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`Topics in Current Chemistry (2019) 377:14
`https://doi.org/10.1007/s41061-019-0239-2
`
`REVIEW
`
`Quaternary Ammonium Compounds: Simple in Structure,
`Complex in Application
`
`Filip Bureš1
`
`Received: 9 October 2018 / Accepted: 25 April 2019 / Published online: 6 May 2019
`© Springer Nature Switzerland AG 2019
`
`Abstract
`Quaternary ammonium compounds, referred to as QACs, are cationic substances
`with a structure on the edge of organic and inorganic chemistry and unique physico-
`chemical properties. The purpose of the present work is to introduce QACs and their
`wide application potential. Fundamental properties, methods of preparation, and uti-
`lization in organic synthesis are reviewed. Modern applications and the use of QACs
`as reactive substrates, reagents, phase-transfer catalysts, ionic liquids, electrolytes,
`frameworks, surfactants, herbicides, and antimicrobials are further covered. A brief
`discussion of the health and environmental impact of QACs is also provided. The
`emphasis is largely on tetraalkylammonium compounds bearing linear alkyl chains.
`
`Keywords Quaternary ammonium compounds · QAC · Synthesis · Surfactant ·
`Herbicide · Antimicrobial
`
`1 Introduction
`
`From their early appearance at the beginning of life on earth, to their first use in
`organic synthesis by Hofmann [1], organic amines constitute an important group of
`natural and reactive substances. In general, four groups can be distinguished: pri-
`mary (RNH2), secondary (R2NH), and tertiary (R3N) amines, and quaternary ammo-
`nium compounds (R4N+, QACs or quats). While the first three classes possess simi-
`lar properties including Lewis nucleophilicity and basicity, due to the presence of
`a lone electron pair on the nitrogen atom, the latter group is cationic and cannot be
`considered as a base/nucleophile or electrophile. Despite eight electrons in the broad
`vicinity of the nitrogen atom, QACs possess completely different electron distribu-
`tion, as shown in Fig. 1. The nitrogen atom in alkylamines is negatively charged,
`whereas it becomes positive in tetraethylammonium ion.
`
` * Filip Bureš
`
`bures@mail.vstecb.cz
`1 The Institute of Technology and Business in České Budějovice, Okružní 517/10,
`370 01 České Budějovice, Czech Republic
`
`Vol.:(0123456789)
`
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`Fig. 1 Optimized molecular structure and charge distribution (electrostatic potential) along ethylamine
`(a), diethylamine (b), trimethylamine (c), and tetraethylammonium (d). Negative potential is shown in
`red, positive in blue
`
`+), respectively, as parent inor-
`Taking ammonia (NH3) and ammonium (NH4
`ganic structures, organic amines are derived by a gradual hydrogen substitution with
`organic residues (R). R generally stands for alkyl chain, benzyl, aryl, or heteroaryl,
`which however may be further functionalized [2]. The replacement of the original
`hydrogen atoms has a significant effect on the properties of the resulting amino and
`quaternary ammonium compounds. Compared to the ammonium cation, QACs are
`
`generally much bulkier (e.g. COSMO volume of NH4+ and Et4N+ is 34 and 160 Å3,
`respectively). Four alkyl/aryl substituents in QACs also account for significant sep-
`aration of R4N+ from its counter anion, especially in solution. It is believed that
` R4N+, often referred to as synthetic alkali metal, is completely dissociated in water
`solutions. As ionic substances, QACs are generally highly soluble in polar and protic
`solvents such as water and alcohols. However, their solubility decreases dramatically
`with increasing chain length, and QACs with R exceeding C14 have low solubility,
`or further are practically insoluble, in water. On the contrary, the solubility of QACs
`bearing long chains in nonpolar solvents is substantially improved. QACs are gen-
`erally solids, but their thermal properties can be modulated to a wide extent by the
`structure and length of the appended R-residues. Another notable feature of QACs is
`their ionic conductivity; their solutions are very good electrolytes. Because of their
`structure comprising both polar (N+) and nonpolar (R) terminuses, QACs are able to
`absorb on a surface or an interface, thus reducing their tension. This feature makes
`them a very popular group of surfactants. QACs exhibit a very wide range of bio-
`logical and antimicrobial activity, which also determines their current application as
`bioactive agents. The aforementioned unique physicochemical properties of QACs
`have resulted in their wide and diverse applications and their large industrial pro-
`duction. With production exceeding 500,000 tons/year worldwide, QACs have been
`included on the list of high-production-volume chemicals by the Organisation for
`Economic Co-operation and Development (OECD) [3].
