WO2025114271A1

WO2025114271A1 - Nucleophilic aromatic substitution in an aqueous medium in the presence of a surfactant

Info

Publication number: WO2025114271A1
Application number: PCT/EP2024/083593
Authority: WO
Inventors: Ryan LITTICH; Warren Miller
Original assignee: Lonza AG; Lonza Bend Inc
Current assignee: Lonza AG; Lonza Bend Inc
Priority date: 2023-11-29
Filing date: 2024-11-26
Publication date: 2025-06-05
Anticipated expiration: 2026-05-29

Abstract

The invention relates to nucleophilic aromatic substitution reactions done in an aqueous medium in the presence of a surfactant, the surfactant is an ethoxyxlate of a secondary alcohol or an alkoxylated Guerbet alcohol.

Description

TITLE

NUCLEOPHILIC AROMATIC SUBSTITUTION IN AN AQUEOUS MEDIUM IN THE PRESENCE OF A SURFACTANT

FIELD OF THE INVENTION

The invention relates to nucleophilic aromatic substitution reactions done in an aqueous medium in the presence of a surfactant, the surfactant is an ethoxylate of a secondary alcohol or an alkoxylated Guerbet alcohol.

BACKGROUND OF THE INVENTION

N. A. Isley et al. in Organic Letters, 2015, 17, 4734-4737 (Isley), disclose nucleophilic aromatic substitution reactions in water enabled by micellar catalysis, the micelles are formed by TPGS-750-M.

TPGS-750-M, due its ester linkages, is prone to hydrolysis at pH < 5 and pH > 8, which narrows its applicability, since many reactions involve conditions outside neutral or near-neutral pH.

There was a need for surfactants providing aqueous micellar solvent systems which are performing over a wide temperature range and a wide pH range, that show low persistence of the emulsion in workup, that do not lead to inseparable - or slowly separating - aqueous and organic phase emulsions during workup, and that minimize or eliminate residual surfactants from downstream processes such as recrystalhzation, distillation, or lyophilization (as non -limiting examples).

The inventors found that ethoxylates of secondary alcohols and ethoxylated Guerbet alcohols as surfactants provide aqueous micellar solvent systems which allow high operating temperatures, a wide range of operating pH, for example a high operating pH, and high reaction yields. The reaction yields actually are improved over the yields obtained by the use of TPGS-750-M. Said surfactants furthermore allow rather low concentrations of surfactant.

SUMMARY OF THE INVENTION Subject of the invention is a method for performing a nucleophilic aromatic substitution reaction comprising: combining a nucleophile and an aromatic electrophile in an aqueous medium; said aqueous medium comprises water, a base, and a surfactant, wherein the surfactant is a surfactant of formula (l) or a surfactant of formula (II) or a mixture thereof;

wherein n is an integer from 2 to 40,

R1 and R2 are identical or different Ci-is alkyl;

(ID

and wherein a is an integer from 2 to 40, b is an integer from 0 to 20,

R3 is selected from the group consisting of methyl, ethyl, propyl and butyl, d is an integer from 0 to 10, c = (d + 2).

DETAILED DESCRIPTION OF THE INVENTION

The nucleophilic aromatic substitution reaction is also called shortly reaction herein for the ease of reading.

The term “nucleophilic aromatic substitution reaction” (NAS or SNAT) as used herein denotes a chemical reaction in which a nucleophile as reagent replaces a leaving group attached to an aromatic ring of a substrate, the aromatic electrophile, resulting in the substitution of one functional group, the leaving group, with another on the aromatic ring of the substrate, the aromatic electrophile. A typical leaving group of the substrate may be nitro (NO2), fluoro (F), chloro (Cl), bromo (Br) or iodo (I).

The reactants of the SNAT are said nucleophile and the substrate, that is said aromatic electrophile. This reaction occurs via a series of concerted electron movements, including the attack of the nucleophile on the electrophihc carbon atom of the aromatic ring, which disrupts aromaticity, via a negatively charged carbanion intermediate and subsequent rearrangements of the n-electrons. The reaction can be accelerated by the presence of electron-withdrawing groups (EWG) on the aromatic ring, particularly in ortho- or para -position to the endocychc C atom on which the substitution of the functional group takes place. The substrate may contain one or more electron withdrawing substituents.

The nucleophilic aromatic substitution reaction takes place in the presence of the surfactant, wherein the surfactant provides for an aqueous micellar system in the aqueous medium. In one embodiment, the invention relates to a nucleophihc aromatic substitution reactions in an aqueous micellar solvent system, wherein the micelles are formed by said surfactant.

At least part of the surfactant is present as micelles contained in the aqueous medium.

Another term for surfactant that is sometimes used is the term emulsifier, within the meaning of the invention these two terms are used interchangeably.

The term “aqueous micellar system” as used herein denotes a dispersion composed of micelles in the aqueous medium, the micelles are spontaneously formed aggregates or clusters of surfactant molecules in the aqueous medium. As used herein, the terms "dispersion" and “emulsion” are used interchangeably to denote a 2 -phase system with a first phase, the dispersed phase, being emulgated or suspended or colloidally dispersed within a second phase, the liquid continuous phase. The three terms "emulgated”, "suspended”, and "dispersed" are used interchangeably herein. In the aqueous micellar system the dispersed phase are the micelles and the continuous phase are the liquid components of the aqueous medium.

Micelles are formed when the concentration of surfactant molecules exceeds the critical micelle concentration (CMC) in a particular solvent. The CMC is the concentration at which the surfactant molecules start to self-assemble and form micelles. At and above the CMC additional surfactant substantially forms micelles. Typically, there is a relatively small range of concentrations separating the Emit below which substantially no micelles are detected and the limit above which substantially all additional surfactant molecules form micelles. In an aqueous micellar system, the hydrophobic tails are clustered or shielded within the core of the micelle, while the hydrophilic head groups form the outer layer that interacts with the surrounding solvent. This arrangement allows the micelles to solubilize and disperse hydrophobic substances within the hydrophobic core, creating a system where the hydrophobic molecules are effectively and evenly distributed in the solvent.

The term “surfactant” as used herein denotes an amphiphilic surfactant molecule that helps to form a stable and homogeneous dispersion or emulsion.

The term “emulsion” refers to a mixture of two or more immiscible hquid substances, where one substance is dispersed in another as small droplets, and wherein the surfactant molecules’ amphiphilic properties enable them to reduce the surface tension between the immiscible substances by forming a layer around the dispersed droplets of one substance, known as the dispersed phase, preventing them from coalescing or separating from the continuous phase. The surfactants of the present invention are capable of forming micelles.

When surfactants are present above the CMC, they allow a compound that is normally insoluble in the solvent being used to dissolve. This occurs because the insoluble species can be incorporated into the micelle core, which is itself solubilized in the bulk solvent by virtue of the head groups' favorable interactions with solvent species.

