nanoparticles. Micro-encapsulation

Trichoderma reesei Cellulase Trichoderma reesei Cellulase

Aspergillus assiutensis VS34 Cellulase and Xylanase

Enzyme performance High biodiesel yield using the recycled lipase by extending the reaction from 2 h to 6 h. Enhanced enantioselectivity (E) of lipase by 50 times in 5% [bmim]CH3SO4. FAME conversion: 89.4% by lipase immobilized on APTES-Fe3O4 magnetic nanoparticles. FAME conversion: 70% after 5 cycles. Easy recovery by external magnetic field.

Ref. [50]

[veim]Tf2N

IL-encapsulated lipase remained active and exhibited excellent stability.

[51]

[bmim]PF6

Improved performance of lignin and phenol degradation in IL (77% in 6 h). Reusability for 11 cycles,

[52]

[emim]CH3SO4

4.5-fold higher activity High resistance Efficient dissolution of lignin Improved performance of immobilized nanohybrid. Reusability for five cycles to 50% of the initial activity.

[53]

Immobilization efficiency: magnetic: 85% and silica: 76% Vmax increased. Reusability: 2 cycles One-pot hydrolysis yield from sugar bagasse 89%. Increased the saccharification by 16.5% Maintained high CMCase (103.2%) and xylanase (99.9) activities after 24 h

[55]

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IL-compatibility

Covalent binding: Immobilization on Fe3O4@SiO2@KIT-6-NH2 nanoparticles Directed evolution, expressed Saccharomyces cerevisiae

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Candida rugosa Lipase Trametes versicolor Laccase

Ionic liquid [C1C3OHPyr]Tf2N

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3

Method of stabilization Functionalization of IL

Pr

2

Enzyme Candida rugosa Lipase (VII) Candida rugosa Lipase Candida rugosa Lipase

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Entry 1

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Table 3. Examples of enzyme activation and modification in ILs for stability enhancement.

Immobilization on chitosancellulase nanohybrid in calcium alginate beads Immobilization on magnetic and silica nanoparticles

[emim]Cl

IL-tolerant

[bmim]Cl [emim]Cl

[emim]OAc

16

[4] [46]

[54]

[emim]Cl [emim]DMP

IL-tolerant microbe: Fusarium oxysporum BN

[emim][H2PO2]

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Catalase form bovine liver

PEHAA

13

Pepsin and trypsin from bovine

Immobilization on the surface of glassy carbon electrode and IL Silica–enzyme–ionic liquid composite

[56]

Higher enzymatic activity than free enzymes.

[59]

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Pr

e-

[bmim]PF6

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Positive supercharging preserved wild type E1 activity in ILs Negative supercharging reduced the activity. Grew on 10% (w/v) of IL. High resistance to phosphate and sulfate-based ILs. Ethanol yield: 0.125 g. g-1 rice straw Reduction of hydrogen peroxide Potential biosensors for analytical applications

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Genetically modified, supercharged

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Acidothermus cellulolyticus Endoglucanase E1 Cellulase

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17

[57]

[58]

3.3. Whole-Cell Reactions in ILs Use of enzymes in processing is becoming an increasingly attractive alternate to frequently used chemical approaches owing to the environmentally friendly process, moderate process conditions, and high selectivity [60]. The poor solubility of the substrate and product in aqueous media has resulted in application of organic solvents to enhance the efficiency. However, organic solvents have a negative effect on both enzymes and microorganisms. Recently, using whole cells as a biocatalyst has attracted great interest in

ro of

biochemical and biological reactions because of cost reduction. Whole-cell-facilitated bioconversion is relatively cost effective and it is easier to perform compared with immobilized-enzyme systems [12].

-p

Investigation of whole-cell biocatalytic reactions in ILs has been less reported compared with reactions in ILs using free enzymes. Implementation of ILs in whole-cell processes is

re

mostly applied in “biphasic transformation”, “extraction fermentation”, or reactions in which

lP

a water-immiscible IL acts as an in situ extractant for toxin removal to prevent cell inhibition and also as a substrate pool. This enables the IL phase to be reused without loss of the process efficiency, which makes IL utilization economically viable. Furthermore, whole cells

na

can redevelop valuable cofactors in redox reactions. They also offer a natural medium for enzymes, which prevents conformational change and protein denaturation [61]. The recent

ur

applications of whole cells in ILs reactions are given in Table 4.

Jo

An efficient esterification process is required to synthesize caffeic acid for various medicinal ester derivatives. Rajapriya et al. [60] used halotolerant Aspergillus niger EXF 4321 as a catalyst in [emim]Tf2N IL. Whole-cell-catalyzed synthesis of caffeic acid phenethyl ester (CAPE) achieved bioconversion of up to 84% after 12 h at 30 °C (see Scheme 1).

18

Table 4. Examples of whole-cell reactions in ILs. Microorganism

IL

1

Penicillium purpurogenum, Li-3 (w-PGUS) Escherichia coli BL21, Pichia pastoris GS115 Escherichia coli

[bmim]PF6

Rhodotorula glutinis ATCC201718

Jo 4

Cryptococcus sp.(M9-3)

Main Findings

Ref.

GAMG yield: 87.63% after 60 h at 60 g L-1 (1.23 U g-1) cells

[62]

Hydrophilic and hydrophobic ILs

re

Reusability: 8 cycles with 85.5% recovery

2-octanone → (R)2-octanol

Average conversion: 98.5% and enantiomeric excesses ≥99.5% (R). Reusability: 25 cycles with no reduction in the conversion.

[63]

(R)-1,2epoxyhexane+ (S)1,2-epoxyhexane → (R)- 1,2epoxyhexanediol+ (S)- 1,2epoxyhexane (4-chlorophenyl)(pyridin-2-yl) methanone (CPMK) → (S)-(4chlorophenyl)(pyridin-2yl)methanol [(S)CPMA]

Addition of 1-heptanol in minute amounts → high enantiomeric ratio of (R)diol (E > 100) without reactivity reduction.

[64]

Excellent enantioselectivity (99%). Good sugar bagasse conversion (92%).

[65]

lP [bmim]PF6 [hmim] PF6 [omin] PF6 [deme]Tf2N

ur

3

[hmpl]Tf2N

na

2

Biocatalysis reaction Glycyrrhizin → glycyrrhetic acid 3O-mono-β-Dglucuronide (GAMG)

-p

Entry

ro of

Scheme 1. Esterification of caffeic acid with alcohol catalyzed by halotolerant A. niger EXF 4321 mycelia as a model reaction for various medicinal applications. Reproduced with permission from [60].

19

Aspergillus niger EXF 4321

[emim]Tf2N

6

Aspergillus ochraceus

[C3mim]PF6

7

Pseudomonas fluorescens

[bmim]PF6/[bmim]THF

caffeic acid+2phenyl ethanol → caffeic acid phenethyl ester+ water Reduction of 11α hydroxylation of 16 α,17epoxyprogesterone (HEP) Transesterification of Ara-C with vinyl laurate

Yield: 84% at [(caffeic acid) 1:20 (2-phenyl ethanol)] in 12 h. Reusability: 5 cycles

[60]

90% conversion 20 g·L−1.

