The present invention relates to a method for alkylating a molecule or an ion.

Alkylation is a reaction, in which an alkyl group is transferred from a first molecule or ion to a second molecule or ion. The first molecule or ion, from which the alkyl group is transferred to the second molecule or ion, is called alkylating agent. Alkylation is a very important reaction in chemistry and biology, why alkylation agents are not only important commercial products, but are also widely present in nature. In nature, for instance alkylation agents are important for the synthesis and manipulation of a variety of biomolecules, including proteins, DNA, RNA, peptides, and carbohydrates. A prominent example for alkylation in nature is the methylation of DNA, during which methyl groups are transferred by enzymes to the bases of the DNA. DNA methylation is supposed to occur in any animate being.

Moreover, alkylating agents are used in the chemical industry, pharmaceutic industry and medicine. For instance, some chemotherapeutic agents are alkylation agents, namely the so called alkylating antineoplastic agents, which attaches alkyl groups to the number seven nitrogen atom of the purine ring of the guanine base of the DNA. The positive function of the alkylating antineoplastic agents as chemotherapeutic agents is due to the fact that cancer cells, in general, proliferate faster and with less error-correcting than healthy cells. On account therefore, cancer cells are more sensitive to the DNA damage resulting from the alkylation initiated by the alkylating antineoplastic agents.

In addition, alkylation of peptides is used in the pharmaceutic industry for example for peptide mapping or for inhibition of peptides. Alkylation reactions are also im- portant in organic synthesis, for example for alkylating amines or as reagents in the Williamson ether synthesis and in the Stork enamine alkylation.

The known alkylating agents used to date, are not completely satisfactory, but are connected with disadvantages. The vast majority of the alkylating agents are known carcinogens and often have a high vapor pressure, i.e. these alkylating agents often are highly volatile at the alkylation temperature, i.e. the temperature at which they are used during the alkylation reaction. For example, dimethyl- sulphate is a cheap and easily produced methylating agent, however it is extreme- ly toxic, corrosive and carcinogenic, and even considered to be a chemical weapon. Other reagents such as iodomethane, triethyloxonium salts and methyltriflate are comparably less toxic, but are still powerful carcinogens having a high vapor pressure at the alkylation temperature and often are not stable in air and water. As a result, they can easily be inhaled during the alkylation by the operators. In addi- tion, for safe storage without risk of explosion security measures are required.

Chiappe et al. describe in Green Chemistry, 2006, pages 277 to 281 a method for the selective preparation of N-monoalkyl-substituted anilines employing ionic liquids as a solvent. Alkyl, allyl and benzyl halides serve as alkylating agents to al- kylate differently substituted anilines as substrates. It was observed that the ionic liquid may promote the alkylation of aromatic amines, but also reduces or eliminates the formation of overalkylation products. Nevertheless, although this method may also be applied for synthesizing more complex structures, as described by Monopoli et al. in European Journal of Organic Chemistry 2012, pages 3105 to 3111 , the method is based on alkyl halides, i.e. on conventional alkylating agents having the above described drawbacks.

In US 8,722,943 B1 a method is disclosed, in which hydroxyl moieties of a polyol are alkylated using alkylating agents for producing alkoxy polyol ethers. Alkyl to- sylates are mentioned as suitable alkylating agents and tosylate moieties may be linked to a resin, such as Dowex 50W. However, the alkyl tosylates do not provide many possibilities for controlling their reactivity and therefore have a limited versatility. In view of the above, the object underlying the present invention is to provide a method for alkylating a molecule, which is safe, which is without health concern for the operators and which is effective.

In accordance with the present invention, this object is satisfied by a method for alkylating a molecule or an ion, wherein the molecule or the ion is alkylated by reacting it with an alkylating agent, wherein the alkylating agent is

i) a compound according to formula (1 ):

formula (1) wherein in formula (1 )

R is a substituted Ci-20-alkyl group, an unsubstituted Ci-2o-alkyl group, a substituted C3-2o-cycloalkyl group or an unsubstituted C3-2o-cycloaalkyl group, R ² is a substituted or unsubstituted Ci-2o hydrocarbon residue or a hydrogen atom, R ³ is a substituted or unsubstituted C1-20 hydrocarbon residue or a hydrogen atom, R ⁴ and R ⁵ are linked with each other to form an aromatic group or are

independently from each other selected from the group consisting of a hydrogen atom, substituted and unsubstituted C1-20 hydrocarbon residues and electron withdrawing groups, and

A ^" is an anion,

or ii) a compound according to formula (4):

formula (4) wherein in formula (4)

R ¹ is a substituted Ci-2o-alkyl group, an unsubstituted C-i-20-alkyl group, a substituted C3-2o-cycloalkyl group or an unsubstituted C-3-2o-cycloaalkyl group,

R ² is a substituted or unsubstituted C-i-2o hydrocarbon residue or a hydrogen atom, R ³ is a substituted or unsubstituted Ci-2o hydrocarbon residue or a hydrogen atom, R ⁴ and R ⁵ are linked with each other to form an aromatic group or are

independently from each other selected from the group consisting of a hydrogen atom, substituted and unsubstituted C1-20 hydrocarbon residues and electron withdrawing groups,

R ⁰ to R ¹³ are independently from each other selected from the group consisting of a hydrogen atom, a substituted Ci-20-alkyl group, an unsubstituted d-20-alkyl group, a substituted C3-2o-cycloalkyl group and an unsubstituted C3-2o-cycloaalkyl group, and

A ^" is an anion, wherein preferably the reaction is performed in the case of using as the alkylating agent a compound according to formula (1 ), in which R ¹ is a substituted C-i-20-alkyl group, in the dark or at ambient light conditions without irradiating any UV radiation in addition to that of the ambient light conditions.

This solution bases on the surprising finding that compounds according to the formulae (1 ) and (4) are not only very effective alkylating agents, since the alkylation residue R ¹ is effectively transferred during the alkylation reaction to the molecule or ion to be alkylated due to the comparable weak bond between the sulfur atom and the residue R , but that these compounds also have a comparable low vapor pressure at the alkylation temperature. Therefore, these compounds do not or at least not significantly produce vapor during the alkylation. Therefore, they are without or at least with at most low health concerns for the operators due to the low risk of being inhaled, but nevertheless very effective. A further advantage of the aforementioned compounds is that they can be easily derivatized at the residues R ² to R ⁵ and varied by selecting an appropriate anion A ^" , so that the reactivity and solubility of the compounds can be tailored to the needs of the specific alkylation reaction. Therefore, the method in accordance with the present invention is versatile. Moreover, these compounds are stable in air and water so as to allow to be safely stored without risk of explosion. All in all, the method in accordance with the present invention is safe, has no or at least no significant health concerns and is effective.

Thus, in accordance with the present invention a molecule or ion is alkylated by reacting it with the aforementioned alkylating agent according to any of general formulae (1 ) and (4). This means that the molecule or ion to be alkylated is different from the alkylating agent and does not derive from the alkylating agent.

Electron withdrawing groups are according to the present invention groups that draw electron density from neighboring groups. This effect can be calculated via quantum chemical methods or observed, for example by nuclear magnetic resonance spectroscopy.

In addition, the term "substituted alky group" means in accordance with the present invention any group comprising at least one terminal CH3 group, thus comprising aralkyi groups (such as benzyl), alkene groups, alkyne groups and the like.

In accordance with a particular preferred embodiment of the present invention, a molecule (and not an ion) is alkylated.

Moreover, it is preferred that the alkylation is performed without irradiating any UV radiation in addition to that of the ambient light conditions and in particular without irradiating any UV radiation by means of a mercury lamp.

Good results are in particular obtained, when the alkylating agent is a compound according to formula (1 ) or a compound according to formula (4), in which each of R ² and R ³ are independently from each other a hydrogen atom, a substituted C1-20- alkyl group, an unsubstituted Ci-20-alkyl group, a substituted C3-2o-cycloalkyl group or an unsubstituted C3-2o-cycloaalkyl group and more preferably in which each of R ² and R ³ are independently from each other a hydrogen atom, a substituted C1-12- alkyl group, an unsubstituted Ci-i2-alkyl group, a substituted C4-i2-cycloalkyl group or an unsubstituted C4-i2-cycloaalkyl group. It is further preferred that residues R ⁴ and R ⁵ in formula (1 ) or in formula (4) are linked with each other to form an aromatic group or are independently from each other selected from the group consisting of a hydrogen atom, a substituted C1-20- alkyl group, an unsubstituted Ci-2o-alkyl group, a substituted C3-2o-cycloalkyl group or an unsubstituted C3-2o-cycloaalkyl group and preferably consisting of a hydrogen atom, a substituted Ci-12-alkyl group, an unsubstituted Ci-12-alkyl group, a substituted C4-i2-cycloalkyl group or an unsubstituted C-4--i2-cycloaalkyl group.

In accordance with another preferred embodiment of the present invention, the alkylating agent is a compound according to formula (1) or a compound according to formula (4), in which:

R ¹ is an unsubstituted Ci-2o-alkyl group, preferably an unsubstituted Ci-i2-alkyl group, or an unsubstituted C3-2o-cycloaalkyl group, preferably an unsubstituted C4-i2-cycloaalkyl group,

each of R ² and R ³ are independently from each other a hydrogen atom, an unsubstituted Ci-20-alkyl group, preferably an unsubstituted Ci-i2-alkyl group, or an unsubstituted C3-2o-cycloaalkyl group, preferably an unsubstituted C4-i2-cycloaalkyl group, and

R ⁴ and R ⁵ are linked with each other to form an aromatic group or are

independently from each other selected from the group consisting of a hydrogen atom, an unsubstituted Ci-2o-alkyl group, preferably an unsubstituted Ci-12-alkyl group, or an unsubstituted C3-2o-cycloaalkyl group, preferably an unsubstituted C4-i2-cycloaalkyl group. It is particularly preferred that residue R ² is equal to residue R ³ in formula (1 ) or in formula (4).

In accordance with an alternative embodiment, in formula (1 ) or formula (4) at least one of R ⁴ and R ⁵ is an electron withdrawing group which is selected from the group consisting of carbonyl groups, hydroxyl groups, halogen atoms, carboxy groups, cyano groups fluorinated and perfluorinated alkyl groups. The provision of such electron withdrawing groups draws electrons from the five-membered aromatic ring system and thus weakens the strength of the bond between the sulfur atom and residue R ¹ , why the residue R ¹ may be more easily transferred during the alkylation reaction. Subsequently, four particular preferred embodiments of the method in accordance of the present invention are described, wherein also preferred embodiments for the aforementioned formula (1 ) are described in this description.

