Nucleophilic aromatic substitution in an aqueous medium in the presence of a poloxamer

Abstract

The invention relates to nucleophilic aromatic substitution reactions done in an aqueous micellar solvent system, wherein the micelles are formed by specific alkoxylated alcohols.

Description

[0001] TITLE NUCLEOPHILIC AROMATIC SUBSTITUTION IN AN AQUEOUS MEDIUM IN THE PRESENCE OF A POLOXAMER 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 a poloxamer. 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. J. D. Smith et al., Green Chemistry, 2018, 201784-1790, discloses a reaction of pentafluorobenzonitrile with a methyl sodium phenyl sulfinate in aqueous medium containing 3 wt% Pluronic F-127, 20 % acetone and a 10-fold molar excess of NaCl. Poloxamers are described in the brochure "Solubility Enhancement with BASF Pharma Polymers - Solubilizer Compendium - Thomas Reintjes (Editor)" of BASF SE, Pharma Ingredients & Services, 68623 Lampertheim, Germany, October 2011, on pages 103 to 111, this brochure is shortly called "BASF Brochure" herein. 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, 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, that minimize or eliminate residual surfactants from downstream processes such as recrystallization, distillation, or lyophilization (as non-limiting examples). The inventors found that poloxamers as surfactants provide aqueous micellar solvent systems which deliver 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. The poloxamers 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, the surfactant is a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer; the amount of water in said aqueous medium is at least 50 wt%; and the combined amount of water, said base and said surfactant is at least 70 wt% of said aqueous medium; the wt % being based on the weight of said aqueous medium. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the data of Table 2, the comparison of conversion versus reaction time at 90 °C in water versus 2 wt% Poloxamer 407. 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 SNAr) 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 SNAr 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 electrophilic carbon atom of the aromatic ring, which disrupts aromaticity, via a negatively charged carbanion intermediate and subsequent rearrangements of the π-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 endocyclic 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, preferably a poloxamer, wherein the surfactant provides for an aqueous micellar system in the aqueous medium. In an embodiment, the invention relates to a nucleophilic 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, "dispersion" relates to 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, colloidally 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 limit 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 stable 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 stable and homogeneous emulsions, i.e. mixtures of two or more immiscible liquid substances, where one substance is dispersed in another as small droplets. 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 can act as emulsifiers that will 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 an 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 believed 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. The surfactant is a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer, it is a ABA-type triblock copolymer with A being poly(ethylene oxide) (PEO), and with B being poly(propylene oxide (PPO), i.e. a PEO-PPO-PEO triblock copolymer. Such a surfactant is obtainable by a synthesis comprising two steps according to scheme (S). In a first step (Step-1) propylene oxide (S-2) is reacted with propylene glycol (S-1) to form PPO (S-3). In a second step (Step-2), PPO is reacted with ethylene oxide (S-4) to form the PEO-PPO- PEO triblock copolymer (S-5). Both of these two steps can be base-catalyzed, e.g. with potassium hydroxide.