The present invention discloses in one embodiment the nucleophilic aromatic substitution reaction catalyzed by micellar catalysis by said surfactant. The term "micellar catalysis", as used herein, relates to a chemical reaction in an aqueous medium by the presence of a surfactant which is capable of forming micelles, preferably at a concentration higher than its critical micelle concentration so that micelles form and the reaction can occur in the environment of said micelles. Without wishing to be bound to a specific theory, it is beheved that the occurrence of said reaction may be due, for example, to higher concentration of the reactants in a micelle, more favorable orientation and solvation of the reactants, or enhanced reaction rate constants in the micelle.

Within the meaning of the invention, any ethoxylated and/or propoxylated surfactant is a mixture of species containing blocks of different numbers of ethylene oxide (EO) units and/or different numbers of propylene oxide (PO) units. Any stated number for the EO units in a polyEO block (PEO block) and any stated number for the PO units in a polyPO block (PPO block) is an average number.

The surfactant of formula (l) is an surfactant is an ethoxyxlate of a secondary alcohol.

In one embodiment of the invention, the surfactant of formula (l) is a polyethoxylated secondary alcohol.

In a particular embodiment, n is an integer from 3 to 35; preferably from 3 to 30; more preferably from 3 to 20; even more preferably n is 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; especially n is 9, 10 or 15.

In a particular embodiment, R1 and R2 are identical or different selected from the group linear or branched C2 is alkyl, C2 10 alkyl, C3 10 alkyl, C39 alkyl, and C3 -8 alkyl; preferably selected from the group linear or branched C3 alkyl, C4 alkyl, C5 alkyl, CG alkyl, C7 alkyl, and Cs alkyl; more preferably selected from the group n-propyl, iso-propyl, 2 -methylpropyl, n-butyl, tert-butyl, iso-butyl, n pentyl, 2, 4- dimethylpentyl, n-hexyl, n-heptyl, and n octyl; even more preferably selected from the group 2 -methylpropyl, n-pentyl, 2,4- dimethylpentyl and n-heptyl.

In a particular embodiment, R1 is 2 -methylpropyl or n-pentyl. In a particular embodiment, R2 is 2,4-dimethylpentyl or n-heptyl. In a particular embodiment, R1 and R2 are identical.

In a particular embodiment, R1 and R2 are different.

In a particular embodiment n is 10, R1 is 2-methylpropyl and R2 is 2,4- dimethylpentyl.

In a particular embodiment n is 9, R1 is n-pentyl and R2 is n-heptyl.

In a particular embodiment n is 15, R1 is n -pentyl and R2 is n-heptyl.

Any of these particular embodiments can be combined with any one or more of the other of these particular embodiments.

Preferably, n is an integer from 3 to 35, more preferably from 3 to 30, even more preferably from 3 to 20, and/or

R1 and R2 are identical or different C2 13 alkyl, more preferably C2 10 alkyl; especially, n is 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, and/or

R1 and R2 are identical or different C3 10 alkyl, preferably C3 9 alkyl, more preferably Cs-8 alkyl; more especially, n is 9, 10, 11, 12, 13, 14, or 15, and/or

R1 and R2 are identical or different and selected from the group consisting of C4 alkyl, C5 alkyl, Cs alkyl, and C~ alkyl.

In a particular embodiment, n is 10 and R1 is C4 alkyl and R2 is C7 alkyl, or n is 9 and R1 is C5 alkyl and R2 is C7 alkyl, or n is 15 and R1 is C5 alkyl and R2 is C7 alkyl.

In a particular embodiment, n is 10 and R1 is 2-methyl-n propyl and R2 is 2, 4-dimethyl-n pentyl, or n is 9 and R1 is n-pentyl and R2 is n-heptyl, or n is 15 and R1 is n-pentyl and R2 is n-heptyl. Surfactants of formula (I) are known to the skilled person and commercially available, for example certain compounds of the Tergitol™ product range of The Dow Chemical Company, US.

In one embodiment of the invention, the surfactant of formula (II) is an alkoxylated Guerbet alcohol.

In one embodiment of the invention, the surfactant of formula (II) is an ethoxylated Guerbet alcohol.

In one embodiment of the invention, the surfactant of formula (II) is a poly alkoxylated Guerbet alcohol.

The term “Guerbet alcohol” as used herein denotes a primary alcohol alkylated on the C atom of the 2 position obtained via self-condensation of a primary alcohol in a Guerbet reaction, named after Guerbet M., Comptes rendus de 1'Academie des sciences (1909) 149:129-132.

In one embodiment of the invention, a is an integer selected from 3 to 40, preferably from 3 to 30, more preferably from 3 to 20; even more preferably 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; especially 9 or 12.

In one embodiment of the invention, b is an integer selected from 0 to 20, preferably from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, more preferably from 0, 1, 2, 3, 4, 5, or 6; even more preferably 0 or 5.

In one embodiment of the invention, d is an integer selected from 0 to 10, preferably from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, more preferably from 1, 2, 3, 4, 5, 6 or 7; even more preferably 1 or 3.

In one embodiment of the invention, R3 is selected from methyl, ethyl, propyl and butyl; particularly R3 is methyl.

In a particular embodiment, a is 9, b is 5, c is 3, d is 1, and R3 is methyl.

In a particular embodiment, a is 9, b is 0, c is 5, and d is 3. In embodiments, b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 0, 1, 2, 3, 4, 5 or 6; and/or

R3 is methyl; and/or a is an integer from 3 to 40, preferably from 3 to 30, more preferably from 3 to 20; and/or d is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1, 2, 3, 4, 5, 6 or 7, more preferably 1,

2, 3, 4 or 5, even more preferably 1 or 3; in particular embodiments, when d is 1 then b is 5, a is 9 and R3 is methyl; or when d is 3 then b is 0, and a is 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, preferably 9 or 12.

Surfactants of formula (II) are known to the skilled person, for example as

Ecosurf™ product range of The Dow Chemical Company, US or WET LF-9™ of TRUNNANO (aka. Luoyang Tongrun Nano Technolgy Co., Ltd), China.

The surfactant is preferably a commercially available surfactant.

In an embodiment, surfactant of formula (l) is Tergitol™ TMN-10, Tergitol™ 15- S'9, or Tergitol™ 15-S-15.

In an embodiment, surfactant of formula (II) is Ecosurf™ EH-9 or WET LF-9™.