`The subsequent sections will focus on recent progress in the chemistry of QACs
`and their prospective uses in various fields. The main purpose of this review is not
`to cover all recent contributions, but rather to demonstrate the wide application
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`potential of QACs as shown in selected examples. The emphasis will be mostly on
`the QACs bearing alkyl chains.
`
`2 Preparation and Chemical Reactivity of QACs
`
`In most cases, the synthesis of QACs is carried out from an amino compound, a
`nucleophile, and its exhaustive alkylation with a variety of electrophilic agents
`(Scheme 1).
`In principle, primary, secondary and tertiary amines can be used; however, the
`latter is the most common and convenient starting material. Quaternization of ter-
`tiary amines is also referred to as Menshutkin reaction. From the history, N-alkyla-
`tion of amines involves Hofmann’s reaction utilizing halogen alkanes (both SN1 and
` SN2 reactions are possible, depending on the haloalkane used). The structure of the
`resulting QAC (R1–4 substituents) can easily be modulated by using appropriate
`starting amine and halogen derivative. There are several known methods for pre-
`paring primary, secondary, and tertiary amines, for instance, reduction of nitrogen-
`containing compounds, reductive amination, Gabriel synthesis, and Hofmann degra-
`dation [4]. Symmetrical QACs can be produced analogously directly from ammonia.
`The alkylating agent R4X represents haloalkane in most cases, but (tosylated) alco-
`hols, dialkyl sulfates, oxonium salts, alkenes in acid media, and organometallic rea-
`gents can also be used [5]. The alkylating agent also determines the counter ion X−
`in the resulting QAC, which however may be further replaced by ion exchange.
`In general, QACs undergo four type of reactions: (a) elimination, (b) substitution,
`(c) rearrangement, and (d) ion exchange reactions, as depicted on Scheme 2.
`The negative inductive effect of the ammonium group results in pronounced acid-
`ification of the hydrogen atoms present at the α-carbon adjacent to the R3N+ resi-
`due. This feature generally determines QAC reactivity, in which a reaction with a
`base/nucleophile results in Hofmann elimination or alkyl displacement. In contrast
`to amines, the R3N+ residue can serve as a good leaving group as well as an alkyl
`
`Scheme 1 General synthetic
`route towards QAC starting
`from primary (a), secondary (b),
`and tertiary amines (c)
`
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`Scheme 2 General reactivity of quaternary ammonium salts
`
`source. The Stevens 1,2-migration may take place upon α-deprotonation as a com-
`peting reaction. This rearrangement has also proved to be a useful strategy in pre-
`paring unsymmetrical tertiary amines. Similar Sommelet–Hauser 1,2-migration has
`also been observed on benzyl substituted QACs. Anion exchange has generally been
`accomplished by passing the QAC solution through various membranes, resins, and
`polymeric membranes [6] such as commercially available Amberlite or Dowex [7].
`
`3 QACs in Organic Synthesis
`
`In organic synthesis and routine laboratory practice, four general functions of QACs
`can be distinguished; the QAC may act as a (1) starting material, (2) reagent, (3) cat-
`alyst, and/or (4) solvent. Application of QACs in organic synthesis was last reviewed
`by Dockx [8]. Since then, the organic synthesis has undergone significant develop-
`ment and QACs have also found various new applications. Hence, the subsequent
`text will focus on selected recent examples and utilization of readily or commer-
`cially available QACs (Fig. 2).