[0002] 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 poly-EO block and any stated number for the PO units in a poly-PO block is an average number. Said surfactants are known to the skilled person as poloxamers, e.g. a PluracareTMor a KolliphorTMof BASF AG, Germany. Other tradenames are PluronicTM, Synperonic™, and LutrolTM. In an embodiment, the surfactant is a compound of formula (I), a is an integer from 5 to 250, b is an integer from 15 to 70; preferably, a is an integer from 10 to 150 and b is an integer from 15 to 70; more preferably, a is from 30 to 110, even more preferably from 50 to 110, especially from 70 to 110, more especially from 90 to 110; more preferably, b is an integer from 20 to 70, even more preferably from 20 to 60, especially from 30 to 60, more especially from 50 to 60; even more preferably, a is from 90 to 110 and b is from 50 to 60. In particular embodiments of the compound of formula (I), a = 11 and b = 21, a = 80 and b = 27, a = 141 and b = 44, or a = 101 and b = 56; preferably a = 80 and b = 27, a = 141 and b = 44, or a = 101 and b = 56; more preferably a = 141 and b = 44, or a = 101 and b = 56; even more preferably a = 101 and b = 56. In particular embodiments, the compound of formula (I) is a poloxamer with values of a and b as follows: Poloxamer 124 a = 11 b = 21 Poloxamer 188 a = 80 b = 27 Poloxamer 237 a = 64 b = 37 Poloxamer 238 a = 207 b = 39 Poloxamer 334 a = 54 b = 61 Poloxamer 335 a = 74 b = 56 Poloxamer 338 a = 141 b = 44 Poloxamer 407 a = 101 b = 56. The surfactant can also be defined by its molecular weight of the polypropylene oxide part (the PPO part) together with the weight percentage (wt%) of the polyethylene oxide part (the PEO part), with the wt% being based on the weight of the surfactant. Any molecular weight of the polypropylene oxide part stated herein is an average molecular weight and any weight percentage of the polyethylene oxide part is an approximate or average weight percentage of the polyethylene oxide part, this is due to the fact that any surfactant is a mixture of individual species containing different numbers of EO units and / or different numbers of PO units due to the polydispersity inherent from the polymerization of ethylene oxide and propylene oxide. In an embodiment, the surfactant is a PEO-PPO-PEO triblock copolymer and has a molecular weight of the polypropylene oxide part of from 1'450 to 4'100 g / mol and a weight percentage of the polyethylene oxide part of from 35 to 85 wt%; preferably, a molecular weight of the polypropylene oxide part of from 1'925 to 4'100 g / mol and a weight percentage of the polyethylene oxide part of from 45 to 85 wt%; more preferably, a molecular weight of the polypropylene oxide part of from 2'150 to 4'100 g / mol and a weight percentage of the polyethylene oxide part of from 65 to 85 wt%; even more preferably, a molecular weight of the polypropylene oxide part of from 2'500 to 4'100 g / mol and a weight percentage of the polyethylene oxide part of from 65 to 85 wt%; especially, a molecular weight of the polypropylene oxide part of from 3'000 to 4'100 g / mol and a weight percentage of the polyethylene oxide part of from 65 to 85 wt%; more especially, a molecular weight of the polypropylene oxide part of from 3'625 to 4'100 g / mol and a weight percentage of the polyethylene oxide part of from 65 to 85 wt%; with the wt% being based on the weight of the surfactant. For certain poloxamers respective values of the average molecular weight of the polypropylene oxide part and of the approximate or average weight percentage of the polyethylene oxide part for specific poloxamers are stated in Table 4.

