Trialkylammonium salt degradation: Implications for methylation and cross-coupling

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Trialkylammonium salt degradation: implications

for methylation and cross-coupling†

Cite this: DOI: 10.1039/d1sc00757b

a

Jack B. Washington,^aMichele Assante,^bChunhui Yan,

David McKinney,^a

All publication charges for this article

have been paid for by the Royal Society

of Chemistry

Vanessa Juba,^aAndrew G. Leach,

Sharon E. Baillie^dand Marc Reid

c

a

*

Trialkylammonium (most notably N,N,N-trimethylanilinium) salts are known to display dual reactivity

through both the aryl group and the N-methyl groups. These salts have thus been widely applied in

cross-coupling, aryl etheriﬁcation, ﬂuorine radiolabelling, phase-transfer catalysis, supramolecular

recognition, polymer design, and (more recently) methylation. However, their application as electrophilic

methylating reagents remains somewhat underexplored, and an understanding of their arylation versus

methylation reactivities is lacking. This study presents a mechanistic degradation analysis of N,N,N-

trimethylanilinium salts and highlights the implications for synthetic applications of this important class of

salts. Kinetic degradation studies, in both solid and solution phases, have delivered insights into the

physical and chemical parameters aﬀecting anilinium salt stability. ¹H NMR kinetic analysis of salt

degradation has evidenced thermal degradation to methyl iodide and the parent aniline, consistent with

a closed-shell S_N2-centred degradative pathway, and methyl iodide being the key reactive species in

applied methylation procedures. Furthermore, the eﬀect of halide and non-nucleophilic counterions on

salt degradation has been investigated, along with deuterium isotope and solvent eﬀects. New

mechanistic insights have enabled the investigation of the use of trimethylanilinium salts in O-

methylation and in improved cross-coupling strategies. Finally, detailed computational studies have

helped highlight limitations in the current state-of-the-art of solvation modelling of reaction in which

the bulk medium undergoes experimentally observable changes over the reaction timecourse.

Received 7th February 2021

Accepted 13th April 2021

DOI: 10.1039/d1sc00757b

rsc.li/chemical-science

applications, is rarely studied in detail. Understanding the

dual reactivity of N,N,N-trimethylanilinium salts thus serves as

the focus of our study.

Introduction

Applications and divergent reactivity of trialkylammonium

salts

Trialkylammonium (specically N,N,N-trimethylanilinium)

salts have found wide-ranging applications in synthesis, span-

ning phase-transfer catalysis,¹supramolecular ion-pairing

catalysis,^2,3host-guest binding studies,⁴O-methylation,⁵O-ary-

lation,⁶heteroatom arylations,⁷C–H methylation,⁸C-aryla-

tion,^9–11uorine radiolabeling,^12–15organometallic ligand

design,^16–21antimicrobial polymer design,²²arene reduction,²³

pH sensing,²⁴and a range of metal-catalysed cross-coupling

methodologies.^25–32The dichotomy of arylation versus methyla-

tion reactivity, while important for optimising the above-listed

^aWestCHEM Department of Pure and Applied Chemistry, University of Strathclyde,

Thomas Graham Building, 295 Cathedral Street, Glasgow, UK. E-mail: marc.reid.

100@strath.ac.uk

^bSchool of Pharmacy and Biomolecular Sciences, Liverpool John Moores University,

Byrom Street, Liverpool, UK

^cDivision of Pharmacy and Optometry, University of Manchester, Stopford Building,

Oxford Road, Manchester, UK

^dGlaxoSmithKline, Shewalton Road, Irvine, North Ayrshire, UK

† Electronic supplementary information (ESI) available. See DOI:

10.1039/d1sc00757b

Fig. 1 Demonstration of dichotomous reactivity of trimethylanilinium

salts in: (A) C–H methylation,⁸(B) Kumada coupling,⁹(C) arene

reduction,²³(D) silylation,²³(E) phenol methylation,⁵and (F) alcohol

arylation.⁶Part (G) summarises the dual reactivity of trimethylanilinium

salts and the key mechanistic problem investigated in this study.

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Arylation methodologies are arguably the most widely drug design, formal access to highly toxic electrophilic methyl

studied of the above-listed anilinium salt applications. Pio- halide reagents in situ via anilinium salts may provide safer

neering developments by Wenkert et al. involved a nickel- alternatives to more widely known carcinogenic and low-boiling

catalysed Kumada-type coupling between Grignard reagents methylating reagents.⁴²

and trimethylanilinium iodides to generate biaryls via C–C

Of the various classes of methylating reagent available,^43–46

bond formation (Fig. 1, Part B).⁹Later developments from electrophilic sources still represent a signicant tool for synthetic