`Utilization of QACs as starting materials is demonstrated in Scheme 2. In par-
`ticular, QACs have found useful application in Hofmann elimination reactions pro-
`ducing alkenes. However, this reaction is generally limited to tetraalkylammonium
`hydroxides. Therefore, most of the ammonium halides are converted to hydrox-
`ides by reacting them with silver oxide prior to thermal elimination. Another use-
`ful feature of this reaction is its possible extension to amines, which may be con-
`verted in  situ into corresponding QACs by exhaustive alkylation with reactive
`methyl iodide. The methyl group has no β-hydrogens and thus cannot compete in
`the subsequent elimination reaction. The three-step reaction sequence is depicted
`
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`Fig. 2 Selected most popular QACs in organic synthesis
`
`Scheme 3 Conversion of amines/QACs into alkenes
`
`Scheme 4 Enantioselective 1,2-migration (Stevens rearrangement) of QACs
`
`in Scheme 3. QAC Hofmann elimination and subsequent utilization of the formed
`alkene as an alkylating reagent in C–H activation was recently demonstrated by
`Schnürch et al. [9]. Benzylic ammonium triflates similar to Triton B were recently
`demonstrated as useful starting materials for carbonylation reaction to amides via
`C–N bond activation [10].
`Despite discrepancies in the mechanistic pathways of base-promoted QAC rear-
`rangements [11, 12], the Stevens rearrangement found useful application in the
`preparation of tertiary amines. Lacour et al. [13] showed that the use of a supra-
`molecular asymmetric ion-pairing strategy enabled the preparation of optically pure
`amines with ee up to 55% (Scheme 4). The Stevens rearrangement was also recently
`utilized in a straightforward synthesis of tetrahydroisoquinoline alkaloids [14].
`Tetraalkylammonium hydroxides, for instance commercially available ben-
`zyltrimethylammonium hydroxide (1, Triton B), are well-known bases capable of
`abstracting hydrogen from various organic substrates and initiating essential reac-
`tions such as aldol condensation, oxidation, olefination, and conjugate addition [15].
`For example, a conversion of dibromoolefins, easily available from various alde-
`hydes by Corey–Fuchs reaction, to 1-bromoalkynes can be accomplished by their
`treatment with Triton B (Scheme 5) [16]. 1-Bromoalkynes proved to be very useful
`
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`Scheme 5 Synthesis of 1-bro-
`molalkynes using Triton B
`
`Scheme 6 TBAH-triggered
`ring closure reaction towards
`1,2,4-oxadiazoles
`
`building blocks for the construction of modern π-conjugated materials via cross-
`coupling reactions [17, 18].
`Tetrabutylammonium hydroxide (2, TBAH) is another frequent and commercially
`available base with similar application potential as mentioned for 1. In 2014, Otaka
`et al. examined various QACs in the construction of 1,2,4-oxadiazoles with potential
`medicinal applications [19]. It was found that the ring closure reaction of O-acylam-
`idoximes could be smoothly and quickly triggered by TBAH (Scheme 6).
`Tetraalkylammonium halides proved to be an efficient source of naked halides,
`fluoride ions in particular. Currently, fluorides are widely used across the spectrum
`of organic synthesis as powerful Lewis bases and reagents [20]. Tetrabutylammo-
`nium fluoride (3, TBAF) is one of the most prominent silicophilic nucleophiles
`capable of generating hypervalent pentacoordinated silicon intermediates, which
`may further undergo a variety of reactions including transmetalation (e.g. within the
`Hiyama cross-coupling reaction) [21]) or C–Si bond cleavage. The reactivity and
`stability of TBAF greatly depends on its hydration [22]. For instance, removal of
`Si-based protecting groups such as trialkylsilyl is accomplished with commercially
`available TBAF·3H2O [23]. A TBAF/THF system proved very convenient for gener-
`ating terminal acetylenes [24] or alcohols, which may be further utilized in fluoride-
`triggered ring opening of photochromic dyes [25] (Scheme 7). The latter, accompa-
`nied by a significant color change, can be utilized for naked-eye detection of F− ions.
`On the contrary, anhydrous TBAF is able to replace C–X with C–F functional
`groups [26]. Truly anhydrous TBAF can be generated by treating hexafluorobenzene
`with tetrabutylammonium cyanide (4, TBACN). It is a very efficient reagent in con-
`verting various halogen, tosyl, and nitro derivatives into the corresponding fluoro
`compounds (Scheme 8).