[0003] The values stated in table 4 are not exact values since as stated above the surfactant, and therewith also any poloxamer, is mixture of species containing different numbers of EO units and / or different numbers of PO units. BASF states in its BASF Brochure that the three digit number characterizes every poloxamer grade: the last of the three numbers that characterize every poloxamer grade is linked to the PEO content (e.g. 188 = 80 % m / m PEO) while the prepending numbers multiplied by 100 give an idea of the average molecular weight of the PPO part (e.g.188 = molecular weight of the PPO part: 1800). The term "poloxamer” within the meaning of the invention not only means specific representatives characterized by said three digit number but also comprises PEO-PPO-PEO triblock copolymer in general, so the term "poloxamer" is used herein as a synonym of the surfactant. Table 5 gives an idea of ranges for the molecular and the weight percentage of the polyethylene oxide part of the five specific poloxamers 124, 188, 237, 338 and 407. The surfactant is preferably a commercially available surfactant. In an embodiment, Surfactant I is selected from the group consisting of Poloxamer 184, Poloxamer 185, Poloxamer 188, Poloxamer 205, Poloxamer 207, Poloxamer 234, Poloxamer 235, Poloxamer 237, Poloxamer 238, Poloxamer 278, Poloxamer 334, Poloxamer 335, Poloxamer 338, and Poloxamer 407; preferably consisting of Poloxamer 205, Poloxamer 207, Poloxamer 235, Poloxamer 237, Poloxamer 238, Poloxamer 278, Poloxamer 335, Poloxamer 338, and Poloxamer 407; more preferably consisting of Poloxamer 237, Poloxamer 238, Poloxamer 278, Poloxamer 338, and Poloxamer 407; even more preferably consisting of Poloxamer 278, Poloxamer 338, and Poloxamer 407; especially consisting of Poloxamer 338, and Poloxamer 407; more especially, Surfactant I is Poloxamer 407. In yet another embodiment, Surfactant I is selected from the group consisting of preferably consisting of Poloxamer 124, Poloxamer 188, Poloxamer 237, Poloxamer 238, Poloxamer 334, Poloxamer 335, Poloxamer 338, and Poloxamer 407; preferably consisting of Poloxamer 124, Poloxamer 188, Poloxamer 338, and Poloxamer 407; more preferably consisting of Poloxamer 188, Poloxamer 338, and Poloxamer 407; even more preferably, Surfactant I is Poloxamer 407. The aqueous medium comprises the water as solvent component. The aqueous medium can comprise at least 60 wt%, preferably at least 70 wt%, more preferably at least 80 wt%, even more preferably at least 85 wt%, 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, said base and said surfactant is at least 80 wt%, more preferably at least 90 wt%; the wt% being based on the weight of said 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 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. The organic solvent can be selected from the group consisting of THF, Me-THF, NMP, NBP, DMSO, DMF, DMA, nitromethane, C1-3alcohol, ethylene glycol C1-4monoalkyl ether, diethyleneglycol C1-4monoalkyl ether, MeCN, and any mixture thereof; preferably from the group consisting of THF, Me-THF, DMF, DMA, methanol, ethanol, n-propanol, iso-propanol, 2-butyoxyethanol, 2-ethoxyethanol, diethyleneglycol monobutyl ether, diethyleneglycol monomethyl ether, MeCN, and any mixture thereof. The aqueous medium may have more than one 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 limits; 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 ranger. 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 Et3N, tri-iso-propyl amine, or DIPEA; in particular, the base is selected from the group consisting of Et3N, 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(II). 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” endocyclic nitrogen. In a more preferred embodiment, 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, 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 SNAr 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. 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 Poloxamer 407; and / or Reaction A is preferably done with the base being K2CO3, K3PO4or 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 Poloxamer 407 or Poloxamer P338; 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 Poloxamer P338; 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 Poloxamer P407 or Poloxamer P338; and / or Reaction D is preferably done with the base being KOH, K2CO3or 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 E as displayed in Reaction Scheme E. Reaction E is preferably done with the surfactant being selected from the group of Poloxamer 407, Poloxamer 338, Poloxamer 188, and Poloxamer 124; more preferably of Poloxamer 407, Poloxamer 338, and Poloxamer 188; 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 Poloxamer 407; 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, 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, 1 fold, molar excess of sodium halide 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 halide. 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, 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, 1 fold, molar excess of a alkali metal halide 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 halide. 