In one embodiment, the surfactant is selected from the list of^;

Tergitol™ TMN-10, a surfactant of formula (l) wherein n = 10, R1 = 2- methylpropyl, and R2 = 2,4-dimethylpentyl;

Tergitol™ 15-S-9, a surfactant of formula (l) wherein n = 9, R1 = n-pentyl, and

R2 = n heptyl;

Tergitol™ 15-S-15, a surfactant of formula (l) wherein n = 15, R1 = n-pentyl, and

R2 = n heptyl;

Ecosurf™ EH-9, a surfactant of formula (II) wherein a = 9, b =5, c = 3, d = 1, and

R3 = methyl;

WET LF-9™, a surfactant of formula (II) wherein a = 9, b -0, c - 5, and d - 3; and mixtures thereof. In one embodiment, the surfactant is a surfactant of formula (I) wherein n = 10, R1 = 2 -methylpropyl, and R2 = 2,4-dimethylpentyl (Tergitol™ TMN-10).

In one embodiment, the surfactant is a surfactant of formula (I) wherein n = 9, R1 = n-pentyl, and R2 = n-heptyl (Tergitol™ 15-S-9).

In one embodiment, the surfactant is a surfactant of formula (I) wherein n = 15, R1 = n-pentyl, and R2 = n-heptyl (Tergitol™ 15-S-15).

In one embodiment, the surfactant is a surfactant of formula (II) wherein a = 9, b =5, c = 3, d = 1, and R3 - methyl (Ecosurf™ EH -9).

In one embodiment, the surfactant is a surfactant of formula (II) wherein a = 9, b -0, c = 5, and d - 3 (WET LF-9™).

The aqueous medium comprises water as solvent component.

In one embodiment of the invention, the aqueous medium comprises at least 50 wt%, preferably at least 60 wt%, more preferably at least 70 wt%, even more preferably at least 80 wt%, especially at least 85 wt%, more especially at least 90 wt%, of water, with the wt% being based on the weight of the aqueous medium.

Preferably, the combined amount of water, base and surfactant is at least 70 wt%, more preferably at least 80 wt%, even more preferably at least 90 wt%; the wt% being based on the weight of the aqueous medium.

In one embodiment the aqueous medium does not contain organic solvents.

In another embodiment the solvent component of the aqueous medium consists of water.

In another embodiment the aqueous medium comprises an organic solvent.

Said organic solvent is a further solvent component of the aqueous medium in addition to the solvent component water.

The organic solvent can be an organic solvent that is used in nucleophilic aromatic substitution reactions. The organic solvent is preferably an organic solvent that is soluble or at least partially soluble in water. In one embodiment, the organic solvent is selected from the group consisting of THF, Me THF, NMP, NBP, DMSO, DMF, DMA, nitromethane, Ci-₃ alcohol, ethylene glycol Ci -4 monoalkyl ether, diethyleneglycol Ci-4 monoalkyl ether, MeCN, and any mixture thereof; preferably from the group consisting of THF, Me-THF, DMF, DMA, methanol, ethanol, n-propanol, iso propanol, 2 -butoxyethanol, 2 ethoxyethanol, diethyleneglycol monobutyl ether, diethyleneglycol monomethyl ether, MeCN, and any mixture thereof.

The aqueous medium may have one or more liquid phase, preferably one or two liquid phases, more preferably one liquid phase.

Preferably, the organic solvent in the chosen amount present in the aqueous medium is soluble in the water of the aqueous medium.

The aqueous medium can comprise 20 wt% or less, preferably 15 wt% or less, even more preferably 10 wt% or less, of the organic solvent, with the wt% being based on the weight of the aqueous medium.

In another embodiment the solvent components of the aqueous medium consist of water and organic solvent, preferably the solvent components of the aqueous medium consists of water and one organic solvent.

The amount of surfactant that is required to obtain an aqueous micellar system depends on the chemical nature of the surfactant and on the amount and composition of the aqueous medium. Such a surfactant which forms micelles in the aqueous medium is preferably used in such amount based on the weight of the aqueous medium that the surfactant forms micelles in the aqueous medium.

A lower limit of the amount of surfactant is typically 0.01 wt%, 0.02 wt%, 0.05 wt%, 0.075 wt%, 0.1 wt%, 0.25 wt%, 0.5 wt%, with a higher value preferred over a lower value; and/or an upper limit of the amount of surfactant is typically 20 wt%, 15 wt%, 10 wt%, 7.5 wt%, 5 wt%, 3 wt%, with a lower value preferred over a higher value. Any of the mentioned lower limits can be combined with any of the mentioned upper Emits.

Preferably, the amount of surfactant typically is from 0.01 to 20 wt%, from 0.01 to 15 wt%, from 0.01 to 10 wt%, from 0.02 to 10 wt%, from 0.05 to 10 wt%, from 0.075 to 10 wt%, from 0.1 to 10 wt%, from 0.1 to 7.5 wt%, from 0.1 to 5 wt%, from 0.25 to 5 wt%, from 0.5 to 5 wt%, from 0.5 to 3 wt%, with a more narrow range preferred over a broader range.

Any amount of surfactant herein is given in wt%, with the wt% being based on the weight of the aqueous medium.

Preferably, the surfactant is present in a concentration which is above its CMC for the chosen aqueous medium at the chosen reaction temperature.

The combined amount of reagent (i.e. the nucleophile) and substrate in the reaction mixture can be from 0.01 to 30 wt%, preferably from 0.01 to 25 wt%, more preferably from 0.01 to 20 wt%, with the wt% being based on the weight of aqueous medium.

The terms “reagent” and “nucleophile” are used interchangeably herein.

The terms “substrate”, “electrophile” and “aromatic electrophile” are used interchangeably herein.

The amount of reagent can be at least a stoichiometric molar amount based on the molar amount of substrate. Preferably, the amount of reagent is from 1 to 1.5 equiv, more preferably from 1 to 1.2 equiv, even more preferably from 1 to 1.1 equiv, the equiv being molar equivalents based on the molar amount of substrate. But also the substrate can be present in an excess over the reagent, so the amount of substrate can be at least a stoichiometric molar amount based on the molar amount of reagent. Preferably, the amount of substrate is from 1 to 1.5 equiv, more preferably from 1 to 1.2 equiv, even more preferably from 1 to 1.1 equiv, the equiv being molar equivalents based on the molar amount of reagent.

The reaction temperature, that is the temperature at which the reaction is performed, can be from 30 to 200 °C, preferably from 45 to 180 °C, more preferably from 60 to 160 °C. The reaction can be done under atmospheric or under elevated pressure! an elevated pressure is preferably above the vapor pressure of the reaction mixture.

The reaction time can be from 5 sec to 24 h, preferably from 10 sec to 24 h, more preferably from 30 sec to 24 h.

The reaction is done in the presence of a base. The base can be any base that is known to facilitate nucleophilic aromatic substitution reaction! preferably, the base is a base that is soluble in the aqueous medium, more preferably that is soluble in water.

Preferably, the base has a pKb of from 0 to 6.8, preferably from 1 to 6.8, more preferably from 1 to 5, even more preferably from 1.5 to 4.5.