Reeves used trimethylanilinium triates and aryl Grignard chemists (Fig. 2). As with all reagents, toxicity, safety, scalability,

reagents with a palladium catalyst to produce functionalised and operational diﬃculty play a key role in the decision to use or

biaryl motifs in high yields under mild conditions.¹⁰Similarly, replace said reagent.⁴²Within the electrophilic class of methylating

MacMillan et al. found that trimethylanilinium triates were reagents, quaternary ammonium salts are somewhat underex-

suitable coupling partners with arylboronic acids in Suzuki plored.⁴⁴Early examples applied tetraalkylammonium and trime-

reactions.¹¹Other notable examples where trimethylanilinium thylanilinium hydroxides and halides to achieve heteroatom-

salts have been used as electrophilic coupling partners include alkylations.^5,47–50From the patent literature, anilinium salts have

Negishi coupling,³³borylation,^34,35amination,³⁶and azole ary- been used to achieve O-methylation in alkaloids.^51,52

lation.³⁷In contrast to the wealth of transition-metal catalysed

To the above-mentioned design and safety-focussed ends,

arylation reactions using anilinium salts, Chatani's team methods that allow for methylation of a substrate in a straight-

provided a rare demonstration that N,N,N-trimethylanilinium forward, safe, and predictable manner are highly desirable.

iodide can be used to transfer a methyl (as opposed to phenyl) Simultaneously, this directed investigation of trimethylanili-

group in nickel-catalysed C(sp²)–H and C(sp³)–H bond forma- nium salts, and specically their degradation behaviour, can

tions (Fig. 1, Part A).⁸Pioneering nickel-catalysed arene reduc- provide strategic insights for the myriad of aforementioned

tion methods from Rand and Montgomery²³showed that ligand applications of these salts.

and solvent variations could be exploited to enable either C–H

or C–Si bond formation from the same anilinium salt source

^{(Fig. 1, Parts C and D). Base-mediated reactions with anilinium}Results & discussion

salts display a similar dichotomy in arylation versus methylation

Solid phase degradation analysis

(Fig. 1, Parts E and F). To optimise the predictable use of tri-

To understand the potential for long-term safe storage of trime-

methylanilinium salts in synthesis, a structured mechanistic

thylanilinium salts, and knowing the potential for reagent

storage to cause adverse degradative eﬀects prior to their use in

synthesis,⁵³our studies began with an investigation of the solid-

analysis of their arylation and methylation reactivities is

required. Herein, we present our investigation of the factors

governing this dichotomous reactivity (Fig. 1, Part G).

state stability of arylammonium halides (primarily aniline

derivatives). Salts 1a–1c and 2a–15a composed the core structural

library employed in our investigations (Fig. 3). Details on the

synthesis and availability of all salts are available in the Experi-

mental ESI (ESI; Section 3).†

Drivers towards understanding the methylating ability of

anilinium salts

The presence or absence of small methyl groups in organic

molecules can bring about large changes in physicochemical

properties.^38,39This has been a particular focus in drug design

where the installation of methyl groups can have drastic eﬀects

on solubility, potency and selectivity; this contested phenom-

enon is dubbed the magic methyl eﬀect.^40,41As such, the present

study to understand trimethylanilinium salts is, in part, an

answer to the call for new methylation reactions.⁴⁰Parallel to

Thermal gravimetric analysis (TGA) was used to estimate

relative thermal stabilities of the salt library over 40–300 ^ꢀC

under both argon and air atmospheres. TGA traces for the argon

experiments are shown in Fig. 4. Detailed onset and peak

degradation temperatures are shown in the Experimental ESI

Section 4.† All salts tested were stable up to 165 ^ꢀC, suggesting

that storage of these compounds at room temperature would be

viable. TGA traces in air were comparable to TGA results ob-

tained under argon.

Fig. 2 Commonly used electrophilic methylating reagents and the Fig. 3 Library of N,N,N-trimethylarylammonium (phenyl and pyridyl)

focus of this study to understand the place of trimethylanilinium salts salts used in mechanistic degradation studies. Further anionic varia-

among them.

tions are also considered.

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distillation apparatus (TVA-SAD) was used to monitor the

decomposition of anilinium iodide salts 1a (unsubstituted

iodide), 7a (4-Br) and 12a (4-Me). Alongside infrared (IR)

analysis, the TVA-SAD studies provided evidence that methyl

iodide was generated during the thermal decomposition of

these trimethylanilinium iodide salts (see Experimental ESI

Section 5†). It is important to note that the relative position of

an electrophilic N–Me group and a halide counterion arising

from crystal packing in the solid state could contribute to

diﬀerent relative thermal stabilities.

Single-point solution phase degradation studies – substituent

and anion eﬀects

Aer investigating the stability of the N,N,N-trimethylanilinium

halide library in the solid state, our attention turned to inves-

tigating their degradation behaviour in solution. DMSO was

strategically chosen as a solvent due to its ability to solubilise

the salts, enabling homogeneous ¹H NMR kinetic analysis.