`Since 1971, QACs have also been well known as phase-transfer catalysts
`(PTC) capable of transporting one reagent across the interface to the other phase
`[27]. Water and a nonmiscible organic solvent are typical examples. This strat-
`egy allows the reaction of less polar organic substrates with a variety of inorganic
`and organic anions, generally not soluble in organic solvents. Commercially avail-
`able QACs used as PTCs include methyltrioctylammonium chloride (5, Aliquat)
`
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`Scheme 7 TBAF-triggered TMS/TBDMS-group removal/ring opening
`
`Scheme 8 Anhydrous TBAF and its application in fluorination reactions
`
`Fig. 3 Selected structure of QACs used as chiral PTCs [28]
`
`and benzyltriethylammonium chloride (6, TEBA). The portfolio of PTC reactions
`is wide and includes displacement reactions, additions, oxidation/reduction, and
`hydrolysis. In 2007, Maruoka and Hashimoto [28] reviewed recent developments
`and applications of chiral PTCs that allow stereoselective alkylation (e.g. synthesis
`of α-amino acids), aldol condensation, and epoxidation, as well as Michael, Man-
`nich, and Strecker reactions. Figure 3 shows the structure of the most efficient opti-
`cally active QACs based on scaffolds including biphenyl/binaphthalene (7], cin-
`chona alkaloid (8), and tartaric acid (9).
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`Scheme 9 N-Hexylation of trithienylimidazole using TEBA as phase-transfer catalyst
`
`The application of PTCs as a green methodology in organic synthesis was
`reviewed by Makosza [29], while Sukanyaa et al. [30] focused on the mechanistic
`aspects and important applications of PTCs. Hence, due to a number of available
`recent reviews on PTCs, I show only one recent very useful example used in our
`laboratories. In general, imidazole undergoes N-methylation with MeI or dime-
`thyl sulfate smoothly in high yield. However, a similar alkylation of electron-rich
`derivatives, such as trithienylimidazole, with higher iodoalkanes is sluggish and
`low-yielding. Hence, using a TEBA/NaOH/H2O/toluene system [31], trithie-
`nylimidazole can be smoothly N-hexylated in 96% yield (Scheme 9).
`Various tetraalkylammonium hydroxides have been examined as TiO2 modi-
`fiers. It was demonstrated that the choice of proper QACs results in a highly pho-
`toactive QAC–TiO2 hybrid material that is able to degrade (oxidize) acetone as a
`model substrate [32].
`In light of their ionic character, QACs are also very popular reaction media,
`which may also be chiral [33]. In addition to water and organic solvents, ionic
`liquids (ILs) represent a new frontier in materials science, capable of bringing
`polar and nonpolar compounds together and facilitating their reaction. The topic
`of ionic liquids was recently covered in a special issue [34]. Figure 4 shows the
`molecular structure of selected, recently developed QAC-derived ILs. A combi-
`nation of the ammonium cation substituted with relatively short C1–C4 alkyls
`−) anion affords low-melting, low-vis-
`and perfluoroalkyltrifluoroborate (RFBF3
`cous, and hydrophobic ILs 10 [35]. Bis(2-ethylhexyl)dimethylammonium cation
`
`Fig. 4 QAC-derived ionic liquids
`
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`(BEDMA), along with various counter anions, has been utilized as stable ILs 11
`that resist prolonged contact with 50% NaOH [36]. ILs 12–14 combining three
`commercially available ammonium cations—didecyldimethylammonium (12,
`DDA), benzalkonium (13, BA), and hexadecyltrimethylammonium (14, CTA)—
`have been combined with xanthene dyes such as fluoresceine and eosin Y to
`obtain dyes with unique physicochemical properties and biological activity [37].
`ILs with DDA and BA cations were also demonstrated as promising wood-pre-
`serving liquids [38].
`Interaction of QACs with fluorescein has also been utilized in their quantita-
`tive determination using sodium tetraphenylboron as a titrant [39].
`
`4 QAC Electrolytes
`
`As already mentioned above, QACs are good electrolytes both in solution and as
`ionic liquids. Hence, tetrabutylammonium hexafluorophosphate (15, TBAHFP) has
`been used as supporting electrolyte for electrochemical measurements, in particular
`cyclic voltammetry (CV) [40]. TBAHFP is sufficiently soluble in dichloromethane
`and acetonitrile to increase their conductivity, is electrochemically inert, can be eas-
`ily purified by crystallization, and therefore widens the electroactive window for CV
`measurements significantly. Tetrabutylammonium tetrafluoroborate (16, TBATFB)
`is another excellent electrolyte for general use. Both 15 and 16 are commercially
`available for a reasonable price and can be recycled [41].