First particular preferred embodiment of the method of the present invention

According to a first particular preferred embodiement of the present invention, the residues R ⁴ and R ⁵ in formula (1 ) are hydrogen atoms.

Thus, in accordance with the first particular preferred embodiement of the present invention the method for alkylating a molecule or an ion comprises the step of reacting the molecule or the ion to be alkylated with an alkylating agent, wherein the alkylating agent is preferably a compound according to formula (2):

formula (2) wherein residues R ¹ , R ² , R ³ and A ^" are defined as described above for the general formula (1 ). The use of a compound according to the formula (2) as alkylating agent allows - in addition to the aforementioned advantages - to very easily remove byproduct. Furthermore, the compound may be easily synthesized, is highly stability and has a comparable low reactivity for higher-temperature applications.

Preferably, in formulae (1 ) and (2) R ² and R ³ are independently from each other a substituted or unsubstituted Ci-20 hydrocarbon residue. It is further preferred that R ² and R ³ are independently from each other a substituted or unsubstituted Ci-2o alkyl group, a substituted or unsubstituted C3-20 cycloalkyl group, a substituted or unsubstituted C2-20 alkenyl group or a substituted or unsubstituted C2-20 alkinyl group. Even more preferably, R ² and R ³ are independently from each other a substituted or unsubstituted C1-10 alkyl group, a substituted or unsubstituted C3-10 cycloalkyl group, a substituted or unsubstituted C2-10 alkenyl group or a substituted or unsubstituted C2-10 alkinyl group. Most preferably, R ² and R ³ are independently from each other a substituted or unsubstituted methyl group, ethyl group, phenyl group, or benzyl group. The reactivity of the compound increases, from least reactive to most reactive, from alkyl to benzyl to alkenyl to phenyl.

In accordance with still a further preferred embodiment, R ² and R ³ in formula (1) and/or in formula (2) are independently from each other a substituted or unsubstituted C1-20 alkyl group, a substituted or unsubstituted C3-20 cycloalkyl group, a substituted or unsubstituted C2-20 alkenyl group or a substituted or unsubstituted C2-20 alkinyl group.

It is even more preferred that R ² and R ³ in formula (1 ) and/or in formula (2) are independently from each other a substituted or unsubstituted C1-10 alkyl group, a substituted or unsubstituted C3-10 cycloalkyl group, a substituted or unsubstituted C2-10 alkenyl group or a substituted or unsubstituted C2-10 alkinyl group. Most preferably, R ² and R ³ are independently from each other a substituted or unsubstituted methyl group, ethyl group or benzyl group. In yet a further preferred embodiment, in formulae (1) and (2) R ² is equal to R ³ . If R ² is equal to R ³ synthesis of the compounds according to formulae (1) and (2) is even easier than in the case that both residues are different to each other.

In formulae (1 ) and (2) R ¹ preferably contains at least one of a hydroxy group and/or an amine group. Some examples for R are a substituted or unsubstituted C-i-20 alkyl group or a substituted or unsubstituted C3-20 cycloalkyl group. It is particularly preferred that R is a substituted or unsubstituted C1-12 alkyl group or a substituted or unsubstituted C4-12 cycloalkyl group. Even more preferably, R ¹ is a substituted or unsubstituted Ci-6 alkyl group or a substituted or unsubstituted C4-8 cycloalkyl group. Most preferably, R ¹ is a methyl group or an ethly group.

Alternatively, R ¹ in formulae (1 ) and (2) is a polymer having a molecular weight of 150 to 500000 g/mol, preferably from 500 to 5000 g/mol. It is particularly preferred that R ¹ is a synthetic polymer and even more preferred that R ¹ is a synthetic polymer having a molecular weight of 150 to 500000 g/mol, preferably from 500 to 5000 g/mol.

Most preferably, in formulae (1 ) and (2) R ¹ is a substituted or unsubstituted C1-12 alkyl group or a substituted or unsubstituted C4-12 cycloalkyl group.

In accordance with a preferred embodiment, the alkylating agent according to formula ( ) or (2) is linked to the surface of a support either covalently through a linker, electrostatically, or by adsorption. It is particularly preferred that the alkylating agent is covalently linked to the surface of the support. Even more preferably, the support is a synthetic polymer, a biopolymer, a metal, silicate, or a ceramic. It is particularly preferred that the method is performed in a tube reactor filled with the alkylating agent linked to the support. This allows to simplify the generation oif the alkylating as well as the separation of the alkylating agent and the alkylated substrate A supported compound can be easily separated from the reaction mix- ture, thus increasing the purity of the final product with less effort. The supported compounds can be furthermore regenerated by treatment with an alkylating agent. Moreover, it allows for the integration in to other systems such as flow and batch.

Preferably, in formulae ( ) and (2) A ^" is an anion which is not alkylated to a degree of more than 10% when being in contact with methyl iodide for 10 minutes at room temperature, at atmospheric pressure in a molar ratio of A ^" to methyl iodide of 1 : 1. This degree is a parameter specifying that the nucleophilicity of the anion A ^" is less than that of methyl iodide. It is even more preferred that in formulae (1 ) and (2) A ^" is an anion containing at least one of a fluorinated hydrocarbon residue, a perfluorinated hydrocarbon residue, and/or an anionic charge centred about a borate, phosphate, phosphonate, sulfate, sulfonate (in particular benzyl sulfonate or methyl sulfonate), acetate, perchlorate, (bi)carbonate, triazolate, and/or cyanamide structure. Even more preferably, in formulae (1 ) and (2) the anion A ^" is selected from the group consisting of BR ¹ , PFe ^" , BCCeHs , triflate, TFSI, FSI, BETI, TFSAM, TSAC and DCA, wherein in BR ¹ V R ¹⁴ is selected from the group consisiting of substituted or unsubstituted C1-20 hydrocarbon residues and halogen atoms. Most preferably, the anion is selected from the group consisting of TFSI, BR ¹ V, PFe ^" and BiCeHs . wherein in BR ¹ V R ¹⁴ is selected from the group consisiting of substituted or unsubstituted C1-10 hydrocarbon residues and halogen atoms. Since these anions cannot be alkylated further by methyl iodide, they do not form volatile compounds during storage or reaction and also improve the thermal stability of such alkylating agents compared with anions that may be alkylated by methyl iodide. Thus, the above mentioned anions improve the security of such alkylating agents for both, storage and handling.

In accordance with yet another preferred embodiment, the alkylation agent is an ionic liquid, more preferably a room temperature ionic liquidAs a room-temperature ionic liquid, the alkylation agent of this embodiment is non-volatile and thus safe. Yet, it can be dissolved easily in another solvent or used as a solvent itself. It can also be injected, sprayed, painted and coated with or without solvent addition. It is also preferred to synthesise an ionic liquid, preferably a room temperature ionic liquid using the method according to the invention.

It is preferable, that in the method an iodide containing salt is added to the alkylating agent in accordance with formula (1 ) or (2), i.e. the alkylating agent is reacted with the molecule or ion in the presence of an iodide containing salt. The molar ratio of the alkylating agent to the iodide containing salt is preferably in a range of 0.01 to 100.000, more preferably in a range of 0.1 to 10.000, even more preferably in a range of 0.1 to 00. When the iodide containing salt is added, the reactivity of the alkylating agent is increased, while the security aspects of the alkylating agent duing storage are not negatively influenced. Any volatile

compound resulting from an alkylation of the iodide is readily consumed in a subsequent reaction with the molecule or the ion to be alkylated, and thus the security for storage and handling is not negatively influenced in a significant manner.

According to another preferred embodiment, the alkylation is performed at a temperature in the range of -50 to 200 °C, more preferably at a temperature in the range of -30 to 100 °C or 50 to 200 °C and even more preferably at a temperature in the range of 10 to 100 °C or 70 to 150 °C. If the method for alkylation is performed below -50 °C, the reaction rate of the alkylation reaction becoms to slow. At temperatures above 200 °C there is a risk that side reaction appear more frequently and the alkylating agent decomposes before the molecule or ion is alkylated in a desired amount.

Different solvents may be used in the method for alkylating a molecule or ion, i.e. the alkylating agent is reacted with the molecule or ion in the presence of a solvent. It is preferred that at least one of water, Ν,Ν-dimethylformamide, dimethyl sulfoxide, Ν,Ν-dimethylacetamide, acetonitrile and/or acetone is used as a solvent.

According to another preferred embodiment, an organic molecule or a

metalorganic molecule is alkylated. It is further preferred that a molecule is alkylated which comprises at least one of a nitrogen atom, a sulphur atom, an oxygen atom and/or a phosphorus atom. It is particularly preferred that a molecule is alkylated which comprises at least one of a primary amine, a secondary amine, a tertiary amine, an ester, an aldehyde, a ketone, an amide, a carboxylate group, an azine group, a phosphin group, a borate group and/or a nitrogen atom in an aromatic system. It is preferable that a biomolecule is alkylated, which has preferably a molecular weight of equal to or greater than 75 g/mol, more preferably of greater than 112 g/mol .

Second particular preferred embodiment of the method of the present invention

According to a second aspect of the present invention, the alkylating agent is pref- erably a compound according to formula (3):

formula (3) wherein in formula (3)

R ¹ , R ² , R ³ and A ^" are defined as described above,

R ⁶ , R ⁷ , R ⁸ and R ⁹ are independently from each other selected from the group consisting of a hydrogen atom, an oxygen atom, a sulfur atom, substituted or unsubstituted C1-20 hydrocarbon residues and electron withdrawing groups, and/or any of R ⁶ , R ⁷ , R ⁸ and R ⁹ is linked to another one of R ⁶ , R ⁷ , R ⁸ and R ⁹ to form a cyclic structure, and X ² , X ³ , X ⁴ and X ⁵ are independently from each other selected from the group consisting of a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom, and/or X ² , X ³ , X ⁴ and X ⁵ form an aromatic ring. Due to the aromatic ring formed by X ² , X ³ , X ⁴ and X ⁵ , the compound according to formula (3) is provided with a large aromatic system and it was found that thereby the reactivity for alkylating a molecule or an ion is increased. The compound according to the formula (3) has more points to introduce functionality, such as attachment to a sol- id-support. Moreover, it further tunes the already heightened reactivity of the system.

It is preferred that in formula (3) X ² , X ³ , X ⁴ and X ⁵ are carbon atoms. Alternatively, residues X ² to X ⁵ may be a combination of either carbon, nitrogen or oxygen. The caffeine structure has the highest reactivity and has nitrogen and carbon. More electronegative elements increase reactivity as long as aromaticity is retained.