The base can be selected from the group consisting of R20(R21)(R22)N, alkali metal salts of carbonate, phosphate and hydroxide, and any mixture thereof! preferably consisting of R20(R21)(R22)N, and Li, Na, K and Cs salts of carbonate, phosphate and hydroxide, and any mixture thereof! more preferably consisting of R20(R21)(R22)N, and Na and K salts of carbonate, phosphate and hydroxide, and any mixture thereof! even more preferably consisting of R20(R21)(R22)N, potassium salts of carbonate, phosphate and hydroxide, and any mixture thereof! especially consisting of R20(R21)(R22)N, potassium salts of carbonate and phosphate, and any mixture thereof! wherein any of the mentioned R20, R21 and R22 are identical or different and independently from each other selected from the group consisting of methyl, ethyl, 2-hydroxyethyl, n-propyl, isopropyl, 2-hydroxypropyl, n-butyl, isobutyl, and tert butyl! more preferably, R20, R21 and R22 are identical or different and independently from each other selected from the group consisting of ethyl and isopropyl! even more preferably, R20(R21)(R22)N is EtaN, tri-iso-propyl amine, or DIPEA; in particular, the base is selected from the group consisting of EtsN, tri iso propyl amine, DIPEA, K2CO3, K3PO4, KOH and any mixtures thereof. The base can be present in the reaction mixture in at least a stoichiometric molar amount based on the molar amount of said electrophile! preferably, the amount of base is from 1 to 10 equiv, more preferably from 1 to 7.5 equiv, even more preferably from 1 to 5 equiv, especially from 1 to 4 equiv, the equiv being molar equivalents based on the molar amount of said electrophile.

Preferably, said nucleophile provides electrons to said electrophile from an atom selected from N, O or S(ll).

Preferably, said nucleophile is selected from the group consisting of aniline, substituted anilines, heteroaryl amines, heterocycles comprising an endocyclic sp²-hybridized nitrogen atom bearing an N-H bond, primary and secondary alkyl amines, phenol, substituted phenols, heteroaryl phenols, primary and secondary alcohols and thiols.

Said endocyclic sp²-hybridized nitrogen atom bearing an N-H bond is colloquially referred to as “pyrrole -like” endocychc nitrogen.

In a more preferred embodiment, said nucleophile is selected from the group consisting of aniline, substituted anihnes, heteroaryl amines, heterocycles comprising an endocyclic sp²-hybridized nitrogen atom bearing an N-H bond, and primary and secondary alkyl amines.

In another more preferred embodiment, said nucleophile is selected from the group consisting of phenol, substituted phenols, heteroaryl phenols, and primary and secondary alcohols.

In another more preferred embodiment, said nucleophile is selected from the group consisting of thiols.

Preferably, said electrophile is a mono-, di-, tri- or tetra-halo substituted arene or heteroarene.

Halo may be F, Cl, Br, or I. Preferably, said electrophile has a leaving group selected from nitro (NO2), F, Cl, Br, and I.

Non limiting examples of SNAT are the Reactions A, B, C, D, E and F shown in the

• Reaction Scheme A for Reaction A,

• Reaction Scheme B for Reaction B,

• Reaction Scheme C for Reaction C,

• Reaction Scheme D for Reaction D, • Reaction Scheme E for Reaction E, and

• Reaction Scheme F for Reaction F.

Reaction Scheme of Reaction A

Reaction Scheme of Reaction B

Reaction Scheme of Reaction C

Reaction Scheme of Reaction D

Reaction Scheme E for Reaction E

Reaction Scheme F for Reaction F

Further subject of the invention is the method for performing a nucleophilic aromatic substitution reaction as described herein, also with all its embodiments, wherein the nucleophilic aromatic substitution reaction is selected from the group of Reaction A, Reaction B, Reaction C, Reaction D, Reaction E and Reaction F; with each of these reactions as displayed in the respective Reaction Schemes A, B, C, D, E and F.

In an embodiment of the invention, subject of the invention is the method for performing a nucleophilic aromatic substitution reaction as described herein, also with all its embodiments, wherein the nucleophilic aromatic substitution reaction is Reaction A as displayed in Reaction Scheme A.

Reaction A is preferably done with the surfactant being WET LF-9! and/or Reaction A is preferably done with the base being KOH.

In an embodiment of the invention, subject of the invention is the method for performing a nucleophilic aromatic substitution reaction as described herein, also with all its embodiments, wherein the nucleophilic aromatic substitution reaction is Reaction B as displayed in Reaction Scheme B.

Reaction B is preferably done with the surfactant being WET LF-9; and/or Reaction B is preferably done with the base being K2CO3.

In an embodiment of the invention, subject of the invention is the method for performing a nucleophilic aromatic substitution reaction as described herein, also with all its embodiments, wherein the nucleophilic aromatic substitution reaction is Reaction C as displayed in Reaction Scheme C.

Reaction C is preferably done with the surfactant being WET LF 9: and/or Reaction C is preferably done with the base being K2CO3. In an embodiment of the invention, subject of the invention is the method for performing a nucleophilic aromatic substitution reaction as described herein, also with all its embodiments, wherein the nucleophilic aromatic substitution reaction is Reaction D as displayed in Reaction Scheme D.

Reaction D is preferably done with the surfactant being Tergitol 15-S 15 or WET LF-9; and/or

Reaction D is preferably done with the base being K3PO4 or KOH.

In an embodiment of the invention, subject of the invention is the method for performing a nucleophilic aromatic substitution reaction as described herein, also with all its embodiments, wherein the nucleophilic aromatic substitution reaction is Reaction E as displayed in Reaction Scheme E.

Reaction E is preferably done with the surfactant being selected from the group of WET LF-9, Tergitol 15-S-9, Tergitol 15-S-15, Ecosurf EH-9, Tergitol TMN-10; and/or

Reaction E is preferably done with the base being K3PO4.

In an embodiment of the invention, subject of the invention is the method for performing a nucleophilic aromatic substitution reaction as described herein, also with all its embodiments, wherein the nucleophilic aromatic substitution reaction is Reaction F as displayed in Reaction Scheme F.

Reaction F is preferably done with the surfactant being WET LF-9; and/or Reaction F is preferably done with the base being K3PO4.

In an embodiment, the aqueous medium contains less than a 10 fold, 9 fold, 8 fold, 7 fold, 6 fold, 5 fold, 4 fold, 3 fold, 2 fold, or 1 fold molar excess of NaCl based on the molar amount of the substrate, the aromatic electrophile, with a lower excess preferred over a higher excess; in particular, the aqueous medium contains no NaCl. In an embodiment, the aqueous medium contains less than a 10 fold, 9 fold, 8 fold, 7 fold, 6 fold, 5 fold, 4 fold, 3 fold, 2 fold, or 1 fold molar excess of sodium hahde based on the molar amount of the substrate, the aromatic electrophile, with a lower excess preferred over a higher excess! in particular, the aqueous medium contains no sodium hahde.