`QAC-derived electrolytes have also been applied in lithium ion batteries, espe-
`cially as room-temperature ionic liquids. Their reductive stability is significantly
`affected by the ammonium cation used, and various QACs have therefore been
`designed to date [42]. Butyltriethylammonium bis(trifluoromethanesulfonyl)imide
`(17, N2224TFSI) or cyclic ammonium salts such as N-alkylmethylpyrrolidinium (18,
`mpyr) or N-alkylmethylpiperidinium (19, mpip) can be considered as representa-
`tive examples (Fig. 5). A solution of QAC 17 and LiTFSI lithium salt exhibited low
`viscosity and high conductivity comparable with conventional organic electrolytes.
`Moreover, the electrolyte is stable up to 5.7 V vs. Li without any signs of decompo-
`sition, is nonflammable, and showed high capacity retention (94%) after 75 cycles
`[43].
`
`Fig. 5 QACs as electrolytes for electrochemical measurements and batteries
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`Fig. 6 QACs used for the
`construction of supramolecular
`frameworks
`
`5 QAC Frameworks
`
`Because of their unique and positively charged structure (Fig. 1), QACs are widely
`applied in supramolecular chemistry (Fig.  6). It has been shown that the proper
`choice of QAC template crucially affects the resulting supramolecular structure,
`especially the cavity size, of porous materials such as zeolites. More or less complex
`QACs such as tetraethyl/tetrapropyl/tetrabutylammonium hydroxides [44], azoben-
`zene-terminated bis(tetraalkyl)ammonium bromides 20 [45], or propellane QAC 21
`[46] afford zeolites and molecular sieves with different 3D structure and pore size.
`QACs may also be directly embedded into a supramolecular framework to obtain
`novel materials with broad applications. For instance, Tohidi et al. demonstrated that
`simple tetrabutylammonium bromide/fluoride (TBAB/TBAF) formed semi-clathrate
`hydrates capable of trapping molecular hydrogen at low pressure [47]. Atmospheric
`carbon dioxide represents another small molecule relevant to the environment. It
`was recently discovered that QACs have extremely high affinity for CO2. Hence,
`Nunes et al. attempted to design and prepare new membrane materials 22 based on
`hydrolyzable triethoxysilane core and one or two peripheral glycidyltrimethylammo-
`nium chloride residues [48]. The polymeric membranes based on 22 featured large
` CO2 solubility coefficients and high selectivity vs. accompanying N2 and H2 gases,
`in both dry and wet conditions.
`
`6 QAC Surfactants
`
`QACs are well-recognized cationic surfactants (surface-active agents) featuring
`a positively charged and hydrophilic head (N+) and hydrophobic tail (long chain)
`(Fig.  7). In contrast to parent amines, QACs are permanent cationic surfactants
`regardless of the pH. Their amphiphilic nature is responsible for the fundamental
`mechanism of their action, which proceeds by reducing interfacial tension between
`two phases (similar to the aforementioned PCT). Two fundamental parameters of
`each surfactant that must be considered before its application are surface activity and
`tendency to self-assemble in solution and form aggregates, micelles, and vesicles
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`Fig. 7 Schematic representation of QAC-derived cationic surfactant and overview of their structures
`
`(critical micelles concentration, CMC) [49]. Despite their lower industrial produc-
`tion as compared to anionic (sulfonate) surfactants, a broad application potential still
`exists for QAC surfactants, including emulsification, dispersion, wetting, foaming,
`stabilization, fabric softeners, antistatic agents, detergents, solid-state extractions,
`and many others.