According to a further embodiment, in formula (3) R ² and R ³ are preferably independently from each other a substituted or unsubstituted Ci-2o hydrocarbon residue. It is particularly preferred that in formula (3) R ² and R ³ are independently from each other a substituted or unsubstituted Ci-2o alkyl group or a substituted or unsubstituted C3-20 cycloalkyi group. More preferably, in formula (3) R ² and R ³ are independently from each other a substituted or unsubstituted C1-10 alkyl group or a substituted or unsubstituted C3-10 cycloalkyi group. Most preferably, in formula (3) R ² and R ³ are independently from each other a substituted or unsubstituted methyl group, ethyl group, phenyl group, or benzyl group. The reactivity of the compound increases, from least reactive to most reactive, from alkyl to benzyl to alkenyl to phenyl. According to another preferred embodiment, in formula (3) R ² is equal to R ³ . This facilitates the synthesis of the compound. It is further preferred that in formula (3) R ² is equal to R ³ and R ² and R ³ are selected from the group consisting of a substituted or unsubstituted Ci-2o hydrocarbon residue. It is particularly preferred that in formula (3) R ² is equal to R ³ and R ² and R ³ are selected from the group consisting of a substituted or unsubstituted C1-20 alkyl group or a substituted or unsubstituted C3-20 cycloalkyl group. Even more preferrably in formula (3) R ² is equal to R ³ and R ² and R ³ are selected from the group consisting of a substituted or unsubstituted C1-10 alkyl group or a substituted or unsubstituted C3-10 cycloalkyl group. Most preferably, in formula (3) R ² is equal to R ³ and R ² and R ³ are selected from the group consisting of a substituted or unsubstituted methyl group, ethyl group or benzyl group.

In formula (3) R preferably contains at least one of a hydroxy group and/or an amine group. Some examples for R in formula (3) are a substituted or

unsubstituted Ci-2o alkyl group or a substituted or unsubstituted C3-20 cycloalkyl group. It is particularly preferred that in formula (3) R ¹ is a substituted or unsubstituted C1-12 alkyl group or a substituted or unsubstituted C4-12 cycloalkyl group. Even more preferably, in formula (3) R ¹ is a substituted or unsubstituted C1-6 alkyl group or a substituted or unsubstituted C4-8 cycloalkyl group. Most preferably, in formula (3) R ¹ is a methyl group or an ethly group. Alternatively, residue R ¹ may be a hydrocarbon residue being attached to a solid-support. This acts as a means to attach the solid-support to a nucleophile.

Alternatively, R is a polymer having a molecular weight of 150 to 500000 g/mol, preferably from 500 to 5000 g/mol. It is particularly preferred that R is a synthetic polymer and even more preferred that R ¹ is a synthetic polymer having a molecular weight of 150 to 500000 g/mol, preferably from 500 to 5000 g/mol.

In accordance with a further preferred embodiment of the present invention, in formula (3) at least one of R ⁶ , R ⁷ , R ⁸ and R ⁹ is an electron withdrawing group which is selected from the group consisting of carbonyl groups, hydroxy! groups, halogen atoms, carboxy groups, cyano groups fluorinated and perfluorinated alkyl groups. As a consequence of providing at least one such electron withdrawing group, the bond between the sulfur atom and R ¹ is weakened and the reactivity of the compound according to forumla (3) is increased. Even more preferably, in formula (3) at least one of R ⁶ , R ⁷ , R ⁸ and R ⁹ is an electron withdrawing group which is selected from the group consisting of carbonyl groups, hydroxyl groups, halogen atoms, carboxy groups, cyano groups fluorinated and perfluorinated alkyl groups and X ² , X ³ , X ⁴ and X ⁵ are carbon atoms.

In another preferred embodiment, in formula (3) R ¹ is a substituted or

unsubstituted C1-20 alkyl group or a substituted or unsubstituted C3-20 cycloalkyl group, at least one of R ⁶ , R ⁷ , R ⁸ and R ⁹ is an electron withdrawing group which is selected from the group consisting of carbonyl groups, hydroxyl groups, halogen atoms, carboxy groups, cyano groups fluorinated and perfluorinated alkyl groups and X ² , X ³ , X ⁴ and X ⁵ are carbon atoms. It is further preferred that in formula (3) R is a substituted or unsubstituted C1-12 alkyl group or a substituted or unsubstituted C4-12 cycloalkyl group, at least one of R ⁶ , R ⁷ , R ⁸ and R ⁹ is an electron withdrawing group which is selected from the group consisting of carbonyl groups, hydroxyl groups, halogen atoms, carboxy groups, cyano groups fluorinated and

perfluorinated alkyl groups and X ² , X ³ , X ⁴ and X ⁵ are carbon atoms. Alternatively, in formula (3) R ¹ is a polymer having a molecular weight of 150 to 500000 g/mol, preferably from 500 to 5000 g/mol, at least one of R ⁶ , R ⁷ , R ⁸ and R ⁹ is an electron withdrawing group which is selected from the group consisting of carbonyl groups, hydroxyl groups, halogen atoms, carboxy groups, cyano groups fluorinated and perfluorinated alkyl groups and X ² , X ³ , X ⁴ and X ⁵ are carbon atoms. It is further preferred that in formula (3) R ¹ is a synthetic polymer, at least one of R ⁶ , R ⁷ , R ⁸ and R ⁹ is an electron withdrawing group which is selected from the group consisting of carbonyl groups, hydroxyl groups, halogen atoms, carboxy groups, cyano groups fluorinated and perfluorinated alkyl groups and X ² , X ³ , X ⁴ and X ⁵ are carbon atoms. Even more preferably, in formula (3) R ¹ is a synthetic polymer having a molecular weight of 150 to 500000 g/mol, preferably from 500 to 5000 g/mol, at least one of R ⁶ , R ⁷ , R ⁸ and R ⁹ is an electron withdrawing group which is selected from the group consisting of carbonyl groups, hydroxyl groups, halogen atoms, carboxy groups, cyano groups fluorinated and perfluorinated alkyl groups and X ² , X ³ , X ⁴ and X ⁵ are carbon atoms.

According to another preferred embodiment of the second aspect of the present invention, in formula (3) at least one of R ⁶ , R ⁷ , R ⁸ and R ⁹ is linked to another one of R ⁶ , R ⁷ , R ⁸ and R ⁹ to form a cyclic structure which preferably is aromatic. Such a linking to an aromatic structure will increase reactivity. Anthracene for example produces a highly reactive alkylation agent. In accordance with a preferred embodiment, the alkylating agent according to formula (3) is linked to the surface of a support either covalently through a linker, electrostatically, or by adsorption. It is particularly preferred that the alkylating agent is covalently linked to the surface of the support. Even more preferably, the support is a synthetic polymer, a biopolymer, a metal, silicate, or a ceramic. It is particularly preferred that the method is performed in a tube reactor filled with the alkylating agent linked to the support. Such supported compounds can be separated from the reaction mixture, thus increasing the purity of the final product with less effort. Furthermore, the supported compounds can be regenerated by treatment with alkylating agent. This allows for integration in to other systems such as flow and batch.

Preferably, in formula (3) A ^" is an anion which is not alkylated to a degree of more than 10% when being in contact with methyl iodide for 10 minutes at room temperature, at atmospheric pressure in a molar ratio of A ^" to methyl iodide of 1 :1. It is even more preferred that A ^" is an anion containing at least one of a fluorinated hydrocarbon residue, a perfluorinated hydrocarbon residue, and/or an anionic charge centred about a borate, phosphate, phosphonate, sulfate, sulfonate (in particular benzyl sulfonate or methyl sulfonate), acetate, (bi)carbonate,

perchlorate, triazolate, and/or cyanamide structure. Even more preferably, the anion is selected from the group consisting of BR ¹ V, PF6~ , B(C6H5)4~, triflate, TFSI, FSI, BETI, TFSAM, TSAC and DCA, wherein in BR ¹ V R ¹⁴ is selected from the group consisiting of substituted or unsubstituted C1-20 hydrocarbon residues and halogen atoms. Most preferably, the anion is selected from the group consisting of TFSI, BR ¹ V, PFe ^" and B(C6H ₅ , wherein in BR ¹ V R ⁴ is selected from the group consisiting of substituted or unsubstituted C1-10 hydrocarbon residues and halogen atoms. Since these anions cannot be alkylated further by methyl iodide, they do not form volatile compounds during storage or reaction and also improve the termal stability of such alkylating agents compared with anions that may be alkylated by methyl iodide. Thus, the above mentioned anions improve the security of such alkylating agents for both, storage and handling.

In accordance with another preferred embodiment, the alkylation agent in accordance with formula (3) is an ionic liquid, more preferably a room temperature ionic liquid. As a room-temperature ionic liquid, the alkylation agent is non-volatile and thus safe. Yet, it can be dissolved easily in another solvent or used as a solvent itself. It can also be injected, sprayed, painted or coated with or without solvent addition. It is also preferred to synthesise an ionic liquid, preferably a room temperature ionic liquid using the method according to the invention. It is preferable, that in the method an iodide containing salt is added to the alkylating agent in accordance with formula (3). The molar ratio of the alkylating agent to the iodide containing salt is preferably in a range of 0.01 to 100.000, more preferably in a range of 0.1 to 10.000, even more preferably in a range of 0.1 to 100. When the iodide containing salt is added, the reactivity of the alkylating agent is increased. When the iodide containing salt is added, the reactivity of the alkylating agent is increased, while the security aspects of the alkylating agent duing storage are not negatively influenced. Any volatile compound resulting from an alkylation of the iodide is readily consumed in a subsequent reaction with the molecule or the ion to be alkylated, and thus the security for storage and handling is not negatively influenced in a significant manner. According to another preferred embodiment, the alkylation is performed at a temperature in the range of -50 to 200 °C, more preferably at a temperature in the range of -30 to 100 °C or 50 to 200 °C and even more preferably at a temperature in the range of 10 to 100 °C or 70 to 150 °C. If the method for alkylation is performed below -50 °C, the reaction rate of the alkylation reaction becoms to slow. At temperatures above 200 °C there is a risk that side reaction appear more frequently and the alkylating agent decomposes before the molecule or ion is alkylated in a desired amount.

Different solvents may be used in the method for alkylating a molecule or ion. It is preferred that at least one of water, Ν,Ν-dimethylformamide, dimethyl sulfoxide, Ν,Ν-dimethylacetamide, acetonitrile and/or acetone is used as a solvent. According to another preferred embodiment, an organic molecule or a

metalorganic molecule is alkylated. It is further preferred that a molecule is alkylated which comprises at least one of a nitrogen atom, a sulphur atom, an oxygen atom and/or a phosphorus atom. It is particularly preferred that a molecule is alkylated which comprises at least one of a primary amine, a secondary amine, a tertiary amine, an ester, an aldehyde, a ketone, an amide, a carboxylate group, an azine group, a phosphin group, a borate group and/or a nitrogen atom in an aromatic system. It is preferable that a biomolecule is alkylated, which has preferably a molecular weight of equal to or greater than 75 g/mol, more preferably of greater than 112 g/mol.