In an embodiment, the aqueous medium contains less than a 10 fold, 9 fold, 8 fold, 7 fold, 6 fold, 5 fold, 4 fold, 3 fold, 2 fold, or 1 fold molar excess of a alkali metal chloride based on the molar amount of the substrate, the aromatic electrophile, with a lower excess preferred over a higher excess! in particular, the aqueous medium contains no alkali metal chloride.

In an embodiment, the aqueous medium contains less than a 10 fold, 9 fold, 8 fold, 7 fold, 6 fold, 5 fold, 4 fold, 3 fold, 2 fold, or 1 fold molar excess of a alkali metal hahde based on the molar amount of the substrate, the aromatic electrophile, with a lower excess preferred over a higher excess! in particular, the aqueous medium contains no alkali metal hahde.

The present invention provides a method of performing said reaction comprising the steps of

(a) providing a reaction mixture comprising the aqueous medium and the reactants, which are said nucleophile and aromatic electrophile, and

(b) allowing the chemical reaction to proceed to provide the product.

After the reaction the product can be isolated by means and techniques known in the art, including for example evaporation of solvents, aggregation or crystallization and filtration, phase separation, chromatographic separation and others.

Abbreviations and definitions used throughout the specification

MeCN acetonitrile

CMC critical micelle concentration DCM dichloromethane

DIPEA N, N-diisopropylethylamine

DMA N,N-dimethylacetamide

DMF N,N dimethylformamide

DMSO dimethyl sulfoxide

EO ethylene oxide or ethylene oxide residue, as the case may be

EOW Enhancement over water

EWG electron- with dr awing group halide in the meaning of the invention a halide is a fluoride, chloride, bromide or iodide compound

HLB Hydrophilic-Lip ophilic Balance

Me-THF 2-methyltetrahydrofuran na not available

NAS nucleophilic aromatic substitution reaction

NBP N-butyl-2-pyrrolidinone, IUPAC l-butylpyrrolidin-2-one, sometimes also called N-butyl pyrrolidone, CAS 3470-98'2

NMP N-methyl-2-pyrrolidone, N-methyP2-pyrrolidinone, IUPAC 1- methylpyrrolidin-2-one, CAS 872-50'4

PO propylene oxide or propylene oxide residue, as the case may be

PEO polyethylene oxide or polypropylene oxide residue, as the case may be

PPO polypropylene oxide or polypropylene oxide residue, as the case may be

RPM rounds per minute

SnAr nucleophilic aromatic substitution reaction

THF tetrahydrofuran

TLC thin layer chromatography wt% weight %. The wt% of any surfactant is based on the amount of the aqueous medium, if not stated explicitly otherwise. EXAMPLES and MATERIALS

Materials

Ecosurf™ EH-9 CAS 64366-70'7, 2-Ethyl hexanol EO-PO Nonionic Surfactant, is a product of The Dow Chemical Company, US. The product has an average of 5 PO and 9 EO units. Source^: Aldrich 2 -Ethyl hexanol has CAS 104-76'7.

Ecosurf™ EH-9 is a surfactant of formula (II) with a = 9, b = 5, d = 1 (thereby c = 3), and R3 = methyl.

Tergitol™ TMN-10, obtained from Aldrich

Tergitol TMN- 10, n = 10

Tergitol™ TMN-10 is a surfactant of formula (l).

Tergitol™ 15-S-9, CAS 2556785-86'3, obtained from Aldrich, is a surfactant of formula (I), wherein n = 9, R1 = n-pentyl and R2 = n -heptyl.

Tergitol™ 15-S-15, obtained from Aldrich, also abbreviated herein with 15-S-15, is a surfactant of formula (I), wherein n = 15, R1 = n-pentyl and R2 = n-heptyl.

Tergitol 15-S-9, n = 9 Tergitol 15-S-15, n = 15

TPGS-750-M CAS 1309573-60-1, Source^ Aldrich

TPGS-750-M with an average of n = 16 to 17

TPGS-1000 CAS 9002-96-4, also called Vitamin E TPGS or Kolliphor™

TPGS, Source BASF

TPGS-1000 with an average of n = 22 to 23

WET LF'9™ Guerbet C12 alcohol, specifically 2 -butyl- 1 -octanol, ethoxylate with an average number of EO units of 9. CAS 60636-37-5 Source^ Luoyang Trunnano Tech Co., Ltd, Luoyang City, Henan Province, China

It is a surfactant of formula (II) with a = 9, b = 0, and d = 3 (thereby c = 5).

Examples

(I) Model Reaction 1 of 2-bromo'l'fluoro'4-nitrobenzene with benzimidazole

The model reaction 1 for evaluating various surfactants is the nucleophilic aromatic substitution between 2-bromo-l-fluoro-4-nitrobenzene and benzimidazole as shown in Scheme 1, which is an embodiment of the Reaction E shown in the Reaction Scheme E: Scheme 1

(ll) Model Reaction 2 of 2 -bromo -1 -fluoro- 4-nitrobenzene with 4-methoxyphenol

Scheme 2, which is an embodiment of the Reaction F shown in the Reaction Scheme F, shows the model reaction 2 of 4-methoxyphenol with 2-bromo-l-fluoro- 4-nitrobenzene.

Scheme 2

(A) Protocol of the procedure of the Model Reaction 1:

The reaction was carried out in a 20 ml glass vial placed in an aluminum block heater equipped with thermostat and magnetic stirring. The aluminum block was pre-heated to the desired temperature.

8.00 ml of water or aqueous surfactant (2 wt% of surfactant based on the amount of water) was added to the vial containing a magnetic stir bar and placed in the pre-heated heating block. To this was added ca. 4.02 mmol (0.475 g +/- 2% weighted in) benzimidazole followed by ca. 4.04 mmol (0.890 g +/- 2% weighted in) 2-bromo-l-fluoro-4-nitrobenzene and then 0.880 g (4.14 mmol) K3PO4. The vial was sealed and stirred at 400 RPM at 45 °C for 18 h.

The reaction was quenched by extraction of the organic reagents and product into ethyl acetate ^: The reaction mixture was poured into a 40 ml vial. The first extraction was done by addition of 20 ml EtOAc and heating to near reflux in a 90 °C heating block with stirring and ensuing phase separation. The next four extractions with 10 ml EtOAc each were likewise heated and stirred and then spotted on a fluorescent TLC plate to determine when the extraction was complete. On the 5th extraction no spot was seen on a fluorescent TLC plate indicating the extraction was complete. The organic fractions were combined and rotoevaporated to dryness providing a dry product.