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-withdrawing group halide in the meaning of the invention a halide is a fluoride, chloride, bromide or iodide compound HLB Hydrophilic–Lipophilic Balance Me-THF 2-methyltetrahydrofuran na not available NAS nucleophilic aromatic substitution reaction NBP N-butyl-2-pyrrolidinone, IUPAC 1-butylpyrrolidin-2-one, sometimes also called N-butyl pyrrolidone, CAS 3470-98-2 NMP N-methyl-2-pyrrolidone, N-methyl-2-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 %, in the BASF Brochure also abbreviated with "% m / m". The wt% (weight %) of any surfactant is based on the amount of the aqueous medium, if not stated explicitly otherwise. The wt% or % m / m of PEO in a poloxamer is based on the weight of the the poloxamer. EXAMPLES and MATERIALS Materials Poloxamer 124 was obtained from Spectrum Chemical (PluracareTML 44) Poloxamer 188 was obtained from Aldrich (Kolliphor™ P188) Poloxamer 338 was obtained from Aldrich (Kolliphor™ P338), abbreviated herein with P338 Poloxamer 407 was obtained from BASF, abbreviated herein with P407 (Kolliphor™ P407) TPGS-750-M CAS 1309573-60-1, Source: Aldrich with an average of n = 16 to 17 TPGS-1000 CAS 9002-96-4, also called Vitamin E TPGS or KolliphorTMTPGS, Source BASF with an average of n = 22 to 23 Examples (I) Model Reaction 1 of 2-bromo-1-fluoro-4-nitrobenzene with benzimidazole The model reaction 1 for evaluating various surfactants is the nucleophilic aromatic substitution between 2-bromo-1-fluoro-4-nitrobenzene and benzimidazole as shown in Scheme 1, which is an embodiment of the Reaction E shown in the Reaction Scheme E: (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-1-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 for NMR analysis of reaction mixture: In order to accurately and reproducibly determine the extent of reaction the dry product obtained from (A) 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 is 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: Table 1 shows the conversion without and with various surfactants (2 wt% of surfactant based on the amount of water). (C) Protocol for determining extent of reaction versus time at 90 °C Comparing conversion in water vs. 2 wt% Poloxamer 407, the wt% being based on the amount of water Using the protocol (A), individual reactions were set up and stirred at 90 °C for specific periods of time. At the destinated timepoint the reaction was quenched by pouring the reaction mixture on ice (8 to 10 g) in a 40 ml vial followed by extraction of the organics into 10 ml aliquots of ethyl acetate until no spot is seen on a fluorescent TLC plate. The extracts are combined and rotoevaporated to dryness. The NMR analysis and calculation of extent of reaction (% conversion) were done as described in Protocol (B). Table 2 shows the results. Figure 1 shows the data of Table 2, the comparison of conversion versus reaction time at 90 °C in water vs. 2 wt% Poloxamer 407. (II) Model Reaction 2 of 4-methoxyphenol with 2-bromo-1-fluoro-4-nitrobenzene 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-1-fluoro- 4-nitrobenzene. Example 16 - water 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-1-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. A proton NMR was collected on a Varian 600 MHz spectrometer and the resulting proton spectrum was integrated with respect to the 4 aromatic protons on the starting phenol (at 6.68 to 6.80 ppm) and the same 4 protons on the product (at 7.05 to 7.23 ppm). The ratio of the area of the signals of these protons on the product divided by the sum of the area of the signals of these protons for the starting phenol and product multiplied by 100 gives the % conversion. The reaction was determined to be 68% complete (68% conversion). Example 17 - 2 wt% Poloxamer 407 Example 16 was repeated with the sole difference that 8.00 ml of 2 wt% Poloxamer 407 in distilled water was placed in a 20 ml vial instead of 8.00 ml of distilled water and preheated to 45 °C. 4-methoxyphenol (0.4996g, 4.02 mmol) was added with stirring. 2-bromo-1-fluoro-4-nitrobenzene (0.8896g, 4.04 mmol) was added with stirring. Lastly, K3PO4(0.8803g, 4.15 mmol) was added with stirring. The vial was sealed and placed in a 90 °C heating block and stirred for 1 hour. 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 x 20 ml extractions were performed with no significant spot being observed in the 4th extract when spotted 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. A proton NMR was collected on a Varian 600 MHz spectrometer and the resulting proton spectrum was integrated with respect to the starting phenol and the product. The reaction was determined by respective NMR analysis as described in Example 16 to be 96% complete (96% conversion), significantly higher than in water alone. Example 18 – Surfactant concentration The model reaction 1 was done according to protocol (A) with various amounts of surfactant P407 as shown in Table 3: (*) 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 0.05 wt% P407 the EOW is 27 / 6 = 4.5 Further Examples 21 to 29 and Comparative Examples Comp A and Comp B 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:

[0004] 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 µm), 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 µL 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: C1x V1= C2x V2where: C1= 0.7 mg / mL as fixed value (to stay in the calibration curve range). V1= 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: 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

CLAIMS 1. 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, the surfactant is a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer; the amount of water in said aqueous medium is at least 50 wt%; and the combined amount of water, said base and said surfactant is at least 70 wt% of said aqueous medium; the wt % being based on the weight of said aqueous medium.

2. The method of claim 1, wherein the surfactant is a compound of formula (I), a is an integer from 5 to 250, b is an integer from 15 to 70; preferably, a is an integer from 10 to 150 and b is an integer from 15 to 70; more preferably, a is from 30 to 110, even more preferably from 50 to 110, especially from 70 to 110, more especially from 90 to 110; more preferably, b is an integer from 20 to 70, even more preferably from 20 to 60, especially from 30 to 60, more especially from 50 to 60; even more preferably, a is from 90 to 110 and b is from 50 to 60.

3. The method of claim 1 to 2, wherein the surfactant has a molecular weight of the polypropylene oxide part of from 1'450 to 4'100 g / mol anda weight percentage of the polyethylene oxide part of from 35 to 85 wt%; preferably, a molecular weight of the polypropylene oxide part of from 1'925 to 4'100 g / mol and a weight percentage of the polyethylene oxide part of from 45 to 85 wt%; more preferably, a molecular weight of the polypropylene oxide part of from 2'150 to 4'100 g / mol and a weight percentage of the polyethylene oxide part of from 65 to 85 wt%; even more preferably, a molecular weight of the polypropylene oxide part of from 2'500 to 4'100 g / mol and a weight percentage of the polyethylene oxide part of from 65 to 85 wt%; especially, a molecular weight of the polypropylene oxide part of from 3'000 to 4'100 g / mol and a weight percentage of the polyethylene oxide part of from 65 to 85 wt%; more especially, a molecular weight of the polypropylene oxide part of from 3'625 to 4'100 g / mol and a weight percentage of the polyethylene oxide part of from 65 to 85 wt%; with the wt% being based on the weight of the surfactant.

4. The method of one or more of claims 1 to 3, wherein the aqueous medium comprises at least 60 wt%, preferably at least 70 wt%, more preferably at least 80 wt%, even more preferably at least 85 wt%, especially at least 90 wt%, of water, with the wt% being based on the weight of the aqueous medium.

5. The method of one or more of claims 1 to 4, wherein the combined amount of water, said base and said surfactant is at least 80 wt%, more preferably at least 90 wt%; the wt% being based on the weight of said aqueous medium.

6. The method of one or more of claims 1 to 5, wherein aqueous medium comprises an organic solvent. Said organic solvent is a further solvent component of the aqueous medium in addition to the water.

7. The method of claim 6, wherein the organic solvent is selected from the group consisting of THF, Me-THF, NMP, NBP, DMSO, DMF, DMA, nitromethane, C1-3 alcohol, ethylene glycol C1-4monoalkyl ether, diethyleneglycol C1-4monoalkyl ether, MeCN, and any mixture thereof; preferably from the group consisting of THF, Me-THF, DMF, DMA, methanol, ethanol, n-propanol, iso-propanol, 2-butyoxyethanol, 2-ethoxyethanol, diethyleneglycol monobutyl ether, diethyleneglycol monomethyl ether, MeCN, and any mixture thereof.

8. The method of claim 6 or 7, 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.

9. The method of one or more of claims 1 to 8, wherein a lower limit of the amount of surfactant is 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 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 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 ranger; with the wt% being based on the weight of the aqueous medium.

10. The method of one or more of claims 1 to 9, wherein the reaction temperature is from 30 to 200 °C, preferably from 45 to 180 °C, more preferably from 60 to 160 °C.

11. The method of one or more of claims 1 to 10, 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.

12. The method of one or more of claims 1 to 11, wherein the base is selected from the group consisting of R20(R21)(R22)N, alkali earth 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 Et3N, tri-iso-propyl amine, or DIPEA; in particular, the base is selected from the group consisting of Et3N, tri-iso-propyl amine, DIPEA, K2CO3, K3PO4and any mixtures thereof.

13. The method of one or more of claims 1 to 12, wherein the base is 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.

14. The method of one or more of claims 1 to 13, wherein said nucleophile provides electrons to said electrophile from an atom selected from N, O or S(II).

15. The method of one or more of claims 1 to 14, 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.

16. The method of one or more of claims 1 to 15, wherein said electrophile is a mono-, di-, tri- or tetra-halo substituted arene or heteroarene.

17. The method of one or more of claims 1 to 15, wherein said electrophile has a leaving group selected from nitro (NO2), F, Cl, Br, and I.

18. The method of one or more of claims 1 to 13, 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;preferably, the nucleophilic aromatic substitution reaction is selected from the group of Reaction A, Reaction B, Reaction C and Reaction D.

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