[66]

Product yield (arabinocytosine laurate synthesis,): 81.1% 5’-regioselectivity >99%,

[67]

ro of

5

To deal with the issue of mass transfer triggered by the high viscosity of some ILs, Yang et al. [67] mixed pure IL with the organic solvent tetrahydrofuran (THF) to form an IL

-p

system for Ara-C transesterification with vinyl laurate to generate arabinocytosine laurate

(Scheme 2). Whole cells of Pseudomonas fluorescens catalyzed acylation with [bmim] PF6,

Jo

ur

na

lP

re

and the yield improved from 4.58% to 81.05%.

Scheme 2. Ara-C with vinyl transesterification catalyzed by whole cells (1, Ara-C; 2, VL; 3, unstable enol; 4, aldehyde; 5, 5′-O-lauryl ara-C; 6, 3′-O-lauryl ara-C) [67]. Creative Commons Attribution License 4.0.

The above is a clear example of using whole cells as a biocatalyst, and it is a strong alternative to conventional methods. The availability of whole cells in ILs enables 20

exploration of pharmaceutical and food applications by using 3rd-generation ILs. More investigation is needed to evaluate toxin secretion and the metabolites during the biocatalytic reactions. While some ILs have a positive influence on reactions, some do not. A possible pathway was summarized by Fan et al. [68]. They pointed out that ILs can exhibit many molecular action modes via interaction with biomacromolecules in cells, such DNA, phospholipid membranes, and proteins. However, the actions may be in the form of metabolic pathway

ro of

disorders in microbial cells, such as DNA damage, transport proteins, altering the membrane permeability, and inhibition or activation of enzymes [68]. Therefore, selecting a suitable IL, tolerant cell strains, and a suitable medium and concentrations are all factors that contribute

-p

to the success of using whole cells as biocatalysts in IL reactions. 3.4. Recent Enzyme-Catalyzed Reactions in ILs

re

IL selection for enzymatic reactions depends on the enzyme performance achieved in the

lP

processing medium. ILs are a suitable medium to enhance enzymes, in contrast to common organic solvents. Nevertheless, based on the nature of the enzyme, the IL may or may not be a candidate for the process or the desired application [69]. From a literature search, we found

na

that lipases are still the main enzymes used in ILs. These include transesterification and interesterification processes, synthesis of surfactants [70], ester synthesis [71], biodiesel

ur

preparation [72], and food and medicinal applications [73]. Lipases act in a wide range of

Jo

media in more than one way and hence act as catalytic agents for biotransformations in ILs and organic solvents [74]. A wide range of enzyme-catalyzed reactions have been performed in ILs. Therefore, we will first summarize the recent studies of reactions catalyzed by lipases in ILs involving acids and esters (Table 5), followed by enzymes other than lipases (Table 6).

21

f

Table 5. Lipase-catalyzed reactions in ILs and their main products. Ionic liquid

Enzyme

Preparation

Reaction

1

[C5mim]Tf2N

CALB

Novozyme 435

n-butanol+ acetic anhydride → butyl acetate

2

[bmim]BF4+ DMSO

RML

Galactose+ oleic acid → Galactose oleate

3

[C16tma]Tf2N

CALB

Lipozyme RMIM immobilized on microporous anion exchange resin Novozyme 435

pr

e-

Isoamyl alcohol+ Acetic acid/ Propionic acid/ Butyric acid/ Valeric acid → Isoamyl acetate/ Isoamyl propionate/ Isoamyl butyrate/ Isoamyl valerate Nerol+ Acetic acid/ Propionic acid/ Butyric acid/ Valeric acid → Neryl acetate/Neryl propionate/ Neryl butyrate/ Neryl valerate/ Geraniol+ Acetic acid/ Propionic acid/ Butyric acid/ Valeric acid → Geranyl acetate/Geranyl propionate/ Geranyl butyrate/ Geranyl valerate

Pr

na l 5

Jo ur

4

Reaction conditions

oo

Entry

[emim]CH3SO3

Burkholderia contaminans (DFS3) lipase

Immobilization

[bmim]TFSI [C4mim]PF6

CALB

Novozyme 435

5 mg mL-1 Novozym 435; 25 °C, 150 min 2h Ratio: DMSO: [bmim]BF4 (1:20) 2% (w/w) Lipozyme RMIM, 60 °C 50 °C

87%

97%-99.9%

97.8- 99.0%

Remarks

Ref.

IL performed better than nheptane Galactose was completely dissolved after 10 min due to DMSO

[75]

Natural flavor, fragrance

[76]

[75]

Reusability: 7 cycles without changes in activity of ILenzyme

97.9- 99.9%

Citronellol+ Acetic acid/ Propionic acid/Butyric acid/ Valeric acid→ Citronellyl acetate/ Citronellyl propionate/ Citronellyl butyrate/ Citronellyl valerate α-D-glucose+ Vinyl acetate→ methyl 6-O-acetyl-α-D-glucopyranoside

40 °C 72 h

Hexanol + dihydrocaffeic acid → Methyl dihydrocaffeate/hexyl

55 °C 72 h

22

Product yield (%) or rate 80%

99.9%

Up to 0.757 g mL−1 76%

68.7–84%

Scaling up to 1 L increased 250-fold

[77]

Antioxidant properties

[78]

Type VII Neat

7

[bmim]Tf2N [dmim] Tf2N [P444ME] Tf2N [P444MEM] Tf2N [N221ME] Tf2N [N221MEM] Tf2N

CALB

Novozyme 435 in the presence of zeolite

8

([(EO)-3Cim][ Tf2N])

CALB

Novozym 435

9

[bmim]TfO

CALB

Novozym 435

oo

Candida rugosa lipase

60 °C 72 h

45%

(S)-1-phenyl ethanol, 2,3-dihydro-1Hinden-1-ol + vinyl octanoate/ pchlorophenyl pentanoate → (R)-1phenylethyl octanoate/ (R)-2,3-dihydro-1H-inden-1-yl octanoate/ (R)-2,3-dihydro-1H-inden-1-yl pentanoate (2bc). Ferulic acid+ lauryl alcohol → Lauryl ferulate (LF)

60 °C 2h (10 wt%) zeolite

32- 85%

60 °C 48 h

90.1%

Glucose + palmitic acid vinyl ester → 6-O-palmitolyglucose ester

40 °C

31.5%

glucose/vinyl palmitate ratio: 1:3. 60 °C , 5 h [bmim]Cl/[bmim][BF4] ratio: 6:4

Degree of substitution DS= 1.19

pr

[bmim]BF4 [bmim]MeSO4

Pr

na l

Candida rugosa lipase

Type VII Neat

Cellulose + methyl palmitate→ cellulose palmitate

Jo ur

[bmim]Cl/[bmim] [BF4]

Table 6. Enzyme-catalyzed-reactions (non-lipase) in ILs and their main products and conditions. Entry Ionic Liquid Enzyme Preparation Reaction 1

[bmim]PF6

Reusability: 3 cycles With 90% activity Reusability: 3 cycles

[4]

LF had a strong antibacterial activity against Gram-negative positive bacteria ILs are good solvents for glucose esterification facile one-step route for synthesis

[80]

[79]

e-

6

10

dihydrocaffeate/dodecyl Dihydrocaffeate/octadecyl dihydrocaffeate Isopropanol+ Ketoprofen ethyl ester → Ketoprofen

f

[hmim]PF6 [omim]PF6

Trametes versicolor Laccase

Immobilization on Fe3O4@SiO2@KIT

Degradation of lignin and phenols from olive

23

Reaction Conditions 45 °C pH 4.5

Product Yield (%) Or Rate Degradation rate: Lignin: 77.3%

[81]

[82]

Remarks

Ref.