(B) Protocol of the procedure of the Model Reaction 1:

To quench the reaction, vial contents were poured into a 500 mL round bottom flask (RBF); the reaction vial was rinsed with 3'5 mL of methanol to ensure complete transfer of reactants to the RBF. The reaction mixture was quenched with 50 mL ethyl acetate and 100 mL isopropanol, then allowed to stir until a homogenous emulsion was achieved. Once fully dissolved, products were rotoevaporated to dryness.

(C) Protocol for NMR analysis of benzimidazole reaction mixtures :

To accurately and reproducibly determine the extent of reaction, the dry product obtained from (A) or (B) was redissolved in a mixture of 20 ml DCM and 6 ml MeOH so that the integration of the imide protons in the NMR spectrum on both the reactant and product are accurately represented. About 1 ml of this solution was dried by rotoevaporation in a vial and then redissolved in d6-DMSO. A proton spectrum was recorded on a 600 MHz Varian NMR. The benzimidazole imide proton is observed as a single peak at about 8.24 ppm and decreases as the reaction progresses toward completion. The imide proton of the product is observed as a single peak at about 8.56 ppm and increases as the reaction progresses toward completion. The areas of these peaks are used to determine the extent of reaction, that is % conversion, by equation 1.

(D) Protocol for NMR analysis of 4-methoxyphenol reaction mixtures ^:

To accurately and reproducibly determine the extent of reaction, the product obtained was redissolved in a mixture of 20 ml DCM and 6 ml MeOH so that the integration of the 4-methoxyphenol ring protons in the NMR spectrum on both the reactant and product are accurately represented. About 1 ml of this solution was dried by rotoevaporation in a vial and then redissolved in d6-DMSO. A proton spectrum was recorded on a 600 MHz Varian NMR. The four 4- methoxyphenol ring protons are observed as two doublet peaks with a second order sp Utting pattern between 6.69 and 6.77 ppm. These peaks decrease as the reaction progresses toward completion. Respective product peaks are observed between 7.08 and 7.20.

The areas of these peaks are used to determine the extent of reaction, that is % conversion, by equation 2.

Example 1 to 8 - benzimidazole reaction at 45 °C 18 h

Table 1 shows the conversion without and with various surfactants (2 wt% of surfactant based on the amount of water).

(*) This value is an average conversion value of three rephcate experiments, the individual values are given in Table 2.

Example 9 - 4-methoxyphenol reaction in water at 45 °C 18 h

8.00 ml of distilled water was placed in a 20 ml vial and preheated to 45 °C. 4- methoxyphenol (ca. 4.02 mmol (0.4988 g +/- 2% weighted in)), was added with stirring. Then 2-bromo-141uoro-4-nitrobenzene (ca. 4.05 mmol (0.8902 g +/■ 2% weighted in)) was added with stirring. Lastly, K3PO4 (0.8802 g, 4.15 mmol) was added with stirring. The vial was sealed and placed in a 45 °C heating block and stirred at 400 RPM for 18 h.

To quench the reaction, vial contents were poured into a 500 mL round bottom flask (RBF); the reaction vial was rinsed with 3'5 mL of methanol to ensure complete transfer of reactants to the RBF. The reaction mixture was quenched with 50 mL ethyl acetate and 100 mL isopropanol, then allowed to stir until a homogenous emulsion was achieved. Once fully dissolved, products were rotoevaporated to dryness. Following rotoevaporation, a second addition of 100 mL isopropanol was performed to remove remaining water from the reaction mixture. The sample was rotoevaporated to dryness. NMR analysis of the reaction using Protocol D and Equation 2 determined the reaction was 56% complete (56% conversion).

Example 10 - 4-methoxyphenol reaction in 2 wt% WET LF-9 at 45 °C 18 h Example 9 was repeated with the sole difference that 8.00 ml of aqueous WET LF-9 (2 wt% of WET LF 9 based on the amount of distilled water) was placed in a 20 ml vial instead of 8.00 ml of distilled water.

From the NMR analysis using Protocol D and Equation 2, the reaction was determined to be 95% complete (95% conversion), significantly higher than in water alone.

Example 11 — 4-methoxyphenol reaction in water at 90 °C 1 h

8.00 ml of distilled water was placed in a 20 ml vial and preheated to 45 °C. 4- methoxyphenol (ca. 4.02 mmol (0.4988 g +/- 2% weighted in)) was added with stirring. Then 2-bromo-l-fluoro-4-nitrobenzene (ca. 4.05 mmol (0.8902 g +/■ 2% weighted in)) was added with stirring. Lastly, K3PO4 (0.8802 g, 4.15 mmol) was added with stirring. The vial was sealed and placed in a 90 °C heating block and stirred for 1 h. The reaction was quenched by extracting the organic reagents and product from the aqueous layer using 20 ml aliquots of EtOAc. A total of 4 times 20 ml extractions were performed with no significant spot being observed in the 4th extract when analyzed on a fluorescent TLC plate. All 4 extracts were combined and rotoevaporated to dryness. The entire sample was re-dissolved in a mixture of 20 ml DCM and 6 ml MeOH. 1 ml of the solution was rotoevaporated to dryness and redissolved in d6-DMSO. Using NMR analysis Protocol D and Equation 2, the integration of the protons on the 4-methoxyphenol ring showed the reaction was 68% complete (68% conversion).

Example 12 - 4-methoxyphenol reaction in 2 wt% WET LF-9 at 90 °C 1 h Example 11 was repeated with the sole difference that 8.00 ml of aqueous WET LF-9 (2 wt% of WET LF-9 based on the amount of distilled water) was placed in a 20 ml vial instead of 8.00 ml of distilled water.

Using NMR analysis Protocol D and Equation 2, the integration of the protons on the 4-methoxyphenol ring showed the reaction was 93% complete, significantly higher than in water alone.

Example 13 - Surfactant concentration The model reaction 1 was done according to protocol (B) with various amounts of surfactant WET LF 9 as shown in Table 2.

Duplicate experiments at each weight percent of WET LF-9 were conducted. If the conversion rates of the duplicate experiments varied by more than 3%, a third rephcate experiment was conducted. Average conversion values were used to calculate the EOW.

(*) Enhancement over water (EOW) is the percent conversion with surfactant present divided by the percent conversion without surfactant under the otherwise same reaction conditions. For example, for 0.1 wt% WET LF-9 the EOW is 51/4.1 = 12.4.

(**) LF-9 means WET LF-9

AvConv means Average Conversion

Further Examples 21 to 25

The following reactions A, B, C and D were done according to the respective Reaction Schemes A, B, C and D. Raw Materials

The following raw materials were used^:

Protocol of the Reactions

Surfactant solution preparation

For the preparation of 2 wt% solution, the wt% of surfactant based on the weight of surfactant solution), 2 g of surfactant were placed in a 250 mL flask, followed by the addition of 98 mL of deionized water. The mixture is left under stirring at ambient temperature and 1000 rpm for 2 hours.