Third particular preferred embodiment of the method of the present invention

According to a third aspect of the present invention, the alkylating agent is preferably a compound according to formula (4):

formula (4) wherein in formula (4) R ¹ , R ² , R ³ , R ⁴ , R ⁵ and A ^" are defined as described above and residues R ⁰ to R ¹³ are independently from each other selected from the group consisting of a hydrogen atom, substituted and unsubstituted Ci-2o

hydrocarbon residues and electron withdrawing groups. Compounds according to the formula (4) may be easily synthesized by methods that can be facilitated in one step. The have more positions for the manipulation of the structure - such as for changing the reactivity, adding functionality or attachment to solid support.

According to a preferred embodiment, in formula (4) R ¹⁰ to R ¹³ are hydrogen atoms. According to another preferred embodiment, in formula (4) R ⁴ and R ⁵ are hydrogen atoms. It is even more preferred that in formula (4) R ⁴ and R ⁵ are hydrogen atoms and that R ¹⁰ to R ¹³ are hydrogen atoms.

According to a further embodiment, in formula (4) R ² and R ³ are preferably independently from each other a substituted or unsubstituted Ci-2o hydrocarbon residue. It is particularly preferred that in formula (4) R ² and R ³ are independently from each other a substituted or unsubstituted Ci-20 alkyl group, a substituted or unsubstituted C3-20 cycloalkyl group, a substituted or unsubstituted C2-20 alkenyl group or a substituted or unsubstituted C2-20 alkinyl group. More preferably, in formula (4) R ² and R ³ are independently from each other a substituted or unsubstituted C1-10 alkyl group, a substituted or unsubstituted C3-10 cycloalkyl group, a substituted or unsubstituted C2-10 alkenyl group or a substituted or unsubstituted C2-10 alkinyl group. Most preferably, in formula (4) R ² and R ³ are independently from each other a substituted or unsubstituted methyl group, ethyl group or benzyl group. In accordance with another preferred embodiment, in formula (4) R ² is equal to R ³ .

In formula (4) R preferably contains at least one of a hydroxy group and/or an amine group. Some examples for R ¹ in formula (4) are a substituted or

unsubstituted C1-20 alkyl group or a substituted or unsubstituted C3-20 cycloalkyl group. It is particularly preferred that in formula (4) R ¹ is a substituted or unsubstituted C1-12 alkyl group or a substituted or unsubstituted C4-12 cycloalkyl group. Even more preferably, in formula (4) R is a substituted or unsubstituted C1-6 alkyl group or a substituted or unsubstituted C4-8 cycloalkyl group. Most preferably, in formula (4) R ¹ is a methyl group or an ethly group.

Alternatively, in formula (4) R ¹ is a polymer having a molecular weight of 150 to 500000 g/mol, preferably from 500 to 5000 g/mol. It is particularly preferred that R ¹ is a synthetic polymer and even more preferred that R ¹ is a synthetic polymer having a molecular weight of 150 to 500000 g/mol, preferably from 500 to 5000 g/mol.

According to another preferred embodiment, in formula (4) R ¹ is a substituted Ci- 20-alkyl group, an unsubstituted Ci-2o-alkyl group, a substituted C3-2o-cycloalkyl group or an unsubstituted C3-2o-cycloaalkyl group, and R ⁴ and R ⁵ are hydrogen atoms. It is particularly preferred that in formula (4) R ¹ is a substituted or unsubstituted C1-12 alkyl group or a substituted or unsubstituted C4-12 cycloalkyl group, and R ⁴ and R ⁵ are hydrogen atoms.

In accordance with an alternative preferred embodiment, in formula (4) R ¹ is a polymer having a molecular weight of 150 to 500000 g/mol, preferably from 500 to 5000 g/mol and R ⁴ and R ⁵ are hydrogen atoms. It is further preferred that in formula (4) R ¹ is a synthetic polymer and R ⁴ and R ⁵ are hydrogen atoms. It is particularly preferred that in formula (4) R ¹ is a synthetic polymer having a molecular weight of 150 to 500000 g/mol, preferably from 500 to 5000 g/mol and R ⁴ and R ⁵ are hydrogen atoms.

It is preferred that in formula (4) at least one of R ⁴ , R ⁵ , R ¹⁰ , R ¹¹ , R ¹² , and R ³ is an electron withdrawing group which is selected from the group consisting of carbonyl groups, hydroxyl groups, halogen atoms, carboxy groups, cyano groups

fluorinated and perfluorinated alkyl groups. As a consequence of providing such electron withdrawing groups, the bond between the sulfur atom and R ¹ is weakened and the reactivity of the compound according to forumla (4) as an alkylating agent is increased. In another preferred embodiment, in formula (4) R ⁴ and R ⁵ are hydrogen atoms and at least one of R ¹⁰ , R ¹¹ , R ¹² , and R ¹³ is an electron withdrawing group. According to another preferred embodiment, in formula (4) R ¹⁰ , R ¹¹ , R ² , and R ³ are hydrogen atoms and at least one of R ⁴ and R ⁵ is an electron withdrawing group which is selected from the group consisting of carbonyl groups, hydroxyl groups, halogen atoms, carboxy groups, cyano groups fluorinated and perfluorinated alkyl groups.

It is also preferred that in formula (4) R is a substituted or unsubstituted Ci-2o alkyl group or a substituted or unsubstituted C3-20 cycloalkyl group, and at least one of R ⁴ R ⁵ , R ⁰ , R ¹¹ , R ¹² , and R ¹³ is an electron withdrawing group which is selected from the group consisting of carbonyl groups, hydroxyl groups, halogen atoms, carboxy groups, cyano groups fluorinated and perfluorinated alkyl groups. It is even further preferred that in formula (4) R ¹ is a substituted or unsubstituted C1-12 alkyl group or a substituted or unsubstituted C4-12 cycloalkyl group, R ⁴ and R ⁵ are hydrogen atoms and at least one of R ¹⁰ , R ¹¹ , R ¹² , and R ¹³ is an electron

withdrawing group which is selected from the group consisting of carbonyl groups, hydroxyl groups, halogen atoms, carboxy groups, cyano groups fluorinated and perfluorinated alkyl groups.

In accordance with yet another preferred embodiment, in formula (4) R ¹ is a polymer having a molecular weight of 150 to 500000 g/mol, preferably from 500 to 5000 g/mol and at least one of R ⁴ , R ⁵ , R ¹⁰ , R ¹¹ , R ¹² , and R ¹³ is an electron withdrawing group which is selected from the group consisting of carbonyl groups, hydroxyl groups, halogen atoms, carboxy groups, cyano groups fluorinated and perfluorinated alkyl groups. It is also preferred that in formula (4) R ¹ is a synthetic polymer and at least one of R ⁴ , R ⁵ , R ¹⁰ , R ¹ , R ¹² , and R ¹³ is an electron withdrawing group which is selected from the group consisting of carbonyl groups, hydroxyl groups, halogen atoms, carboxy groups, cyano groups fluorinated and

perfluorinated alkyl groups. Most preferably, in formula (4) R ¹ is a synthetic polymer having a molecular weight of 150 to 500000 g/mol, preferably from 500 to 5000 g/mol and at least one of R ⁴ , R ⁵ , R ¹⁰ , R ¹ , R ¹² , and R ³ is an electron withdrawing group which is selected from the group consisting of carbonyl groups, hydroxyl groups, halogen atoms, carboxy groups, cyano groups fluorinated and perfluorinated alkyl groups.

In accordance with a preferred embodiment, the compound according to formula (4) is linked to the surface of a support either covalently through a linker, electrostatically, or by adsorption. It is particularly preferred that the alkylating agent is covalently linked to the surface of the support. Even more preferably, the support is a synthetic polymer, a biopolymer, a metal, silicate, or a ceramic. Such supported compounds can be separated from the reaction mixture, thus increasing the purity of the final product with less effort. Furthermore, the supported compounds can be regenerated by treatment with alkylating agent. This allows for integration in to other systems such as flow and batch. It is particlularly preferred that the method is performed in a tube reactor filled with the alkylating agent linked to the support.

Preferably, in formula (4) A ^" is an anion containing at least one of a fluorinated hydrocarbon residue, a perfluorinated hydrocarbon residue, and/or an anionic charge centred about a borate, phosphate, phosphonate, sulfate, sulfonate (in particular benzyl sulfonate or methyl sulfonate), acetate, perchlorate, triazolate, and/or cyanamide structure. Even more preferably, the anion is selected from the group consisting of BR V, PFe ^" , B(C ₆ H ₅ )4 ^" , triflate, TFSI, FSI, BETI, TFSAM, TSAC and DCA, wherein in BR ¹ V R ¹⁴ is selected from the group consisiting of substituted or unsubstituted Ci-2o hydrocarbon residues and halogen atoms. Most preferably, the anion is selected from the group consisting of TFSI, BR ¹ V, PF6~ and B(C6H5)4 ^_ , wherein in BR V R ¹⁴ is selected from the group consisiting of substituted or unsubstituted C1-10 hydrocarbon residues and halogen atoms. Since these anions cannot be alkylated further by methyl iodide, they do not form volatile compounds during storage or reaction and also improve the termal stability of such compounds compared with anions that may be alkylated by methyl iodide. Thus, the above mentioned anions improve the security of such alkylating agents for both, storage and handling.

In accordance with another preferred embodiment, the alkylation agent is an ionic liquid, more preferably a room temperature ionic liquid. As a room-temperature ionic liquid, the alkylation agent is non-volatile and thus safe. Yet, it can be dissolved easily in another solvent or used as a solvent itself. It can also be injected, sprayed, painted or coated with or without solvent addition. It is also preferred to synthesise an ionic liquid, preferably a room temperature ionic liquid using the method according to the invention. It is preferable, that in the method an iodide containing salt is added to the alkylating agent according to formula (4). The molar ratio of the alkylating agent according to formula (4) to the iodide containing salt is preferably in a range of 0.01 to 100.000, more preferably in a range of 0.1 to 10.000, even more preferably in a range of 0.1 to 100. When the iodide containing salt is added, the reactivity of the alkylating agent is increased. When the iodide containing salt is added, the reactivity of the alkylating agent is increased, while the security aspects of the alkylating agent duing storage are not negatively influenced. Any volatile compound resulting from an alkylation of the iodide is readily consumed in a subsequent reaction with the molecule or the ion to be alkylated, and thus the security for storage and handling is not negatively influenced in a significant manner.