Immobilized laccase retained 70% of its

[52]

pomace

5h

Azocasein → casein+ azo dye

oo

f

-6-NH2 nanoparticles [Cho]Cl [(CH3)4N]Br

Alcalase® 2.5 L from Bacillus licheniformis, Flavourzyme® 500 L from Aspergillus oryzae Neutrase® 0.8 L from Bacillus amyloliquefaciens

Neat

3

[mim]Fo

D-amino acid oxidase from porcine kidney

Neat

4

[Cho]OAc

α-chymotrypsin from bovine pancreas

Neat

Casein → amino acids

25 °C pH 7.00

5

[bmim]Br

α-amylase Bacillus licheniformis, Type XII–A)

CH3COOK as an additive

Starch → glucose

pH 7.66-7.67 0.200 mol L−1 CH3COOK

6

[TMA][OH]

O-acetylhomoserine aminocarboxypropylt ransferas

Neat

L-homoserine → Lmethionine

10% IL 37 °C 6h pH 7.5

7

[bmim]Br

Chitin deacetylase

Neat

Deacetylation of chitosan

8

[emim]OAc

Neat

IL-chitin → Nacetylglucosamine

9

[emim]OAc

Chitinase from Streptomyces albolongus ATCC 27414 β-glucosidase (BG)

45 °C pH 4.0 20 min a) 105 °C, 30 min b) 55 °C, pH 5.00, 48 h

IL-tolerant

Switchgrass (cellulose

75 °C, 2-24 h

e-

L-alanine → H2O2

Pr

na l

Jo ur

Alcalase® (pH 8.00, 50 °C) Flavourzyme® (pH 6.00, 50 °C) Neutrase® 0.8 L (pH 7.00, 50 °C).

pr

2

24

37 °C pH 9.0 30 min 40% IL

Phenols: 76.5%

16-fold increase t1/2 From 5 min to 90 min The relation Vmax/Km increased by 20% Vmax 6.1 mM min-1 Km 19.70 mM

initial activity after 21 days Reusability: 11 Cycles 2.5-fold increase in the catalytic activity 50% reduction of Ea

[83]

Improved activities towards other Lamino acids such as L- Pro and L-Arg

[84]

(Tm) increased from 48.9 °C to 58 °C in the IL t1/2= 30 days

[Cho]OAc is a strong stabilizer

[85]

90% activity in 80% IL for 2 weeks 50% activity after one month

[86]

74 g.L-1 Lmethionine in IL medium 35 g.L-1 of Lmethionine in free-IL system KA = 1.913 (µmol mL-1)

Enzyme activity enhanced 3-fold

[87]

An increase in activity of up to 160% IL improved enzyme performance

[88]

IL recycled

[90]

76.11%

81.2% glucose

[89]

13

[Bmpy]Cl

Cellooligomers → glucose

Cellic® CTec2,

a) Trichoderma reesei ATCC 26921 cellulase b) Aspergillus niger cellobiose

a) neat

Bagasse powder (cellulose + hemicellulose) → glucose+ xylose Bagasse powder (cellulose + hemicellulose) → glucose+ xylose

70 °C, 72 h

100%

[91]

45 °C, 20 h

100%

Retain activity for 6 h Active in 20% IL

Regeneration required, Electrodialysis to separate sugars 8-fold increase in the cellulose conversion

[93]

f

[Cho]OAc

a) Cel5A & Cel7B b) Cel7A c) Xyn11

Lignin recovered

oo

12

a) Trichoderma reesei endoglucanases b) cellobiohydrolase c) xylanase Trichoderma viride cellulase

87.4% xylose

pr

[dmim]DMP

e-

11

IndiAge® Super GX Plus, Genencor

+ hemicellulose)→ glucose +xylose Cellulose → glucose

b) Novozyme 188

Pr

[bmim]Cl

recombinant

Jo ur

na l

10

cellobio- hydrolase (CBH) Endocellulase T. reesei

25

Pretreatment: 25 °C, 60 min ultrasound Hydrolysis: 50 °C, 48 h

80% glucose 72% xylose

Pretreatment: 120 °C, 10 Hydrolysis: 40 °C, 48 h

96%

[92]

[94]

Moniruzzaman and Ono [95] used commercial Laccase Y120 (EC. 1.10.3.2) from Trametes sp. for delignification of wood chips in an aqueous IL. They successfully extracted 50% of the lignin using laccase and 5% [emim]OAc in buffer solution. They found that the IL has the ability to dissolve lignin and enhances the oxidase performance and efficiency. Moreover, they showed that IL pretreatment did not significantly change the chemical composition of the wood, but altered its structure and rendered its surface more accessible to the enzyme [96]. Financie et al. [97] then used [emim]DEP for pretreatment of oil palm frond

ro of

biomass. They found that the IL pretreatment enhanced enzymatic delignification with Trametes sp. Laccase. In addition, the recovered material contained lower lignin content (8.5 wt%) that the untreated material (24 wt%).

-p

Fan and co-workers [98] investigated the inhibition kinetics of trypsin by various

ammonium and imidazolium-based ILs. They found that the inhibition caused by the IL

re

belongs to the reversible-competitive type. It is surprising that the enzyme can possibly

lP

recover its activity once the IL is removed with no effect on the activation energy. Liu and co-workers [84] investigated the improved performance of enzymes in [mim]Fo by taking a close look at the structure of the D-amino acid oxidase (DAAO) active site. Structure

na

comparison of the DAAO–L-Ala complex in buffer and the complex formed in [mim]Fo (DAAO–[mim]Fo–L-Ala, Fig. 4) showed that with the IL availability, L-Ala would occupy

is very similar to that in buffer. A large unoccupied patch of electron density at the

Jo

L-Ala

ur

the same binding site as that of L-Ala in buffer. Moreover, the overall structure of DAAO-IL–

entrance of the active site could be fitted with the IL. It was presumed that the Ala reaction catalyzed by DAAO first dehydrogenates the amino acid to the corresponding imino acid coupled with FAD reduction, and the imino acid will then be hydrolyzed to ammonia and αketo acid. Thus, transfer of the α-proton to FAD and attack of H2O at the α-amino group play key roles in amino acid enzyme-catalyzed oxidization. Therefore, the interaction between the

26

cation and the active site in the presence of [mim]Fo results in L-Ala being in a better location for nucleophilic attack to the amino group by water or successful transfer of the α-

lP

re

-p

ro of

proton to FAD [84].

ur

na

Fig. 4. Schematic illustration of the DAAO–L-Ala complex interaction with [mim]Fo. (a) DAAO structure. (b) Interaction between DAAO and D-Ala. Interaction between DAAO and L-Ala in the (c) absence and (d) presence of [mim]Fo IL. The active site residues are shown in the stick representation and colored green (carbon atoms), blue (nitrogen atoms), and red (oxygen atoms). The L-Ala molecule is shown in the stick presentation and colored yellow (carbon atoms), blue (nitrogen atoms), and red (oxygen atoms). The IL is shown in pink. Hydrogen bonds are shown as dashed lines. Reproduced by permission of The Royal Society of Chemistry [84]. Link to article.