Experimental procedure

The reaction was conducted in a 5 mL microwave vial equipped with a magnetic stirring bar, placed in an aluminum block, connected to a temperature probe. The Substrate (0.70 - 0.85 mmol, 1 equiv) was added to the vial, followed by the Reagent (0.70 - 0.85 mmol, 1 equiv) and a base (0.71 - 0.87 mmol, 1.02 equiv). Then, 2 mL of aqueous surfactant solution were added, the vial was sealed, placed in the aluminum block and the heterogeneous mixture was stirred at 700 rpm for 16 h at 50 °C.

For quenching the reaction, 6 mL of ethyl acetate were added and the resulting mixture was stirred for 20 min, followed by phases separation, with the aqueous layer at the bottom and the organic layer at the top.

Protocol of the Analysis

Calibration curve

The calibration curve was created by preparing five standard solutions of known concentration of the analytical reference standard (0.1 mg/mL, 0.2 mg/mL, 0.4 mg/mL, 0.8 mg/mL and 1.0 mg/mL).

The analytical reference standard was the respective product of the respective reaction, was not bought but internally synthesized and quantified according to known and standard procedures.

These standard solutions were analyzed by HPLC, and the peak area for each injection was used to create the plot of peak area (AU) versus concentration (mg/mL), resulting in a linear curve that fits the measured data with a high coefficient of determination (R² > 0.9995).

Method.: HPLC analysis The HPLC analysis was performed using YMC Triart C18 column (50 mm x 3 mm ID, 3 pm), and^:

Eluent A: 0.05 vol% TFA (trifluoroacetic acid) in water Eluent B: 0.05 vol% TFA (Trifluoroacetic acid) in acetonitrile

Yield calculation via HPLC

In general, to remain within the range of the calibration curve, an aliquot of the organic layer (contained in the 5 mL microwave vial used for the reaction) was taken and diluted to 1 mL with acetonitrile to obtain a solution with a final concentration of 0.7 mg/mL. Then, 400 pL of the latter were transferred into a filtered-vial and then injected into HPLC. The volume of the aliquot to be taken was calculated according to Equation 1.

Equation 1: where:

Ci = 0.7 mg/mL as fixed value (to stay in the calibration curve range).

Vi = volume used for dilution, i.e., 1 mL with acetonitrile.

C₂ = Maximum theoretical concentration of the product in 6 mL ethyl acetate V₂ = volume of aliquot to take.

The measurement of the peak area, obtained from the HPLC chromatogram, was used to determine the concentration by the calibration curve! while the actual yield was calculated according to Equation 2:

Equation 2

Table with the parameters of the examples and the yields

Reaction A was done with Substrate S-A as substrate, Reagent R-A as reagent providing Product P-A as product. Reaction B was done with Substrate S-B as substrate, Reagent R-B as reagent providing Product P B as product.

Reaction C was done with Substrate S-C as substrate, Reagent R-C as reagent providing Product P C as product. Reaction D was done with Substrate S-D as substrate, Reagent R-D as reagent providing Product P A as product.

The table shows the various examples which were done according to the "Protocol of the Reaction" and analyzed according to the "Protocol of Analysis" Comp means Comparative Example. Comp A was done without surfactant, Comp B was done with TPGS-750-M as surfactant.

Claims

1. A method for performing a nucleophihc aromatic substitution reaction comprising: combining a nucleophile and an aromatic electrophile in an aqueous medium; said aqueous medium comprises water, a base, and a surfactant, wherein the surfactant is a surfactant of formula (l) or a surfactant of formula (II) or a mixture thereof;

wherein n is an integer from 2 to 40,

R1 and R2 are identical or different C145 alkyl;

(ID

and wherein a is an integer from 2 to 40, b is an integer from 0 to 20,

2. The method of claim 1, wherein n is an integer from 3 to 35; preferably from 3 to 30; more preferably from 3 to 20; even more preferably n is 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; especially n is 9, 10 or 15; and/or R1 and R2 are identical or different selected from the group linear or branched C2-13 alkyl, C2-10 alkyl, Cs-io alkyl, C39 alkyl, and Ga s alkyl; preferably selected from the group linear or branched C3 alkyl, C4 alkyl, C5 alkyl, CG alkyl, C7 alkyl, and Cs alkyl; more preferably selected from the group n- propyl, iso-propyl, 2 -methylpropyl, n-butyl, tert-butyl, iso-butyl, n-pentyl, 2,4- dimethylpentyl, n-hexyl,n-heptyl, and n-octyl; even more preferably selected from the group 2-methylpropyl, n-pentyl, 2, 4- dimethylpentyl and n-heptyl; and/or

R1 is 2-methylpropyl or n-pentyl; and/or

R2 is 2, 4- dimethylpentyl or n-heptyl! and/or n is 10, R1 is 2-methylpropyl and R2 is 2, 4- dimethylpentyl; and/or n is 9, R1 is n-pentyl and R2 is n-heptyl! and/or n is 15, R1 is n-pentyl and R2 is n-heptyl.

3. The method of claim 1 or 2, wherein n is an integer from 3 to 35, more preferably from 3 to 30, even more preferably from 3 to 20, and/or

R1 and R2 are identical or different Cs-io alkyl, preferably C39 alkyl, more preferably Cs-8 alkyl; more especially, n is 9, 10, 11, 12, 13, 14, or 15, and/or

R1 and R2 are identical or different and selected from the group consisting of C4 alkyl, C5 alkyl, CG alkyl, and C7 alkyl; in particular, n is 10 and R1 is C4 alkyl and R2 is C7 alkyl, or n is 9 and R1 is C5 alkyl and R2 is C7 alkyl, or n is 15 and R1 is C5 alkyl and R2 is C7 alkyl; more in particular, n is 10 and R1 is 2-methyl-n-propyl and R2 is 2, 4-dimethyl-n-pentyl, or n is 9 and R1 is n-pentyl and R2 is n-heptyl, or n is 15 and R1 is n-pentyl and R2 is n-heptyl.

4. The method of one or more of claims 1 to 3, wherein a is an integer selected from 3 to 40, preferably from 3 to 30, more preferably from 3 to 20; even more preferably 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; especially 9 or 12; and/or b is an integer selected from 0 to 20, preferably from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, more preferably from 0, 1, 2, 3, 4, 5, or 6; even more preferably 0 or 5; and/or d is an integer selected from 0 to 10, preferably from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, more preferably from 1, 2, 3, 4, 5, 6 or 7; even more preferably 1 or 3; and/or

R3 is selected from methyl, ethyl, propyl and butyl; particularly R3 is methyl; and/or a is 9, b is 5, c is 3, d is 1, and R3 is methyl; and/or a is 9, b is 0, c is 5, and d is 3.