According to yet another preferred embodiment, the alkylation is performed at a temperature in the range of -50 to 200 °C, more preferably at a temperature in the range of -30 to 100 °C or 50 to 200 °C and even more preferably at a temperature in the range of 10 to 100 °C or 70 to 150 °C. If the method for alkylation is performed below -50 °C, the reaction rate of the alkylation reaction becoms to slow. At temperatures above 200 °C there is a risk that side reaction appear more frequently and the alkylating agent decomposes before the molecule or ion is alkylated in a desired amount.

Different solvents may be used in the method for alkylating a molecule or ion. It is preferred that at least one of water, Ν,Ν-dimethylformamide, dimethyl sulfoxide, Ν,Ν-dimethylacetamide, acetonitrile and/or acetone is used as a solvent.

According to another preferred embodiment, an organic molecule or a

metalorganic molecule is alkylated. It is further preferred that a molecule is alkylated which comprises at least one of a nitrogen atom, a sulphur atom, an oxygen atom and/or a phosphorus atom. It is particularly preferred that a molecule is alkylated which comprises at least one of a primary amine, a secondary amine, a tertiary amine, an ester, an aldehyde, a ketone, an amide, a carboxylate group, an azine group, a phosphin group, a borate group and/or a nitrogen atom in an aromatic system. It is preferable that a biomolecule is alkylated, which has preferably a molecular weight of equal to or greater than 75 g/mol, more preferably of greater than 112 g/mol.

Fourth particular preferred embodiment of the method of the present invention As set out above, it is according to the present invention particularly preferred that A ^" is an anion which is not alkylated to a degree of more than 10% when being in contact with methyl iodide for 10 minutes at room temperature, at atmospheric pressure in a molar ratio of A ^" to methyl iodide of 1 :1. Since the anion A ^" is not easily alkylated, the formation of a volatile compound during storage of the compound according to the present invention does not occur, providing for safe storage and handling of the compound according to the present invention , while still providing a powerful alkylation agent. More specifically, the anion of this embodiment is a less nucleophile compound than iodine so as to im- prove the stability of the compounds, to depress their melting points so as to obtain non-volatile compounds not forming harmful vapors and thus harmless and safe alkylation compounds, which are less reactive than the corresponding halogenide salts and thus allow selective alkylations. It is preferable that in the compound used according to the present invention A ^" is an anion containing at least one of a fluorinated hydrocarbon residue, a

perfluorinated hydrocarbon residue, and/or an anionic charge centred about a borate, phosphate, phosphonate, sulfate, sulfonate (in particular benzyl sulfonate or methyl sulfonate), acetate, perchlorate, triazolate, (bi)carbonate, and/or cyanamide structure. More preferably, the anion is selected from the group consisting of BR ¹ V, PFe ^" , BfCeHs . triflate, TFSI, FSI, BETI, TFSAM, TSAC and DCA, wherein in BR ¹ V R ¹⁴ is a moiety selected from the group consisting of substituted or unsubstituted C1-20 hydrocarbon residues and halogen atoms. Most preferably, the anion is selected from the group consisting of TFSI, BR ¹ V, PF6 ^~ and B(C6Hs)4, wherein in BR ¹ V R ¹⁴ is selected from the group consisiting of substituted or unsubstituted C1-10 hydrocarbon residues and halogen atoms.

In accordance with another preferred embodiment, the compound used according to the present invention is an ionic liquid, more preferably a room temperature ionic liquid. As a room-temperature ionic liquid, the alkylation agent is non-volatile and thus safe. Yet, it can be dissolved easily in another solvent or used as a solvent itself. It can also be injected, sprayed, painted or coated with or without solvent addition. According to another preferred embodiment, the compound used according to the present invention is linked to a surface of a support either covalently through a linker, electrostatically, or by adsorption.

Subsequently, the present invention is described by means of figures and exam- pies, which do, however, not limit the present patent application, wherein:

Fig. 1 shows the strucutres of preferred anions of the compounds used in the method according to the present invention. Fig. 2a shows a thermogravimetric analysis of compounds according to formula

(2), wherein R is one of methyl, ethyl, n-buthyl, n-hexyl, n-octyl or n- dodecyl, R ² and R ³ are methyl groups, and the anion is iodide. Fig. 2b shows a thermogravimetric analysis of compounds according to formula (2), wherein R ¹ is one of methyl, ethyl, n-buthyl, n-hexyl, n-octyl or n- dodecyl, R ² and R ³ are methyl groups, and the anion is TFSI.

Fig. 2c shows a thermogravimetric analysis of compounds according to formula

(2), wherein R ¹ is one of methyl, ethyl, n-buthyl, n-hexyl, n-octyl or n- dodecyl, R ² is benzyl, R ³ is a methyl group, and the anion is iodide.

Fig. 2d shows a thermogravimetric analysis of compounds according to formula

(2), wherein R ¹ is one of methyl, ethyl, n-buthyl, n-hexyl, n-octyl or n- dodecyl, R ² is benzyl, R ³ is a methyl group, and the anion is TFSI.

Fig. 2e shows the hydrolysis reaction scheme of a compound according to

formula (2) and of a compound according to formula (3).

Fig. 3a shows the structure of seven alkylating agents, which were used in

examples 2 to 8.

Fig. 3b shows the reaction scheme of the alkylation of pyridine with any of the alkylating agents shown in Fig. 3a as performed in examples 2 to 8.

Fig. 4 shows some examples of compounds that were alkylated using an

alkylating agent in accordance with the present invention in examples 9 to 38.

Fig. 5 shows in general the synthesis of the alkylating agent in accordance with the invention.

Fig. 6 shows the conversion of pyridine to methylpyridinium as a function of anion for thiobenzimidazolium alkylating salts used in example 46. Fig. 7 shows the scheme for the bottom-up production of alkylating resin particles using a flow reactor setup as described in example 47. In Fig. 1 several strucutres of preferred anions, as they have been described above for the particular preferred embodiments, are shown. Each of R ¹⁴ of the compounds illustrated in Fig. 1 may be a substituted or unsubstituted C1-20 hydrocarbon residue or a halogen atom. DCA is the abreviation for dicyanamide, TFSAM for 2,2,2-trifluoromethylsulfonyl-N-cyanoamide, TSAC for 2,2,2-trifluoro-N- (trifluoromethylsulfonyl)acetamide, FSI for bis(fluorosulfonyl)imide, TFSI for bis(trifluoromethanesulfonyl)imide and BETI for bis(perfluoroethylsulfonyl)imide. None of these anions is methylated to a degree of more than 10% when being in contact with methyl iodide for 10 minutes at room temperature, at atmospheric pressure in a molar ratio of the anion to methyl iodide of 1 :1.

Example 1

As shown in Fig. 2a - in which a thermogravimetric analysis of compounds according to formula (2), wherein R ¹ is one of methyl, ethyl, n-buthyl, n-hexyl, n-octyl or n-dodecyl, R ² and R ³ are methyl groups, the anion is iodide, is shown - respective compounds according to formula (2), wherein R ¹ is one of methyl, ethyl, n-buthyl, n-hexyl, n-octyl or n-dodecyl, R ² and R ³ are methyl groups, the anion is iodide show a thermal decomposition at around 120°C to 170°C. By changing the anion from iodide to TFSI, as shown in Fig. 2b the thermal compositions begins at a temperature at around 270°C, i.e. the thermal stability of the alkylating agent is increased by change of the anion from iodide to TFSI. The same derives from a comparison of Fig. 2c with Fig. 2d, which are

thermogravimetric analyses of compounds as shown in Fig. 2a and 2b except that residue R ² in these compounds is a benzyl group. In each thermogravimetric analysis, approximately 10 mg of sample were heated at 10 °C/min under a nitrogen atmosphere (20 mL/min) to 800 °C.

Plotting the decomposition temperature Tdec as a function of the melting

temperature T _m for each of the aforementioned iodide salts reveals a relationship between melting and thermal stability. For the compounds shown in Fig. 2a (also designated as series 1 below), both Tdec and T _m were found to be between about 110 and 165 °C, whereas the compounds shown in Fig. 2c (also designated as series 2 below) revealed lower melting temperatures. The higher melting temperature of the compounds shown in Fig. 2a is likely a result of the efficient packing of the thioimidazolium heterocycle, which is disrupted by the introduction of the benzyl substituent in compounds shown in Fig. 2c. In general, higher melting points impart greater thermal stability, although differences in the relationship between Tdec and Tm for these two series are observed as shown in the below Table 1. In the case for series 1 , T _m /Tdec ratios are between 0.92 and 0.97, meaning that decomposition occurs just after melting (within a 6 to 10 °C window). In contrast, these values are lower for series 2 at 0.63 to 0.87, where the salts exist in a molten state prior to decomposition. This trend was not observed for any of the TFSI salts since they were isolated as liquids at room temperature. An increase in Tdec was observed for all TFSI salts, with mass loss onset observed from 282 to 310 °C for those shown in Fig. 2b and 280-303 °C for those shown in Fig. 2d. While the TFSI salts here are more stable, they are generally lower in stability when compared to some imidazolium salts with decomposition

temperatures above 400 °C26

Table 1 : The melting (Tm) and decomposition points (Tdec) of series 1 and 2 iodide salts Series # R ¹ chain length Tm (°C) Tdec (°C) Tm Tdec

1 -iodide a (CH ₃ ) 152.1 157.3 0.967

b (C2H5) 111.9 122.0 0.917

C (C4H9) 163.5 169.0 0.967

d (CeHi ₃ ) 117.7 121.7 0.967

e (C-8H17) 118.5 125.3 0.945

f (C12H25) 126.1 134.3 0.939

2-iodide a (CHa) 87.1 125.0 0.697

b (C2H5) 101.1 116.5 0.868

c (C ₄ H9) 72.9 108.3 0.673

d (CeHi3) 82.5 106.3 0.776

e (CeHi7) 68.9 108.5 0.629

f (Cl2H25) 77.4 121.4 0.638

The use of new chemical compounds in commercial sectors often requires an understanding of their environmental impact in case of spill or contamination during use or transport. This is in light of the fact that a variety of alkyl halides are known to be very toxic towards animals, but also fungi, bacteria, and some plants. Thioimidazolium salts could conceivably release these compounds in natural environments and thus pose a danger to these organisms. As well, related quaternary salts are known to be powerful antiseptic agents used commercially and may accumulate in the environment, however the antiseptic properties of thioimidazolium salts are not known.