Jo

Compared with lipases, the use of other enzymes in ILs is minimal. However, new studies

involving catalase, chitinase, and oxidases are rapidly increasing. This is evidence that IL enzyme-catalyzed reactions have an effect on the current research trend.

4. Bioprocess Applications

27

In addition to enzymatic reactions, ILs are also used as alternatives to organic solvents in multiphase-bioprocessing applications. In this regard, room-temperature ILs (RTILs) play a major role in the developed bioprocesses.

4.1 Enzymatic Polymerization in ILs

ro of

Recently, there has been great interest in ring-opening polymerization (e-ROP) of cyclic esters using enzymes as an alternate process for preparing bioresorbable or biodegradable

polymers. RTILs are excellent green solvents in enzymatic polymerization reactions. They have emerged because of their ability to dissolve inorganic, organic, polar and non-polar

-p

organometallic, and polymeric compounds. ILs are also able to control the miscibility with

re

many organic solvents. One way to produce polyesters is by lipase-catalyzed condensation of diols with dicarboxylic acids or their derivatives, such as esters, activated esters, and cyclic

lP

and polymeric anhydrides [99]. The recent developments in enzymatic condensation and

Jo

ur

na

polymerization in ILs along with their yields and process conditions are given in Table 7.

28

Reaction conditions

Product Yield (%) or Rate 62%

Remarks

Ref.

MW= 26,200 g mol-1

[100]

65 °C, 264 h

29.5%

hyperbranched structure

[101]

a) 90 °C, 169 h b) 65 °C, 120 h

a-63.2% b-16.5%

a) MW=37,800 b) 1700 g mol-1

[102]

oo

1

f

Table 7. Enzyme-catalyzed condensation and polymerization reactions in ILs. Entry Ionic Liquid Enzyme Preparation Reaction

CALB

Novozyme 435

ε-caprolactone (ε-CL) → PCL L-lactide (LLA) → PLLA

pr

[C4(C6Im)2]PF6

90 °C, 48 h

[bmim]PF6

CALB

Novozyme 435

3

[hmim]PF6

CALB

Novozyme 435

4

[bmim]PF6

CALB

(1,4-dioxane)-2-one (DO) → PDO

70 °C, 18 h

-

MW= 182,100 g mol-1

[103]

5

a) [bmim]PF6 b) DMA

CALB

Novozyme 435 Coated with 10% IL [bmim]PF6 Novozyme 435

a) L-lactide (LLA) → PLLA b) ε-caprolactone (ε-CL) → PCL

a) 60% b) 46%

MW= 10 000–20 000 g mol-1

[104]

6

[emim]BF4

α-chymotrypsin

Neat

51%

Enhanced activity

[105]

7

[bmim]PF6

Thermolysin

Neat

9

[emim]Cl

Trametes versicolor laccase horseradish peroxidase (HRP)

Addition of TX100 Addition of Ca2+

Enhanced catalytic activity by 34-fold Improved stability

[106]

CTAB

40 °C 24 h 60 °C pH 4.00 4 °C pH 8.00

95%

8

2-aminoaryl ketones+αmethylene → quinoline (condensation) Z-Asp+ Phe → Z-aspartame (peptide) Indole → 2,2-bis(3’-indolyl)indoxyl (trimerization) Free radical polymerization

a) 130 °C, 7 days b) 70 °C, 48 h 55 °C, 24 h, 20% IL

Enhanced activity by 3-fold

[108]

e-

2

Jo ur

na l

Pr

L-lactide (LLA) → PLLA

29

73%, 80%

[107]

Although the temperature is a crucial factor in enzymatic reactions, high temperature does not prevent polymerization of L-lactide (LLA) at 130 °C [104] (Scheme 3). This confirms the positive effect of ILs on polymerization reactions and the suitability of CALB

ro of

(Novozyme 435) for many reactions in IL.

-p

Scheme 3. Enzymatic ring-opening polymerization of LLA [104]. Creative Commons AttributionNonCommercial 3.0 Unported Licence.

re

ILs based on the imidazolium cation have also been proven to be suitable media to

lP

stabilize lipases. Furthermore, they are also good solvents for lactide. The obtained polylactides have relatively high molecular weights. It is presumed that the branching degree of

na

the polymer can be regulated by controlling the process conditions [101].

ur

4.2 Protein and Enzyme Extraction for Biocatalysis Over the past few years, biomolecule extraction, such as amino acid, protein and enzyme

Jo

extraction, in ILs has attracted interest owing to the extraordinary solvent properties of ILs [109–111]. ILs can be used as solvents for protein extraction as pure ILs or aqueous ILs. Some studies have suggested that pure ILs improve the thermal stability and catalytic activity of proteins [112,113]. In pure ILs, most proteins disperse but do not consistently dissolve. Pure ILs are unable to dissolve proteins without causing them to denature [114,115]. ILs containing a very small amount of water, which are known as hydrated ILs, are commonly 30

used in protein applications [116]. Extraordinary protein stability in hydrated ILs has been reported by a few groups, which cannot be achieved in aqueous solution [116,117]. The cations and anions of ILs commonly have an equal influence on protein stabilization [118]. The interactions of proteins with cations and anions are affected by the Hofmeister ion series. The interactions depend on the chaotropic and kosmotropic properties of the ions in the IL. Chaotropes are “structure breakers” that decrease the protein stability in aqueous medium, whereas kosmotropes are regarded as “structure makers” because they enhance the

ro of

protein stability in solution [119]. A combination of kosmotropic (strongly hydrated) anions and chaotropic (weakly hydrated) cations is the best to investigate the enzyme–IL interaction. Hence, the anions are highly polarizable and more hydrating than the cations [120,121].