`Hexadecyltrimethylammonium bromide (HTAB), in other words cetyltrimeth-
`ylammonium bromide/chloride (23, CTAB/CTAC), along with dodecyltrimeth-
`ylammonium bromide (24, DTAB), benzalkonium chloride (25, BAC), tricoco-
`methylammonium chloride (26, Adogen 464), and bis(alkyloxycarbonylethyl)
`dimethylammonium chloride (27, esterquat) belong to the most prominent QACs
`with long alkyl chains that are commercially available and widely used. The funda-
`mental physicochemical properties of QAC surfactants can be easily modulated by
`the QAC structure and by adding other electrolytes into solution, as recently shown
`for CTAB and LiCl [50]. The extent of interaction and stabilization of nanoparticles
`and proteins with cationic DTAB was studied and compared with anionic analogue
`(sodium dodecylsulfate, SDS), which revealed that the roles of the two surfactants
`are interestingly different, and the resulting three-component system can be easily
`tuned by the surfactant used [51]. Whereas Adogen has been reported to prevent
`corrosion of metals [52], esterquats [53] are a group of modern cationic surfactants
`with rapidly growing use in laundry as high-performance scented fabric softener
`[54].
`The effect of surfactants on the given surface can also be seen in improving its
`conductivity/reducing its resistivity. Hence, QACs are used as antistatic agents capa-
`ble of eliminating spark discharges and preventing dust and dirt from accumulat-
`ing on the surface. This is a very important feature for plastics and fibers/textiles,
`especially in the automotive industry [55]. In principle, the antistatic protection can
`be nondurable or durable. Nondurable protection can be achieved by using stand-
`ard ditallowdimethlammonium chloride (DTDMAC) surfactants such as distearyldi-
`methylammonium chloride (28, DSDMAC), which is deposited on the surface by
`weak electrostatic and hydrophobic interaction [56]. Durable antistatic protection
`
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`Fig. 8 Heteroaromatic and
`aliphatic QACs with herbicidal
`properties
`
`that can withstand repeated laundering requires a surface polymeric network cross-
`linking strategy such as copolymerization of diallyldimethylammonium chloride
`(29, DADMAC) with acrylamide [57].
`
`7 QAC Herbicides and Pesticides
`
`Since the discovery of the desiccating properties of young plants caused by cetyl-
`trimethylammonium bromide 23 (CTAB) within the last century, QACs have also
`become a widely used group of herbicides and pesticides. For instance, bipyridine
`derivative 30 (paraquat, Fig. 8) has a long history dating back to 1882, when it was
`prepared and used for the first time as a viologen indicator. Its herbicidal properties
`were discovered in 1957, and it has since become the third most commonly used
`pesticide worldwide [58]. Both bipyridine derivatives 30 and 31 are nonselective,
`contact, and fast-acting herbicides with a mechanism of action based on their facile
`redox reaction and formation of reactive radicals. The use of paraquat herbicide has
`been banned since 2007 in the EU, USA, and many other countries for its toxicity
`and low biodegradability [59]. However, the redox properties of viologens are cur-
`rently widely utilized in redox flow batteries [60, 61]. The group of aliphatic QACs
`reported as herbicides and pesticides further contain 2-chloroethyltrimethylammo-
`nium chloride (32, chlormequat) or cyclic dimethylpiperidinium chloride (33, mepi-
`quat). The current literature focuses mostly on analytical methods for the detection
`and determination of the aforementioned QACs 30–33 in various environments and
`matrices such as plants, food, water, and soil. Given the ionic nature of QACs, meth-
`ods that have been developed include solid-phase extraction [62], liquid chromatog-
`raphy–electrospray tandem mass spectrometry [63], capillary electrophoresis [64],
`and modern fluorescence sensing using pyrene derivatives [65]. In contrast to the
`development of analytical methods, only a few synthetic attempts have been made to
`further modify and improve the structure of parent QAC herbicides.
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`Fig. 9 Structural modifications towards novel (multi)QACs with antimicrobial activity
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`8 QAC Antibacterials
`
`Along with their above-mentioned properties and applications, QACs have
`also been recognized as biocides with activity against a wide range of bacteria,
`viruses, yeasts, and fungi [66–68]. Hence, QACs include common disinfectants,
`antiseptics, preservatives, and sterilization agents used in households, hospi-
`tals, the textile/food industry, and water treatments. For instance, benzalkonium
`chloride (25, BAC, Fig. 7) was marketed as the antimicrobial agent “Zephirol”
`as early as 1935 [69]. BAC and didecyldimethylammonium chloride (12, DDAC,
`X = Cl, Fig. 4), another aliphatic QAC, are traditional membrane-active antimi-
`crobial agents with a similar minimum inhibitory concentration (MIC) against
`Staphylococcus aureus (0.4–1.8 ppm) [70]. Because of the increasing microbial
`resistance towards these traditional QACs, new-generation QACs have recently
`been designed and developed (Fig. 9). In light of the limited possibility of QAC
`structural variations, a common strategy involves the introduction of multiple
`heads and tails to obtain so-called multiQACs. Minbiole et al. [71] investigated
`more than 200 QACs including paraquats (un)symmetrically N-disubstituted with
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`Fig. 10 QACs for surface immobilization and copolymerization
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`various alkyl chains 34, TMEDA derivatives 35, and further extended analogues
`with three (36) and four heads (37). The MIC values measured against a standard
`panel of bacteria (Gram-positive and Gram-negative) ranged from 1 to 16 μM.