To provide a first glimpse, the antimicrobial activity of 1a-iodide (i.e. a compound of the formula shown in Fig. 2a with R being methyl) and 1f-iodide (i.e. a compound of the formula shown in Fig. 2a with R being n-dodecyl) against

Pseudomonas aeruginosa, a particularly difficult bacterium for many disinfectants and an organism associated with some hospital-acquired infections (see below Table 2). It was found that at relatively high concentrations, 1a-iodide displayed no significant activity towards this species, with a Iog10-reduction (Ig) of only <3.68 being achieved under the conditions imposed by EN1040 at up to 0.1 wt% even after 30 minutes contact. In contrast, 1f-iodide was much more potent. At a concentration of > 0.0028 a log 10 reduction of > 5 was achieved using a contact time of 30 minutes. Compared to the reference benzalkonium chloride (BAC), 1f- iodide is a poorer disinfectant, thus providing some evidence that the alkylation function in this particular case does not provide any advantage towards

Pseudomonas aeruginosa toxicity, and instead likely functions according to the established mechanisms associated with conventional quaternary salts. In addition to their antimicrobial properties, the degradation of thioimidazolium salts in water is of particular interest, namely because of the robust stability many conventional quaternary salts display coupled with their heavy use, leading to antimicrobial resistance and persistence in the environment. This is highlighted by the fact that the imidazolium heterocycle is extraordinarily resistant to biodegradation, which is also a common problem among a number of other common ILs. Many cationic surfactants include hydrolysable ester linkages to improve their degradation, however the metabolites often persist, including the cationic portion of the surfactant. One solution is to design new cations that are capable of undergoing a precise degradation process to form neutral metabolites that could be further broken down.

Table 2: Quantitative suspension test for the bactericidal activity of 1a-iodide and 1f-iodide in comparison to benzalkonium chloride (BAC) standard at different times. Substance Concentration (wt %) Target reduction of 5 Log-io cfu

5 min 10 min 30 min

8.0χ10· ¹ y y y

BAC (reference) 4.0x10- ³ y y y

1.0x10- ³ X X y

8.0x10- ² X X X

1a-iodide 4.0x10- ² X X X

8.0x10- ³ X X X

4.0x10 ^"3 X X y

1f-iodide 2.8x10- ³ X X y

2.0x10- ³ X X X

It was previously reported that 1a-iodide is stable in water at 95 °C for up to 16 h. In contrast, it was found in the present invention that more electrophilic

thioimidazolium cations derived from benzimidazole are not as water stable and will quickly hydrolyse (4 h, 95 °C; Figure 4) to form thione or ketone and thiol byproducts, which can be further degraded in the environment. The ability to controllably hydrolyse these salts helps to limit their persistence in the biospehere where they can interact with wildlife. For example, 1f-iodide is easily degraded in alkaline solution. The decomposition rate is reduced when a slight excess (2 eq.) of NaOH is used for compound 1c-iodide (see Figure 2e) and can be measured by 1 H NMR spectroscopy (98% decomposition, 120 h, room temperature). In the presence of weaker bases such as K2CO3, the decomposition rate was

dramatically lowered with only 3% decomposition in the same time. These experiments demonstrate that thioimidazolium salts may serve as a promising platform for the design of environmentally friendly disinfectants. Examples 2 to 15

Alkylation reactions reactions were performed with the seven compounds shown Fig. 3a, in which X ^" is iodide, and with the seven compounds shown in Fig. 3a, in which X ^" is TFSI. Each of the fourteen compounds was used to alkylate pyridine according the the reaction scheme shown in Fig. 3b.

For each example, a 1 :1 molar ratio of alkylating agent and pyridine (0.1851 mmol) were dissolved in DMSO-c/6 (0.4 mL) and added to a standard NMR tube. The sample was then heated to reaction temperature (50 or 90 °C) and analyzed in- situ every hour by H-NMR spectroscopy for up to 13 hours. Pyridine conversion was determined by comparing the integration values of pyridine (δ = 7.99 or 7.35) to 1-methylpyridinium product (δ = 8.13), while alkylating agent conversion was determined by comparing the integration values of the thioimidazolium salt to the thione product. Second-order rate constants were obtained by plotting 1/[Pyr]t as a function of time and measuring the slope. The results are shown in Table 3.

Table 3: Rate constants for reaction of fourteen compounds with pyridine in DMSO.

Examples 16 to 45

The methylation of compounds shown in Fig. 4 was conducted in either DMSO-c 6 (examples 16 to 30) or D2O (examples 31 to 45).

Reactions in DMSO-c/6

Compound 2-I (20 mg, 0.074 mmol) was combined with 1 eq. of each of the substrates shown in Fig. 4 and DMSO-c/6 (0.5 mL) in an NMR tube. After 24 hours the reaction mixture was analyzed by ¹ H-NMR spectroscopy to determine whether methylation proceeded. Conversion values were determined by comparing the integration values of the N-CH3 functionality on 2-I (δ = 3.901) to N-CH3 on the 1 ,3-dimethylimidazolethione byproduct (δ = 3.448) after alkylation. Conversions were generally low, so the reactions were heated to first 50 °C and then 80 °C at 24 hour intervals, and analyzed by H-NMR spectroscopy prior to increasing temperature.

It was found that 2-I is stable at these temperatures in DMSO, so that any decomposition that occurs must be a result of nucleophilic substitution

Reactions in D2O

The same reactions were performed in D2O. The procedures were similar to the those in DMSO-d6, except the reactions were conducted in small vials with mag- netic stirring bars.

The conversion data of all these examples are shown in table 4. Table 4: Reaction of compound 2-1 with various nucleophiles for 24 hrs at different temperatures in DMSO-d6. Reported conversions are %consumed alkylator for a given nucleophile.

RT (%) 50 °C (%) 80 °C (%)

1,1,3,3-

1 23

tetramethylguanidine 98

2-pyrrolidone - - -

4-aminophenol 1 16 74

Acetic acid, sodium salt - 14 41

Acetic acid, glacial - - -

Aniline - 15 76

Benzyl amine - 27 97

Benzyl alcohol - - -

Diethylamine 2 37 99

Diphenyl sulfide - <1 3

Ethanolamine <1 31 96

L-alanine - 4 25

Methanol - - -

Triethylamine 8 39 94

Triphenyl phosphine 1 19 88

Synthesis of alkylating agents for formula (1 ) to (3)

Synthesis of all substances used in the examples followed a general procedure (Fig. 5). 1 was synthesized from tetramethylthiourea, which is commercially available and used as received. Step 1 : Quaternization

Briefly, the parent amine (1-methylimidazole, 1-phenylimidazole, 1-(2- chlorophenyl)imidazole, or 1-methylbenzimidazole; 25 mmol) was quaternized with 2 eq Mel or BzCI (50 mmol) in acetonitrile (100 ml_) at room temperature for 24 hours. The solution was then concentrated (30 ml_), precipitated in diethylether (500 ml_), and volatiles evaporated in-vacuo to isolate the iodide/chloride salts as an off-white powder in good yield (80%). Caffeine was quaternized with 4 eq. of Mel (100 mmol) in acetonitrile (100 mL) at 80 °C for 48 hours (70%). Step 2: Sulfurization

All quaternized salts (10 mmol) were dissolved in MeOH (40 mL) followed by the addition of 2 eq. of elemental sulfur (20 mmol) and stirred for 10 minutes. Once a suspension was obtained, 2 eq. of potassium carbonate (20 mmol) was added and left stirring for up to 48 hours. MeOH was then fully evaporated in-vacuo and the residue rinsed with water (3x50 mL) and recrystallized from isopropanol and dried in-vacuo to isolate off-white crystals (60%).

Step 3: S-alkylation

The sulfurized product (5 mmol) was dissolved in acetonitrile (30 mL) followed by the addition of 2 eq. alkyliodide (10 mmol) and stirred at room temperature for up to 48 hours. Volatiles were removed in-vacuo at no more than 50 °C to isolate the S-alkylated iodide salts in quantitative yields.

Step 4: An ion-exchange with TFSI

The S-alkylated iodide salts displayed variable solubility properties in water depending on the alkyliodide used for S-alkylation, with n-octyl and n-dodecyl salts displaying low solubilities in water, but excellent solubility in dichloromethane. As a result, two procedures were developed for the anion exchange reaction depending on their solubilities In water:

S-alkylated iodide salts (4 mmol) were dissolved in water (15 mL) followed by the addition of a slight excess of LiTFSI (4.1 mmol). This resulted in the formation of a precipitate or a biphasic system, which was stirred for 24 hours before rinsing with water (3x5 mL), until the rinsing solutions passed the silver nitrate test. The product was then dried in-vacuo to isolate the TFSI salts as either a liquid, or in some cases a solid (6 and 7, 60%).

In dichloromethane:

S-alkylated iodide salts with either a n-octyl or n-dodecyl appendages (4 mmol) were dissolved in dichloromethane (10 mL) followed by the addition of solid LiTFSI (4 mmol). The slurry was stirred for 24 hours before filtering off the lithium iodide by gravity filtration. The solution was then rinsed with water (3x5 mL) and then dried in-vacuo to isolate the TFSI salts (60%).

Compound information

2-l-Me

H-NMR (400 MHz, DMSO-d6): δ = 2.52 (s, 3H), 3.90 (s, 6H), 7.91 (s, 2H).

1 ³ C{ ¹ H}-NMR (100 MHz, DMSO-d6): δ = 17.01 (s), 36.10 (s), 124.66 (s), 140.73 (s).

2-l-Et

H-NMR (400 MHz, DMSO-d6): δ = 1.17 (t, 3H, ¹ J = 7.4 Hz), 3.05 (q, 2H, J = 7.6 Hz), 3.91 (s, 6H), 7.95 (s, 2H). ¹³ C{ H}-NMR (100 MHz, DMSO-d6): δ = 15.13 (s), 29.64 (s), 36.23 (s), 124.96 (s), 139.48 (s).

2-l-Bu

¹ H-NMR (400 MHz, DMSO-d6): δ = 0.87 (t, 3H, J = 7.2 Hz), 1.36 (m, 2H), 1.48 (m, 2H), 3.02 (t, 2H, = 7.4 Hz), 3.90 (s, 6H), 7.93 (s, 2H). ¹³ C{ ¹ H}-NMR (100 MHz, DMSO-d6): δ = 13.30 (s), 20.95 (s), 31.46 (s), 34.57 (s), 36.19 (s), 124.93 (s), 139.63 (s). 2-l-Hex

¹ H-NMR (400 MHz, DMSO-d6): δ = 0.85 (t, 3H, ¹ J = 7 Hz), 1.25 (m, 4H), 1.33 (m, 2H), 1.49 (m, 2H), 3.02 (t, 2H, J = 7.4 Hz), 3.90 (s, 6H). ¹³ C{ H}-NMR (100 MHz, DMSO-d6): δ = 13.81 (s), 21.88 (s), 27.38 (s), 29.43 (s), 30.53 (s), 34.88 (s), 36.21 (s), 124.91 (s), 139.71 (s).