-p

Metrick et al. [122] suggested that when a protein molecule is dissolved in an aqueous

medium, it possesses several charged groups on the surface that are accountable for the

re

interactions with the ions in the medium. The charged groups are presumed to strongly

lP

interact with the kosmotropic cations and chaotropic anions [122]. According to this theoretical concept, the capacity of an ion in the “water structure”, which is known as the kosmotropicity, is directly linked to the ion hydration degree. However, the kosmotropicity of

na

the anion is not the only factor that regulates the performance of enzymes in an IL medium. The behavior of enzymes in aqueous IL solution could differ from that in the IL with a trace

ur

amount of water or the pure IL [1,123].

Jo

Kohno et al. [124] investigated the effect of water in the tetrabutylphosphonium Ntrifluoromethanesulfonyl leucine ([P4444][Tf-Leu]) IL phase on extraction of cytochrome-c (Cyt-c). They found that water in the IL phase is closely linked to protein stabilization and dissolution. The aqueous IL (>21 wt% water) effectively extracted Cyt-c. In addition, the hydrated IL maintained the secondary structure of the protein and prevented its denaturation.

31

Regular liquid extraction with organic solvents results in impurities in the proteins, which might impair biological examination because such organic solvents could have a toxic effect on bioprocesses. In comparison, IL-based aqueous two-phase systems (ATPSs) offer a biocompatible medium for gentle extraction and purification of biological molecules, such as nucleic acids, enzymes, and proteins [125]. In addition to conventional imidazolium-based ILs, novel classes of ILs used in IL-ATPS applications for protein separation include ILs with the cholinium cation [126,127], ammonium cation containing the oligoethyleneglycol [128]

ro of

or oligopropyleneglycol unit [114,129], hydroxyl-functionalized ammonium cation [130], quaternary ammonium or phosphonium cation [131], and guanidinium cation [132], and the anionic part derived from more environmentally benign sources, such as biological buffers

-p

[133], amino acids [134], and carboxylic acids [114]. Desai et al. [129] used an IL-based ATPS to extract the plant protein Rubisco (Ribulose-1, 5-biphosphate carboxylase

re

oxygenase) using Iolilyte 221 PG and sodium potassium phosphate buffer (Fig. 5). IL-based

lP

ATPS extraction was investigated as a novel alternative method to the regular PEG-based two-phase system. They found that the IL-based ATPS achieves higher separation of Rubisco than the PEG-based system. However, a high concentration of the IL resulted in aggregation

na

of the protein. The study revealed that the protein stability and aggregation in ILs are affected by the size and complexity of the protein. Using Cyphos 108, they found that the anion has a

ur

strong influence on the protein stability. They found that the structure and function of

Jo

Rubisco is stable at ∼10% v/v IL. However, they noted that each IL may behave differently. ILs have also recently been applied to protein removal from biological fluids, namely, blood.

32

ro of

-p

Fig. 5. Structures of (a) Iolilyte 221 PG and (b) Cyphos 108. Reproduced by permission of The Royal Society of Chemistry [129]. Link to article.

re

Zeng et al. [109] used the guanidine-based 1,1,3,3-tetramethylguandine acrylate IL ATPS for protein extraction. They achieved extraction efficiency of bovine serum albumin (BSA) of

lP

up to 99.62%. There were no chemical interactions between the IL and BSA during the extraction process, and the conformational shape of the protein was not changed by

na

extraction. They suggested that the main driving forces for protein separation using ILs are aggregation and the embrace phenomenon, which depend on the hydrogen bonding

ur

interaction, hydrophobic interaction, and the effect of the salt. All of the results of the above studies show that IL-based ATPSs have the potential to offer new opportunities in protein

Jo

extraction. Ge et al. [135] used [3-(dimethylamino)-1-propylaminium formate ([dmapa]Fo)] IL to extract proteins from microbial cells (yeast). They found that this IL can be easily removed under vacuum, so pure protein can be obtained. They found that the proteins in the yeast cell walls are highly O-glycosylated and their O-linked saccharides are attached to the cell wall components (most likely, β-D-glucans) by covalent bonds. They determined that the pH of the IL solution at which the O-chains have the tendency to be cleaved by beta33

elimination is 9.0 (alkaline), which releases the O-glycosylated proteins. More importantly, the chemical properties of the yeast proteins extracted by the IL did not change. Moreover, the protein maintained its biological functions. Suarez Garcia et al. [130] used an IL-based ATPS (Iolilyte 221PG) to obtain Rubisco, BSA, and total protein from two green microalgae of industrial interest (Tetraselmis suecica and Neochloris oleoabundans). A high-value microalgal protein was obtained. Ren and co-workers [136] used an IL-based ATPS and the TACN-based ligand affinity for selective extraction and purification of His-tagged proteins

ro of

(hexahistidine). The IL could be easily recovered by adding ethylenediaminetetraacetic acid, followed by re-immobilization of the metal ions. The method showed potential as a practical

re

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substitute for recombinant protein purification (Scheme 4).

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Scheme 4. Synthesis of TACN-IL-based AIL 3. Reproduced with permission from [136].

na

Chen et al. [132] modified the surface of silica-coated magnetic Fe3O4 nanoparticles (MNPs) with hydroxy functional ILs for BSA extraction by magnetic solid-phase extraction

ur

(MSPE). The BSA extraction efficiency reached 86.92%. Desorption of the proteins was up

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to 94.91% with recovery of approximately 95% of the MNPs from each run of five cycles.

4.3 Production of Biofuels

Because of their significant ecological benefits and properties as solvents and catalysts,

ILs have attracted great attention for biofuel production. They have been increasingly used in dissolution, pretreatment, and hydrolysis of lignocellulose for production of bioethanol, as well as esterification and transesterification for biodiesel production [137]. 34

Biodiesel is the product of transesterification of animal or plant fats, and it is a sustainable eco-friendly substitute to petroleum diesel. Biodiesel is formed using catalysts, such as chemical catalysts or biocatalysts (i.e., lipases) [50]. Transesterification is the process where the carboxylic acid esters react with alcohol in the presence of a catalyst to form fatty acid methyl esters (FAMEs) and water [138]. Transesterification requires high energy and glycerol recovery is challenging. Therefore, the possibility of biodiesel production by the lipase-catalyzed reaction in IL media has been investigated. Some ILs are well known for

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their ability to enhance biodiesel production, such as [bmim]Tf2N and [bmim]PF6. Hydrophobic imidazolium-based ILs are more compatible with lipases because they offer protection to the enzyme by preventing it from dissolving in the aqueous phase of the

-p

reaction medium [139].

Su and co-workers [140] produced biodiesel from Chinese tallow kernel oil using

re

Candida rugosa lipase (CRL) in [hmim]PF6. They found that CRL is more efficient in the IL

lP

(95.4%) than in a non-IL medium (35%). In another study, Novozym 435 was used with [bmim]PF6 to catalyze biodiesel production from waste canola oil [141]. It was reported that the IL enhanced the lipase activity. Hydrophobic ILs based on long alkyl side-chain cations,

na

such as N-octadecyl-N′,N′′,N′′′-trimethylammonium bis(trifluoromethylsulfonyl)amide, can be switched over a range of temperatures and act like sponges. They are excellent

ur

monophasic reaction media as the liquid phase for lipase-catalyzed alcoholysis, whereas as

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the solid phase, the reaction mixture can be easily separated into three phases (pure biodiesel, glycerol, and solid IL) by centrifugation [142]. The switchable ILs allow easy removal and reuse of the IL-biocatalyst system for sequential cycles and are appropriate for scale-up (Fig. 6). Amino-acid-based ILs with quaternary ammonium and cholinium cations have been also reported for catalytic conversion of oils with transesterification yields of 98.0–99.8% in tetrabutylammonium arginine ([TBA][Arg]) [143].