5. The method of one or more of claims 1 to 4, wherein b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 0, 1, 2, 3, 4, 5 or 6; and/or

6. The method of one or more of claims 1 to 5, wherein in one embodiment, the surfactant is a surfactant of formula (I) wherein n = 10, R1 = 2 -methylpropyl, and R2 = 2,4-dimethylpentyl; in one embodiment, the surfactant is a surfactant of formula (I) wherein n = 9, R1 = n-pentyl, and R2 = n-heptyl; in one embodiment, the surfactant is a surfactant of formula (l) wherein n = 15, R1 = n pentyl, and R2 = n heptyl; in one embodiment, the surfactant is a surfactant of formula (II) wherein a = 9, b =5, c = 3, d = 1, and R3 = methyl; in one embodiment, the surfactant is a surfactant of formula (II) wherein a = 9, b =0, c = 5, and d = 3.

7. The method of one or more of claims 1 to 6, wherein the aqueous medium comprises at least 50 wt%, preferably at least 60 wt%, more preferably at least 70 wt%, even more preferably at least 80 wt%, especially at least 85 wt%, more especially at least 90 wt%, of water, with the wt% being based on the weight of the aqueous medium.

8. The method of one or more of claims 1 to 7, wherein the combined amount of water, base and surfactant is at least 70 wt%, more preferably at least 80 wt%, even more preferably at least 90 wt%; the wt% being based on the weight of the aqueous medium.

9. The method of one or more of claims 1 to 8, wherein the aqueous medium comprises an organic solvent.

10. The method of claim 9, wherein the organic solvent is selected from the group consisting of THF, Me-THF, NMP, NBP, DMSO, DMF, DMA, nitromethane, Ci-3 alcohol, ethylene glycol Ci-4 monoalkyl ether, diethyleneglycol Ci-4 monoalkyl ether, MeCN, and any mixture thereof; preferably from the group consisting of THF, Me THF, DMF, DMA, methanol, ethanol, n-propanol, iso-propanol, 2-butoxyethanol, 2-ethoxyethanol, diethyleneglycol monobutyl ether, diethyleneglycol monomethyl ether, MeCN, and any mixture thereof.

11. The method of claim 9 or 10, wherein The aqueous medium comprises 20 wt% or less, preferably 15 wt% or less, even more preferably 10 wt% or less, of the organic solvent, with the wt% being based on the weight of the aqueous medium.

12. The method of one or more of claims 1 to 11, wherein a lower hmit of the amount of surfactant is typically 0.01 wt%, 0.02 wt%, 0.05 wt%, 0.075 wt%, 0.1 wt%, 0.25 wt%, 0.5 wt%, with a higher value preferred over a lower value! and/or an upper limit of the amount of surfactant is typically 20 wt%, 15 wt%, 10 wt%, 7.5 wt%, 5 wt%, 3 wt%, with a lower value preferred over a higher value! preferably, the amount of surfactant typically is from 0.01 to 20 wt%, from 0.01 to 15 wt%, from 0.01 to 10 wt%, from 0.02 to 10 wt%, from 0.05 to 10 wt%, from 0.075 to 10 wt%, from 0.1 to 10 wt%, from 0.1 to 7.5 wt%, from 0.1 to 5 wt%, from 0.25 to 5 wt%, from 0.5 to 5 wt%, from 0.5 to 3 wt%, with a more narrow range preferred over a broader range! with the wt% being based on the weight of the aqueous medium.

13. The method of one or more of claims 1 to 12, wherein the reaction temperature is from 30 to 200 °C, preferably from 45 to 180 °C, more preferably from 60 to 160 °C.

14. The method of one or more of claims 1 to 13, wherein the base has a pKb of from 0 to 6.8, preferably from 1 to 6.8, more preferably from 1 to 5, even more preferably from 1.5 to 4.5.

15. The method of one or more of claims 1 to 14, wherein the base is selected from the group consisting of R20(R21)(R22)N, alkali metal salts of carbonate, phosphate and hydroxide, and any mixture thereof! preferably consisting of R20(R21)(R22)N, and Li, Na, K and Cs salts of carbonate, phosphate and hydroxide, and any mixture thereof! more preferably consisting of R20(R21)(R22)N, and Na and K salts of carbonate, phosphate and hydroxide, and any mixture thereof! even more preferably consisting of R20(R21)(R22)N, potassium salts of carbonate, phosphate and hydroxide, and any mixture thereof; especially consisting of R20(R21)(R22)N, potassium salts of carbonate and phosphate, and any mixture thereof! wherein any of the mentioned R20, R21 and R22 are identical or different and independently from each other selected from the group consisting of methyl, ethyl, 2-hydroxyethyl, n-propyl, isopropyl, 2-hydroxypropyl, n-butyl, isobutyl, and tert-butyl! more preferably, R20, R21 and R22 are identical or different and independently from each other selected from the group consisting of ethyl and isopropyl! even more preferably, R20(R21)(R22)N is EtsN, tri-iso-propyl amine, or DIPEA; in particular, the base is selected from the group consisting of EtsN, tri-iso-propyl amine, DIPEA, K2CO3, K3PO4 and any mixtures thereof.

16. The method of one or more of claims 1 to 15, wherein the base can be present in the reaction mixture in at least a stoichiometric molar amount based on the molar amount of said electrophile! preferably, the amount of base is from 1 to 10 equiv, more preferably from 1 to 7.5 equiv, even more preferably from 1 to 5 equiv, especially from 1 to 4 equiv, the equiv being molar equivalents based on the molar amount of said electrophile.

17. The method of one or more of claims 1 to 16, wherein said nucleophile provides electrons to said electrophile from an atom selected from N, 0 or S(II).

18. The method of one or more of claims 1 to 17, wherein said nucleophile is selected from the group consisting of aniline, substituted anilines, heteroaryl amines, heterocycles comprising an endocyclic sp² hybridized nitrogen atom bearing an N-H bond, primary and secondary alkyl amines, phenol, substituted phenols, heteroaryl phenols, primary and secondary alcohols and thiols.

19. The method of one or more of claims 1 to 18, wherein said electrophile is a mono-, di-, tri- or tetra-halo substituted arene or heteroarene.

20. The method of one or more of claims 1 to 19, wherein said electrophile has a leaving group selected from nitro (NO2), F, Cl, Br, and I.

21. The method of one or more of claims 1 to 16, wherein the nucleophilic aromatic substitution reaction is selected from the group of Reaction A, Reaction B, Reaction C, Reaction D, Reaction E and Reaction F; with each of these reactions as displayed in the respective Reaction Schemes A, B, C, D, E and F;