`QACs 34–37 are easily accessible from commercially available amines via qua-
`ternization, and it has been proved that flexible and multi-headed QACs are less
`prone to antimicrobial resistance. Bis-quaternaryammonium compounds 38 and
`39 extended by a central dioxoalkane linker (Fig.  9) showed activity against a
`broad spectrum of Gram-positive/negative bacteria, yeasts, and molds, with MIC
`values exceeding those measured for standard benzalkonium chloride 25 [72].
`Loftsson et al. focused on soft antimicrobial agents 40 bearing a labile linker
`which may undergo facile (non)enzymatic degradation into nontoxic building
`blocks [73]. QACs 40 with C12-C18 alkyl chains proved to be the most potent
`antibacterial agents.
`QAC with antibacterial properties can be further surface-immobilized on nan-
`oparticles, polymeric backbone, glass, or membrane [74]. For instance, polyeth-
`yleneimine-based nanoparticles peripherally modified with QACs 41 (Fig.  10)
`embedded in restorative composite resin, prepared by simple quaternization,
`were reported as antibacterial agents [75]. It has been shown that the antibacterial
`activity significantly depends on the alkyl residue; the most potent compound was
`an octyl (C8) derivative. Fu [76] and Mathias [77] adopted a very similar strat-
`egy in preparing antibacterial polymeric materials by utilizing methacrylic acid
`as polymerizable terminus appended to QAC core. Whereas dimethylalkylammo-
`nium was utilized as QAC core in 42, monomer 43 is more complex, featuring
`1,4-diazabicyclo[2]octane (DABCO)-derived central QAC and an ester linker.
`Both authors claimed that chain length (R) and polymer size were the factors most
`significantly affecting the measured minimum bactericidal concentration (MBC)
`values against Gram-positive/negative bacteria. In 2012, similar dimethacrylate-
`QACs were also applied as precursors of antibacterial polymers used in stomatol-
`ogy [78]. Hyperbranched polyurea represents another useful polymeric backbone,
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`Fig. 11 Selected examples of naturally occurring aliphatic QACs
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`which, upon modification with QAC residues, demonstrated high contact-killing
`efficacy with a different mechanism of action than in solution [79]. Transparent
`glass coatings using triethoxysilane-QAC 41 proved to be very efficient antibacte-
`rial surface treatment [80].
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`9 QAC Safety and Environmental Impact
`
`Besides the aforementioned unnatural QAC examples 1–44, there exist a number of
`natural aliphatic quaternary ammonium compounds, including choline 45, glycine
`betaine 46, and l-carnitine 47 (Fig. 11), that feature specific and valuable functions
`in the biosphere [81].
`However, environmental and health concerns have been reported for synthetic
`QACs in light of their large global production and steadily increasing application.
`These include the following most important aspects:
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`• general toxicity [82, 83];
`• accumulation of QACs in soil, sludge/sewage, water, and plants [84];
`• bacterial and antibiotic resistance and co-/cross-resistance [85, 86]; and
`• risk of asthma [87, 88].
`
`In parallel with the aforementioned antibacterial and herbicidal effects of QACs,
`their toxicity has been reported towards various aquatic and terrestrial (micro)organ-
`isms including fish. Depending on the QAC structure, the toxicity may be as low as
`0.1 mg/l. A quantitative structure–activity relationship (QSAR) study by Jing et al.
`[89] showed a direct correlation between topological parameters and EC50 values of
`13 aliphatic