35

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Fig. 6. Schematic illustration of the sponge-like IL hypothesis. (A) [C18tma] Tf2N net as a dry sponge. (B) Sponge swollen with methyl oleate. (C) “Wet” sponge after wringing out by centrifugation. Reproduced by permission of The Royal Society of Chemistry [142]. Link to article.

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It is presumed that ILs provide a large contact area between the oil particles and the enzyme, which enhances the activity. Furthermore, ILs produce a biphasic system, which

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facilities product separation in the final stage. In most of the reported studies, the biodiesel

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yield was higher in hydrophobic ILs than in organic solvents or solvent-free media (Table 8).

36

f

oo

Table 8. Examples of lipase-catalyzed biodiesel production in ILs along with the optimum conditions. Ionic Liquid

Lipase

Preparation

Substrate

Solvent

1

[hmim]PF6

Candida rugosa lipase

Neat

Chinese tallow kernel oil

Methanol/IL

2

[bmim]PF6

Neat

Corn oil

3

[bmim]PF6

Neat

Corn oil

4

[bmim]PF6

Penicillium expansum lipase (PEL) Penicillium expansum lipase (PEL) CALB

Novozym 435

5

a) [bmim]PF6 b)[bmim]Tf2N

CALB

Novozym 435

6

a)[C16mim] Tf2N b)[C18mim] Tf2N

CALB

7

[bmim]PF6

8

[bmim]PF6

Biodiesel Yield (%) 95.4%

Remarks

Ref.

IL boosted the lipase efficacy from 35% to 95.4% Less 53% HC emission, less 49% CO emission

[140]

40 °C, 25 h

a) 69.7% b) 19.4%

12-fold enhanced lipase activity

[144]

a) Methanol/IL b)tert-butanol

40 °C, 25 h

a) 86% b) 52%

PEL tolerates methanol in IL and organic solvents.

[145]

Waste canola oil

Methyl acetate/IL

48 °C, 24 h

72%

[141]

Food waste oil

Methanol/IL

50 °C, 14 h

a) 72% b) 48%

IL and methyl acetate increased lipase activity Scale-up (500 mL) yield: 30% Increasing the enzyme loading increased the yield

Novozym 435 suspended in IL

Triolein

Methanol/IL

60 °C, 6 h

a) 98% b) 98%

a) Recycled: 9 cycles b) Recycled: 7 cycles selective extraction achieved enzyme recovery achieved

[147]

a) Penicillium expansum lipase b) CALB

a) Neat b) Novozym 435

Millettia pinnata Seed Oil

Methanol/IL

a) 40 °C, 48 h b) 60 °C, 48 h

a) 93.5% b) 48.4%

a) Recycled: 5 times b) Recycled: 5 times Less activity reported in (a)

[148]

a) CALB b) Penicillium expansum Lipase (PEL)

a) Novozym 435 b) Addition of starch

Chlorella vulgaris lipid extract

1) Methanol/IL 2) tert-butanol

50 °C, 48 h

a) 86% b) 91%

PEL offers higher activity and higher yield

[149]

a) Methanol/IL b)tert-butanol/

e-

Pr

na l

Jo ur

Conditions 40 °C, 48 h

pr

Entry

37

in tertbutanol a) 48.6% and b) 44.4%),

[146]

9

[C1C3OHPyr]Tf2N

Candida rugosa lipase

Neat

Soybean oil

a) n-hexane b)tert-butanol c) methanol/IL

25 °C, 2 h

10

[OmPy]BF4

Neat

Soybean oil

Methanol/IL

11

[bmim]PF6

Burkholderia cepacia lipase (BCL) Rhizomucor miehei lipase

Lypozime RMIM

Methanol/IL

12

[C18tma] Tf2N

CALB

Novozym 435

degummed palm oil (DPO) Triolein

Recycled: prolonged from 2 h to 6 h

[150]

40 °C, 12 h

82.2%

Recycled: 58% of lipase activity was lost after 3 cycles.

[151]

45 °C, 6 h

68.89%

Recycled: 4 times with lipase activity reduction about 4%

[152]

100%

half-life time: 1370 days, 60 °C Sponge-like IL

[142]

pr

oo

f

a) 2.1% b) 13.3% c) 90%

Jo ur

na l

Pr

e-

Methanol/IL

38

60 °C, 8 h

Lignocellulose transformation to simple sugars has attracted interest because of the biomass accessibility and the great potential for bioethanol production. Because of the complex structure of lignocellulose, it requires pretreatment before enzymatic hydrolysis can occur. Several methods for pretreatment of lignocellulose have been proposed, including hot water treatment [153], acid [154] and alkaline [155] treatment, microbial bioconversion [156], microwave treatment [153], and ultrasonication [158]. However, many drawbacks of these methods have been reported regardless of the high yield that can be generated from the

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biomass. Hence, IL pretreatment has emerged as a potential option. ILs exhibit excellent dissolution capability for lignocellulosic materials and generate an amorphous and porous

structure that is prone to enzymatic hydrolysis by cellulase [57]. Although ILs show excellent

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dissolution potential of cellulose, a major shortcoming is that some ILs have biological

toxicity that hinders the cellulase activity or impairs microbial growth that is essential for

re

fermentation [159]. Although some studies have shown that the IL residues in the regenerated

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biomass might inhibit the rate of saccharification and microbial fermentation, many recent studies have successfully generated high bioethanol yields in ILs. The pathways of cellulosic

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bioethanol production using ILs are summarized in Fig. 7.

39

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Fig. 7. Two proposed pathways for bioethanol production from lignocellulosic biomass. Reproduced with permission from [9].

IL-assisted pretreatment approaches have been shown to be more effective than

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conventional approaches using ammonia or dilute acid. Previously, IL pretreatment processes involved extensive washing to remove the IL residues that prevent cellulolytic enzymes and

ur

growth inhibition [159]. However, extensive washing of the treated biomass generates a large amount of dilute IL aqueous solution, which results in high cost for treating the resultant

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wastewater and recovering the IL from the dilute solution by evaporation [93]. Therefore, a one-pot process involving in situ enzymatic saccharification without washing has been introduced. Herein, we will report the progress in bioethanol production by the enzymecatalyzed process in IL media (Table 9).