2-l-Oct

¹ H-NMR (400 MHz, DMSO-d6): δ = 0.85 (t, 3H, J = 6.8 Hz), 1.23 (m, 8H), 1.32 (m, 2H), 1.49 (m, 2H), 3.01 (t, 2H, ¹ J = 7.4 Hz), 3.89 (s, 6H), 7.93 (s, 2H). ¹³ C{ ¹ H}- NMR (100 MHz, DMSO-d6): δ = 13.90 (s), 21.98 (s), 27.73 (s), 28.30 (s), 28.48 (s), 29.48 (s), 31.10 (s), 34.85 (s), 36.20 (s), 124.92 (s), 139.72 (s).

2-l-Dodecyl

¹ H-NMR (400 MHz, DMSO-d6): δ = 0.85 (t, 3H, J = 7 Hz), 1.23 (m, 16H), 1.32 (m, 2H), 1.49 (m, 2H), 3.02 (t, 2H, J = 7.4 Hz), 3.90 (s, 6H), 7.94 (s, 2H). ¹³ C{ H}- NMR (100 MHz, DMSO-d6): δ = 13.89 (s), 22.03 (s), 27.73 (s), 28.34 (s), 28.64 (s), 28.82 (s), 28.88 (s), 28.94 (s), 29.47 (s), 31.22 (s), 34.87 (s), 36.21 (s), 124.90 (s), 139.71 (s). 2-TFSI-Me

H-NMR (400 MHz, DMSO-d6): δ = 2.51 (s, 3H), 3.90 (s, 6H), 7.88 (s, 2H).

3C{ H}-NMR (100 M, DMSO-d6): δ = 16.82 (s), 36.01 (s), 119.42 (q, ¹ J = 319.5 Hz), 124.71 (s), 140.75 (s). 2-TFSI-Et

¹ H-NMR (400 MHz, DMSO-d6): δ = 1.17 (t, 3H, J = 7.4 Hz), 3.04 (q, 2H, J = 7.2 Hz), 3.90 (s, 6H), 7.92 (s, 2H). ³ C{ ¹ H}-NMR (100 MHz, DMS0-d6): δ = 15.10 (s), 29.58 (s), 36.16 (s), 119.41 (q, ¹ J = 319.9 Hz), 125.01 (s), 139.50 (s). 2-TFSI-Bu

¹ H-NMR (400 MHz, DMS0-d6): δ = 0.88 (t, 3H, J = 7.2 Hz), 1.36 (m, 2H), 1.49 (m, 2H), 3.01 (t, 2H, ¹ J = 7.2 Hz), 3.90 (s, 6H), 7.91 (s, 2H). ¹³ C{ H}-NMR (100 MHz, DMSO-d6): δ = 13.26 (s), 20.97 (s), 31.48 (s), 34.54 (s), 36.13 (s), 119.42 (q, ¹ J = 319.9 Hz), 124.96 (s), 139.72 (s).

2- TFSI-Oct

H-NMR (400 MHz, DMSO-d6): δ = 0.85 (t, 3H, ¹ J = 6.8 Hz), 1.25 (m, 4H), 1.33 (m, 2H), 1.50 (m, 2H), 3.01 (t, 2H, ¹ J = 7.4 Hz), 3.89 (s, 6H). ³ C{ ¹ H}-NMR (100 MHz, DMSO-d6): δ = 13.80 (s), 21.90 (s), 27.42 (s), 29.46 (s), 30.57 (s), 34.82 (s), 36.14 (s), 119.41 (q, ¹ J = 319.8 Hz), 124.96 (s), 139.73 (s). 2-TFSI-Dodecyl

¹ H-NMR (400 MHz, DMSO-d6): δ = 0.85 (t, 3H, ¹ J = 6.8 Hz), 1.24 (m, 8H), 1.33 (m, 2H), 1.50 (m, 2H), 3.01 (t, 2H, ¹ J = 7.4 Hz), 3.89 (s, 6H), 7.91 (s, 2H). ¹³ C{ H}- NMR ( 00 MHz, DMSO-d6): δ = 3.87 (s), 22.00 (s), 27.76 (s), 28.32 (s), 28.50 (s), 29.49 (s), 31.13 (s), 34.84 (s), 36.13 (s), 119.41 (q, J = 319.9 Hz), 124.95 (s), 139.73 (s).

3- l-Me

¹ H-NMR (400 MHz, DMS0-d6): δ = 2.38 (s, 3H), 3.93 (s, 3H), 5.54 (s, 2H), 7.38 (m, 5H), 8.00 (m, 2H). ³ C{ H}-NMR (100 M, DMS0-d6): δ = 17.36 (s), 36.20 (s), 52.06 (s), 124.02 (s), 125.55 (s), 127.70 (s), 128.46 (s), 128.90 (s), 134.76 (s), 140.70 (s).

3-l-Et

¹ H-NMR (400 MHz, DMSO-d6): δ = 1.11 (m, 3H), 2.94 (m, 2H), 3.94 (s, 3H), 5.56 (s, 2H), 7.38 (m, 5H), 8.05 (m, 2H). ¹³ C{ ¹ H}-NMR (100 MHz, DMS0-d6): δ = 14.77 (s), 30.11 (s), 36.43 (s), 52.08 (s), 124.26 (s), 125.78 (s), 127.71 (s), 128.47 (s), 128.85 (s), 134.67 (s), 139.53 (s).

3-l-Bu

1H-NMR (400 MHz, DMSO-d6): δ = 0.80 (t, 3H, J = 7.2 Hz), 1.25 (m, 2H), 1.40 (m, 2H), 3.93 (s, 3H), 5.55 (s, 2H), 7.37 (m, 5H), 8.04 (m, 2H). ³ C{ H}-NMR (100 MHz, DMS0-d6): δ = 13.25 (s), 21.01 (s), 31.16 (s), 34.97 (s), 36.41 (s), 52.08 (s), 124.31 (s), 125.73 (s), 127.60 (s), 128.43 (s), 128.85 (s), 134.72 (s), 139.74 (s). 3-l-Hex

¹ H-NMR (400 MHz, DMSO-d6): δ = 0.83 (t, 3H, J = 7 Hz), 1.20 (m, 6H), .40 (m, 2H), 2.85 (t, 2H, ¹ J = 7.6 Hz), 3.93 (s, 3H), 5.55 (s, 2H), 7.37 (m, 5H), 8.78 (m, 2H). ¹³ C{ H}-NMR (100 MHz, DMSO-d6): δ = 13.80 (s), 21.83 (s), 27.43 (s), 29.13 (s), 30.47 (s), 35.23 (s), 36.40 (s), 52.07 (s), 124.32 (s), 125.73 (s), 127.57 (s), 128.43 (s), 128.85 (s), 134.73 (s), 139.77 (s).

3-l-Oct

H-NMR (400 MHz, DMSO-d6): δ = 0.85 (t, 3H, J = 7 Hz), 1.18 (m, 10H), 1.40 (m, 2H), 2.85 (t, 2H, ¹ J = 7.6 Hz), 3.92 (s, 3H), 5.54 (s, 2H), 7.37 (m, 5H), 8.04 (m,

2H). ¹³ C{ ¹ H}-NMR (100 MHz, DMSO-d6): δ = 13.91 (s), 21.97 (s), 27.77 (s), 28.22 (s), 28.42 (s), 29.17 (s), 31.08 (s), 35.22 (s), 36.39 (s), 52.07 (s), 124.32 (s), 125.73 (s), 27.57 (s), 28.42 (s), 28.84 (s), 34.73 (s), 139.78 (s). 3-l-Dodecyl

H-NMR (400 MHz, DMSO-d6): δ = 0.85 (t, 3H, ¹ J = 6.8 Hz), 1.23 (m, 18H), 1.40 (m, 2H), 2.85 (t, 2H, ¹ J = 7.6 Hz), 3.92 (s, 3H), 5.54 (s, 2H), 7.36 (m, 5H), 8.04 (m, 2H). ³ C{ H}-NMR (100 MHz, DMSO-d6): δ = 13.921 (s), 22.05 (s), 27.77 (s), 28.27 (s), 28.66 (s), 28.77 (s), 28.87 (s), 28.95 (s), 29.18 (s), 31.24 (s), 35.23 (s), 36.39 (s), 52.07 (s), 124.31 (s), 125.73 (s), 127.58 (s), 128.41 (s), 128.83 (s), 134.73 (s), 139.77 (s).

3-TFSI-Me

¹ H-NMR (400 MHz, DMSO-d6): δ = 2.38 (s, 3H), 3.94 (s, 3H), 5.55 (s, 2H), 7.39 (m, 5H), 7.99 (m, 2H). ¹³ C{ H}-NMR (100 M, DMSO-d6): δ = 17.22 (s), 36.11 (s), 52.11 (s), 119.44 (q, ¹ J = 319.8 Hz), 124.04 (s), 125.57 (s), 127.69 (s), 128.46 (s), 128.88 (s), 134.72 (s), 140.71 (s).

3-TFSI-Et

H-NMR (400 MHz, DMSO-d6): δ = 2.38 (s, 3H), 3.94 (s, 3H), 5.55 (s, 2H), 7.39 (m, 5H), 7.99 (m, 2H). ³ C{ H}-NMR (100 MHz, DMSO-d6): δ = 17.22 (s), 36.11 (s), 52.11 (s), 119.44 (q, ¹ J = 319.9 Hz), 124.04 (s), 125.57 (s), 127.69 (s), 128.46 (s), 128.88 (s), 134.72 (s), 140.71 (s). 3-TFSI-Bu

¹ H-NMR (400 MHz, DMSO-d6): δ = 0.81 (t, 3H, J = 7.4 Hz), 1.26 (m, 2H), 1.41 (m, 2H), 2.50 (s, 2H), 2.86 (t, 2H, J = 7.4 Hz), 3.93 (s, 6H), 5.54 (s, 2H), 7.37 (m, 5H), 8.02 (m, 2H). ¹³ C{ ¹ H}-NMR (100 MHz, DMSO-d6): δ = 13.17 (s), 21.00 (s), 31.16 (s), 34.92 (s), 36.30 (s), 52.11 (s), 119.42 (q, J = 319.9 Hz), 124.34 (s), 125.75 (s), 127.58 (s), 128.44 (s), 128.85 (s), 134.71 (s), 139.76 (s).