40

f

Substrate

[emim]OAc

Cellulase

Celluclast® 1.5 L, Novozyme 188

2

[emim]H2PO2

3

[emim]OAc

Fusarium oxysporum BN Trichoderma reesei cellulase

Isolate IL-tolerant Novo-Celluclast Aqueous

4

[bmim]OAc

cellulase-displaying yeast:

Bagasse

5

[Cho]OAc

Saccharomyces cerevisiae MT81/cocdBEC1 Cellulase Trichoderma reesei RUTC30 cellulase

Isolate IL-tolerant

Empty fruit bunch

6

[Cho]OAc

Aspergillus niger cellulase

Neat

Paperboard mill sludge (PMS)

Novozymes (Frankinton, NC) enzyme mixture> CTec2 and HTec2 Novozymes

Cellulases, CTec2, and hemicellulases, HTec2

8

[bmim]Cl

Cellulase, β-glycosidase, xylanase

Rice straw

e-

Eucalyptus

Pr

na l

Jo ur

[emim]OAc

Aspen wood (Populus tremula)

pr

1

7

a) Corn stover b) switchgrass

a) Mixed softwood b) Mixed hardwood c) Rice straw 41

Reaction conditions

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Table 9. Bioethanol production in enzyme-catalyzed IL media. Entry Ionic liquid Enzyme Preparation

Pretreatment: 120 ºC, 5h Hydrolysis: 50 ºC, 24 h 50 °C, 12 h Pretreatment: 150 ºC, 30 min Hydrolysis: 48 h Fermentation: 72 h Pretreatment: 120 C, 30 min Hydrolysis +fermentation: 96 h Pretreatment: 75 C, 60 min Hydrolysis: 48 h/ Fermentation: 72 h Pretreatment: 120 C, 60 min Hydrolysis: 48 h/ Fermentation: 32 °C, 24 h Pretreatment 100 °C, 3h Hydrolysis: 37 °C, 24 h Pretreatment: 130 °C, 2h Hydrolysis: 24 h

Bioethanol Yield % 81%

Remarks

Ref.

Regeneration involved

[160]

64.2%

No regeneration

[57]

33.9%

Regeneration involved

[161]

72.4%

Regeneration involved

[162]

87.94%

No regeneration (0ne-pot)

[163]

21.73 g L-1

Energy= 5.36 kJ g-

[164]

1

a) 87% b) 96%

Enhanced biomethane production

[165]

a) 95.4 b) 99.5 c) 95.2

Recycled: 4 cycles 20-fold increase in cellulose

[166]

Isolate IL-tolerant

10

[emim]OAc

Cellulase

Celluclast 1.5L, Novozyme

Novozyme 188

Sunn hemp fiber (cellulose) → glucose

Pr

Cellulase

na l

[bmim]Cl+ CuCl2 catalyst

Rice straw

Jo ur

11

f

oo

Cellulase, Xylanase

pr

[bmim]Cl

e-

9

d) Sugarcane bagasse Sunflower stalks

42

Pretreatment: 90 °C, 2 h (IL+NaOH) Hydrolysis: 50 °C, 72 h Pretreatment: 120 °C, 5h Hydrolysis: 45 °C, 24 h Fermentation: 38 ºC,

d) 97.6

digestibility

36.27%.

Increased the sugar yield 2-fold

[167]

79.7%

3-fold improvement

[168]

75.6%

Glucose, HMF, LA and FA: 78.7%, 26.8%, 44.9% and 17.8%

[169]

48 h, SSF Pretreatment: 160– 200 °C, 46 min

The biofuel production yields in ILs and conventional media are compared in Fig. 8. Considering the recyclability and green nature of ILs, application of ILs to enzyme-catalyzed biofuel production is promising.

100

80 Bio-Ethanol 70

Bio-Butanol

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Yield %

90

Biodiesel 60 50 Conventional

ILS

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Method

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Fig. 8. Comparison of the biofuel yields in ILs and conventional solvents based on the yield of the biofuel form [170–174].

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5. IL and Enzyme Combination for Biotransformation ILs are not only used as reaction media for enzymes, but they are also used as reagents

na

and cosolvents for biotransformation. Some examples include IL-coated enzymes, IL

ur

membranes, and biosensors.

5.1 IL-Coated Enzymes for Biocatalysis

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Enzyme performances can be enhanced significantly using IL coated enzyme [14]. Although most of the reported examples are limited to only lipases due to their wide range applications. ILs act as support materials for enzymes and can act as protective agents. For instance, coating Novozyme 435 with 10 wt% [bmim]PF6 for 6 h, the poly(1,4-dioxan-2-one) polymer with 182,100 g mol−1 molecular weight can be formed. In this polymerization reaction, using IL-coated lipase is much more effective than using the IL as a solvent [103]. 43

The novel magnetic extractant PEG 4000 modified Fe3O4 nanomaterial coated with dianionic amino acid IL (Fe3O4@PEG@DAAAIL) was used for trypsin extraction combined with MSPE (Fig. 9). The capacity of trypsin extraction reached 718.73 mg g−1. Furthermore, the

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na

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re

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extraction capacity was maintained above 90% for eight successive cycles [175].

Fig. 9. Synthetic route of Fe3O4@PEG@IL and its application to magnetic solid-phase extraction. Reprinted with permission from [175].

Kadotani and co-workers [172] have coated Burkholderia cepacia lipase (BCL) with three types of pyridinium ILs and tested their performances using transesterification of 44

alcohols as a model reaction. The results showed that 1-ethylpyridin-1-ium cetyl-PEG10 sulfate (PYET) had the best results in IL coating. The transesterification of alcohols, i.e., 1(pyridin-2-yl)ethanol, 1-(pyridin-3-yl)ethanol, 1-(pyridin-4-yl)ethanol, and 4-phenylbut-3-en2-ol progressed faster with IL-coated BCL rather than free-lipase reaction [176], An excellent enantioselectivity (E> 200) was also achieved[176]. Suo et al. [173] modified magnetic chitosan nanoparticles (CS-Fe3O4) with IL. The prepared carrier (IL-nano) was used to immobilize PPL. PPL-IL-nano showed 1.93-fold higher specific activity than non-IL

ro of

particles. PPL–IL–nano showed 382% recovery of the activity. The PPL–IL–nano system retained 84.6% of the initial activity after ten cycles with easy recovery with a magnetic field. Goto and co-workers [46] encapsulated CRL in surfactant aggregates formed in IL monomer

-p

and incorporated it into polymer frameworks by free radical polymerization of 1-vinyl-3ethylimidazolium bis(trifluoromethyl-sulfonyl) amide) ([veim][Tf2N]) IL. The CRL

re

encapsulated within the IL polymer showed outstanding stability in aqueous media.

lP

Furthermore, the biopolymer maintained most of its activity after five cycles, and the IL polymer was recovered by centrifugation [51].