3-TFSI-Hex

¹ H-NMR (400 MHz, DMSO-d6): δ = 0.84 (t, 3H, J = 7 Hz), 1.20 (m, 6H), .42 (m, 2H), 2.85 (m, 2H), 3.93 (s, 3H), 5.55 (s, 2H), 7.37 (m, 5H), 8.02 (m, 2H). ³ C{ H}- NMR (100 MHz, DMSO-d6): δ = 13.71 (s), 21.82 (s), 27.44 (s), 29.14 (s), 30.47 (s), 35.19 (s), 36.29 (s), 52.11 (s), 1 9.42 (q, J = 319.9 Hz), 124.34 (s), 125.74 (s), 127.55 (s), 128.42 (s), 128.83 (s), 134.71 (s), 139.79 (s). 3-TFSI-Oct

¹ H-NMR (400 MHz, DMSO-d6): δ = 0.85 (t, 3H, J = 7 Hz), 1.19 (m, 10H), 1.42 (m, 2H), 2.85 (t, 2H, ¹ J = 7.4 Hz), 3.92 (s, 3H), 5.54 (s, 2H), 7.37 (m, 5H), 8.02 (m, 2H). ¹³ C{ ¹ H}-NMR (100 MHz, DMSO-d6): δ = 13.84 (s), 21.97 (s), 27.77 (s), 28.22 (s), 28.42 (s), 29.17 (s), 31.09 (s), 35.18 (s), 36.30 (s), 52.09 (s), 119.41 (q, J = 319.9 Hz), 124.33 (s), 125.74 (s), 127.55 (s), 128.42 (s), 128.83 (s), 134.71 (s), 139.79 (s).

3- TFSI-Dodecyl

¹ H-NMR (400 MHz, DMSO-d6): δ = 0.85 (t, 3H, ¹ J = 7 Hz), 1.23 (m, 18H), 1.41 (m, 2H), 2.85 (t, 2H, J = 7.4 Hz), 3.92 (s, 3H), 5.54 (s, 2H), 7.37 (m, 5H), 8.02 (m,

2H). ¹³ C{ ¹ H}-NMR (100 MHz, DMSO-d6): δ = 13.91 (s), 22.07 (s), 27.79 (s), 28.28 (s), 28.68 (s), 28.79 (s), 28.88 (s), 28.96 (s), 28.97 (s), 29.19 (s), 31.26 (s), 35.19 (s), 36.33 (s), 52.09 (s), 119.41 (q, J = 319.9 Hz), 124.34 (s), 125.75 (s), 127.57 (s), 128.44 (s), 128.85 (s), 134.75 (s), 139.79 (s).

4- I

¹ H-NMR (400 MHz, DMSO-d6): δ = 2.34 (s, 3H, S-CH ₃ ), 4.00 (s, 3H), 7.67 (m, 5H), 8.13 (s, 1 H), 8.17 (s, 1 H). ³ C-NMR (100 MHz, DMSO-d6): δ = 17.2 (s), 36.3 (s), 125.0 (s), 125.1 (s), 126.3 (s), 129.7 (s), 130.5 (s), 135.3 (s), 141.8 (s). 4- TFSI

H-NMR (400 MHz, DMSO-d6): δ = 2.33 (s, 3H, S-CH ₃ ), 4.00 (s, 3H), 7.67 (m, 5H), 8.12 (s, 1 H), 8.17 (s, 1 H). ³ C{ H}-NMR (100 MHz, DMSO-d6): δ = 17.2 (s), 36.3 (s), 125.0 (s), 125.1 (s), 126.3 (s), 129.7 (s), 130.5 (s), 135.3 (s), 141.8 (s). ¹³ C-NMR (100 MHz, DMSO-d6): δ = 17.1 (s), 36.3 (s), 1 19.4 (q, ¹ JC-F = 320 Hz), 125.1 (s), 125.2 (s), 126.3 (s), 129.7 (s), 130.6 (s), 135.3 (s), 141.8 (s).

5- I

1H-NMR (400 MHz, DMSO-d6): δ = 2.40 (s, 3H, S-CH ₃ ), 4.00 (s, 3H), 7.67 (m, 2H), 7.84 (m, 2H) 8.21 (s, 1 H), 8.22 (s, 1 H). ³ C-NMR (100 MHz, DMSO-d6): δ =

17.2 (s), 36.6 (s), 125.4 (s), 125.8 (s), 128.7 (s), 129.8 (s), 130.1 (s), 130.4 (s), 132.6 (s), 132.9 (s), 142.5 (s). 6-I

¹ H-NMR (400 MHz, DMSO-d6): δ = 2.72 (s, 3H, S-CH ₃ ), 4.13 (s, 6H), 7.72 (m, 2H), 8.06 (m, 2H). ³ C-NMR (100 MHz, DMSO-d6): δ = 17.1 (s), 33.2 (s), 1 13.2 (s), 126.7 (s), 132.1 (s), 149.9 (s). 6-TFSI

¹ H-NMR (400 MHz, DMSO-d6): δ = 2.71 (s, 3H, S-CHs), 4.13 (s, 6H), 7.72 (m, 2H), 8.07 (m, 2H). ¹⁹ F-NMR (376 MHz, DMSO-d6): δ = -78.8 (s) ³ C-NMR (100 MHz, DMSO-d6): δ = 17.0 (s), 33.1 (s), 1 13.2 (s), 1 19.4 (q, JC-F = 320 Hz), 126.8 (s), 132.1 (s), 149.9 (s).

7-I

¹ H-NMR (400 MHz, DMSO-d6): δ = 2.59 (s, 3H, S-CH ₃ ), 3.29 (s, 3H), 3.79 (s, 3H), 4.19 (s, 3H), 4.23 (s, 3H). ¹³ C-NMR (100 MHz, DMSO-d6): δ = 28.0 (s), 31 .7 (s),

33.3 (s), 34.2 (s), 103.9 (s), 139.1 (s), 150.3 (s), 152.2 (s), 165.6 (s). 7-TFSI

¹ H-NMR (400 MHz, DMSO-d6): δ = 2.59 (s, 3H, S-CH ₃ ), 3.29 (s, 3H), 3.79 (s, 3H), 4.19 (s, 3H), 4.23 (s, 3H). ¹³ C-NMR (100 MHz, DMSO-d6): δ = 17.5 (s), 28.5 (s), 32.1 (s), 35.6 (s), 36.3 (s), 108.6 (s), 119.4 (q, JC-F = 320 Hz) 140.0 (s), 145.8 (s), 150.0 (s), 152.9 (s).

Synthesis of alkylating agents for formula (4)

Synthesis proceeded using a modified Debus-Radiziszewski reaction. Briefly, me- thylamine (40 wt% in water, 0.40 g, 12.88 mmol) was added to acetic acid (0.90 g, 15.0 mmol) in a vial dropwise at 0 °C and then warmed to room temperature. In a separate vial, 4-(methylthio)benzaldehyde (1.08 g, 7.08 mmol) was combined with glyxoal (40 wt% in water, 0.748 g, 12.88 mmol), 2 ml_ isopropanol, and 1.25 ml_ acetic aicd. The two vials were then combined quickly and left stirring for 24 hours, after which the solution was extracted with ethyl acetate (3x50 mL) and a 5 ml_ aqueous solution of LiTFSI (4.0 g, 14.0 mmol) added to the reaction mixture. A brown oil was formed upon addition and was rinsed with water (3x10 mL) and dried in-vacuo to isolate the product.

Example 46

In this example, the role different anions have on the reactivity of the thiobenzim- idazolium salts was assessed by examining the reaction kinetics for the methyla- tion of pyridine. Four salts of the cation shown in figure 2a, in which R is methyl, with the anions shown in figure 6, i.e. methyl sulfonate, PF6 ^" , triflate and benzyl sulfonate, respectively, were used as alkylating agents. The four alkylating agents were reacted with 1 equivalent of pyridine in DMSO and the percent conversion to 1-methylpyridinium monitored by 1 H NMR spectroscopy for up to 12 h. Second order rate constants were obtained by plotting 1/[Pyr] as a function of time and measuring the slope. With respect to reactivity, as shown in figure 6 it is found that both anion choice had a noticeable effect on the alkylating abilities of these salts. Example 47

(Bottom-up synthesis of alkylating resin beads from thioimidazolium monomers using flow chemistry)

In this example, resin beads were produced from alkylation thioimidazolium salt monomers in a bottom-up approach. Thioimidazolium monomer and crosslinker were combined with photoinitiator in aqueous solution and slowly injected in to a fast stream of silicone oil within plastic tubing as shown in figure 7. More specifically, aqueous solution was injected from a syringe into a T-joint where silicone oil was introduced. The droplets were passed through a coiled tube and exposed to UV light before being collected. The aqueous solution formed evenly sized droplets, which were separated and carried by the silicone oil through a UV-reactor (>300 nm, 115W, 5 min). During this time, the initiator was cleaved and the monomer photopolymerized to form evenly sized crosslinked beads, which were collected. After rinsing with pentane, ethanol, water, and ethanol once more, the resin was air died. It was found that these beads could be used as a polymer-supported alkylator similar to Merrifield resin-functionalized thioimidazolium salts and repre- sents a methodology whereby alkylating resin is produced directly from thioimidazolium monomer. The resulting particles were comprised of many smaller particles that have bound together to create one larger resin particle. This approach produces some porosity, which helps to facilitate mass transport within the particle.

(Regeneration and refunctionalization of alkylating resins with different alkyl groups)

The ability to regenerate the resin multiple times significantly reduces waste and is key for their practical use where resin replacement is both costly and technically difficult. Ideally, spent resin should be capable of regeneration by treatment with alkyl iodide and be quantitative over multiple cycles. As well, spent resin should be able to undergo functionalize with any number of different alkyl iodides, thus providing a convenient and general platform for solid-supported alkylations. To determine this, regeneration experiments were performed whereby the nucleophile 1-methylimidazole (0,10 g) was transferred in a flask containing acetonitrile (3 ml_) and the alkylating resin with a transferrable alkyl moiety (0,11 g) and heated to 80°C for 24 h. After removal of the resin, the solution was concentrated by rotary evaporation and analyzed by H NMR to assess the conversion percentage of 1- methylimidazole in 1 ,3-methylimidazolium iodide. The loading of alkylator was determine by the conversion of 1-methylimidazole and related to the mass of resin used to give loading values in mmol of alkylator per gram of resin. The resin was then washed several times with acetonitrile and acetone and then dried under vacuum. It was regenerated in MeCN containing excess Mel and used once more to alkylate the nucleophile. It was found that over 5 cycles the activity of the resin did not change, with an activity of ~1.1 mmol/g of resin. After the 5 ^th cycle the resin was alkylated with nBul and tested in the same way. It was found that over 3 cycles the activity did not change with a loading of -3.7 mmol/g of resin. It is believed that the higher loading here is a result of improved swelling of the resin as a result of butylation. These results show that one set of resin can be used multiple times to methylate or butylate a nucleophile.