Gomes and co-workers [177] developed a novel third-generation biosensor based on the

na

Marinobacter hydrocarbonoclasticus metalloenzyme (nitric oxide reductase, NOR) that reduced NO in denitrification processes. Multiwalled carbon nanotubes (MWCNTs)

ur

combined with [bmim]BF4 and NOR accumulated on the pyrolytic graphite electrode (PGE)

Jo

surface. The biosensor was stable for one month with 79–116% of its initial response. Laccase-mediator systems have various applications in green oxidation, but their uses are

limited because of deactivation caused by the oxidized reactive mediators. Rehmann et al. [178] partitioned the mediator into the water-immiscible [C6mim][AOT] IL, whereby the laccase (Trametes versicolor) retained 54, 41, 35, and 35 of its activity after 188 h in the mediators 4-hydroxybenzyl alcohol, ABTS [(2,2’-azino-bis(3-ethylbenzthiazoline-6-sulfonic

45

acid)], hydroxybiphenyl, and phenothiazine, respectively. Their study demonstrated the role of ILs in protection against the mediator deactivation effect. Biphasic catalytic systems constructed by combining enzymes, IL, and supercritical carbon dioxide (scCO2) highlight the “arsenal” of green tools to develop clean chemical reactions of industrial importance. Lozano et al. [179] developed a system that ran with a continuous substrate feed, which was supplied by the scCO2 phase to the biocatalyst–IL (Novozyme 525L covalently attached to [C18mim] Tf2N). The products were redirected to the

ro of

supercritical phase to directly generate pure biodiesel (Fig. 10). The system showed excellent

ur

na

lP

re

-p

recovery and recyclability for 45 cycles.

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Fig. 10. Setup of the experimental packed-bed reactor loaded with immobilized lipase on SILLPs for continuous biodiesel production by methanolysis of triolein (T, triolein; M, methanol; G, glycerol; B, methyl oleate (biodiesel). Reprinted with permission from [179].

It can be concluded that IL systems with a very small amount of certain ions can

contribute to a very large increase in the enzyme enantioselectivity or activity. Hence, ILs can be precisely adjusted for potential applications in biocatalysis.

5.2 ILs and Enzymes in the Sol–Gel Method 46

The sol–gel method involves condensation and hydrolysis reactions to synthesize solid materials, such as metal oxides, from solution-state precursors [180]. The sol–gel method is useful for immobilization of biomolecules and offers improved performance compared with free enzymes. In the sol–gel immobilization process, the gel shrinks during condensation and the drying process, which can result in partial denaturation of enzymes. To tackle the issue, amino acids, sugars, polyvinyl alcohol, surfactants, crown ethers, and polyols are often used as additives to alter the carriers [11]. For instance, enzyme-catalyzed precipitation of silica by

ro of

trypsin and pepsin produced by the sol–gel method in IL generates a composite material that exhibits high enzymatic activity. Kato et al. [181] investigated the structural features of this

silica–enzyme–IL composite material. The composite was generated from a combination of

-p

tetraethoxysilane and organo-functionalized triethoxysilane in IL by direct hydrolysis and

enzyme-catalyzed polycondensation reactions. Higher hydrolysis and condensation activities

re

were achieved after encapsulating the enzymes in the silica–IL composite compared with the

lP

free-enzyme solution [181].

The IL sol–gel method is highly dependent on the application and molecules to be incorporated. For example, Viau et al. [182] prepared several sets of ionogels from various

na

silica or organosilica sources and various [bmim] ILs. They found that formic acid solvolysis is the only approach that generates transparent, crack-free, and non-exuding monoliths from

ur

an IL with the [Tf2N] anion. The material has potential applications in photochemistry and

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photosensors. Zarcula et al. [183] found that using [Omim]BF4 as an additive in OcTMOS/TMOS silane sol–gel for entrapping Pseudomonas fluorescens lipase doubled the activity and increased the recovery 1.56-fold in acylation of racemic 2-heptanol in hexane by vinyl acetate. They found that the structure of the OcTMOS/TMOS silane sol–gel lipase immobilized with the IL has an amorphous structure in contrast to the non-IL sol–gel which has an irregular porous structure [183]. Protic ILs (monoethanolamine-based) have also been

47

used as additives for immobilization of lipase from Burkholderia cepacia in hybrid sol–gel matrices, where the activity and recovery improved 35-fold [184]. Vila-Real and co-workers [2] developed a novel IL combined with the TMOS/glycerol sol–gel matrix for enzyme immobilization of naringinase. Naringinase is a complex of α-l-rhamnosidase and β-dglucosidase responsible for glycosylation of natural glycosides. IL–TMOS/glycerol had a positive effect on the enzyme performance during 50 successive cycles. The efficiency of IL– TMOS/glycerol increased with the cation hydrophobicity of the [omim] IL. The [E3-MPy]

ro of

and [E2-MPy] cations resulted in a 150% increase in the activity of α-rhamnosidase. For the anions, the most hydrophobic anions (Tf2N−, BF4−, and PF6−) resulted in higher activity. Naringinase was encapsulated in TMOS/glycerol@[omim]Tf2N and

-p

TMOS/glycerol@[C2OHmim]PF6, and higher stability and efficacy were achieved.

It is presumed that ILs act as a template in the sol–gel process during gelation and as a

re

stabilizer to protect the enzyme from deactivation [11]. Furthermore, the support material

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enables reusability of the catalyst, which reduces the process cost and increases the

6.

na

efficiency.

Conclusions and Future Outlook

ur

Based on the literature published in the last decade, we can conclude that 2nd and 3rdgeneration ILs have emerged as excellent solvents for enzymatic reactions due to their

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biocompatible nature. Specially, ILs obtained from cheap renewable raw materials are environmentally attractive for bioconversions of substrates that are insoluble or sparingly soluble in water and other common organic solvents. Enormous enzyme-catalyzed reactions can be performed with comparable and sometimes, better yields and activities in ILs than in organic solvents. More importantly, enzymes show excellent operational stability at higher temperature. Of particular importance has been found that enzymes can recover easily from 48

ILs reaction media and reuse several times without losing significant activity. We expect that ILs will play a significant role in the biocatalysis of various substrates, particularly derived from renewable resources to develop sustainable bioprocesses. We have noted a few issues that need to be addressed: 1) Examining the existing ILs in terms of their toxicity to biological molecules, recycling and reuse should be the priorities of research, rather than examining the physical parameters. In this context, successfully produced carriers/materials and nanoparticles

ro of

should be commercialized to enable scale-up production in IL-enzyme system. 2) Although an enormous number of publications are available in the IL field, there is very limited cost-benefit analysis consideration. More research should be directed

-p

towards cost analysis and simulation for industrial applications.

3) Even though several breakthroughs have been reported, many prospects for research

re

exist, such as process improvement, new sources of enzymes, IL-tolerant enzymes,

lP

cocktail preparation, and cost reduction.

4) ILs have become an ideal choice for many applications, including whole-cell reactions, enzymes, protein extraction, and purification. From the research trends, ILs

na

can be applied to a large number of fields owing to their tunable properties.

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Declarations of interest: none

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Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Funding This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

Acknowledgments 49

We thank Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript. We also thank Ms. Shiva Rezaei (Department of Chemical and Environmental Engineering,

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University Putra Malaysia) for her assistance in regenerating some figures.

50

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[17]

ro of

[6]

-p

[5]

re

[4]

lP

[3]

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