Additionally, the high boiling point of DMSO allowed for ex-

ible temperature studies. This solvent also links to earlier NMR

kinetics investigations involving methyl iodide⁵⁶and DMSO-

mediated methylation studies.^57,58Importantly, detailed

studies applying solvents applicable to a broader range of

methylation and catalytic chemistries is also included (see

Experimental ESI Sections 20 and 22†). A graph showing the

extent of degradation of each salt aer a 20 min period is shown

in Fig. 6. Consistent with TGA analysis, electron-poor salts were

the most susceptible to thermal degradation in DMSO (Fig. 7);

salts with a predominantly resonance electron-withdrawing 4-

substituent, 4-formyl (3a) and 4-benzoyl (4a), were shown to

degrade by 83 ꢁ 6% and 70 ꢁ 6%, respectively, and signicantly

more so than the unsubstituted iodide 1a at 16 ꢁ 2%. Salts

containing 4-chloro (6a; 30 ꢁ 11%) and 4-bromo (7a; 39 ꢁ 5%)

substituents were only slightly destabilised with respect to 1a,

Fig. 4 Mass vs. temperature trace determined via thermal gravimetric

analysis (TGA) for an illustrative subset of the salt library, analysed

under an argon atmosphere. Temperature range: 40–300 ^ꢀC.

Temperature ramp: 10 ^ꢀC min^ꢂ1. Temperatures between 40–139 ^ꢀC

and >280 ^ꢀC have been omitted as no observable change in mass was

observed for any of the salts in these temperature ranges. Single-step

degradation proﬁles are indicative of sublimation.

In general, compounds with more electron decient aryl

groups were more susceptible to thermal degradation (Fig. 5).

All salts, with the exception of 1c (unsubstituted chloride), 3a

(4-CHO) and 4a (4-Bz), showed a smooth, single-step TGA

trace, potentially indicative of sublimation. It seemed plau-

sible that the main salt decomposition products would be the

parent functionalised amino arene and its respective methyl

halide, arising from a retro-Menshutkin reaction.⁵⁴This

hypothesis was consistent with the observation that more

electron-poor salts degraded at lower temperatures than

comparitively electron rich salts. Complementary thermal

volumetric analysis (TVA)⁵⁵coupled with a sub-ambient

Fig. 6 Relative degradation of a range of N,N,N-trimethylanilinium

iodides upon heating in DMSO-d₆(0.06 M) at 120 ^ꢀC for 20 min;

Fig. 5 TGA analysis for the degradation of anilinium iodide salts, 1,2,4,5-tetramethylbenzene was used as an internal standard to

supporting the role of electron-withdrawing aryl substituents in calculate the concentration of the anilinium salt before and after

promoting thermal degradation. Additional analyses for samples heating. Results and associated errors are calculated from triplicate

degraded under air can be found in the Experimental ESI, Section 4.†⁵⁴runs.

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counter-anion eﬀect on solution-phase stability. The degrada-

tions of N,N,N-trimethylanilinium iodide (1a), bromide (1b),

and chloride (1c) were analysed aer heating to 120 ^ꢀC for

20 min in DMSO-d₆(Fig. 8). A clear trend emerged where

degradation was more advanced aer 20 min in 1c (chloride; 85

ꢁ 2%) than 1b (bromide; 42 ꢁ 2%) and 1a (iodide; 23 ꢁ 3%).

This is consistent with the reported order of halide nucleophi-

licity in polar aprotic solvents.^60,61As described below, the

reaction in which methyl halide is formed is close to thermo-

neutrality and thus small changes in the stability of ion pairs

and of carbon halide bonds can provide a thermodynamic

explanation for the observed order of thermal stability in

solution.^12,62

Understanding the eﬀect of additives alongside salt degra-

dation is relevant for applications of these anilinium salts in

cross-coupling methodologies.^11–17To this end, an equimolar

quantity of selected halide salts was added to solutions of 1a in

DMSO-d₆and the degradation measured over 20 min at 120 ^ꢀC

(Fig. 9). Anilinium degradation was only accelerated by 3 of the

10 additives tested, namely LiCl, and tetrabutylammonium

(TBA) salts of uoride and chloride. The more pronounced

anilinium cation degradation in the presence of TBACl versus

LiCl and KCl is tentatively attributed to higher solubility of the

former in DMSO. The low solubility of LiF, NaI, NaBr, NaCl, and

KCl in DMSO means it also possible that there was a lower-than-

calculated (or even negligible) concentration of additive halide

ions in solution. Indeed, with these reactions being conducted

in NMR tubes, ineﬃcient mixing may only exacerbate any

solubility issues. Addition of TBAI (i.e. additional iodide beyond

that in the anilinium salt itself) proved statistically similar to no

additive at all. A related report on uoride-mediated anilinium

degradation has evidenced strong ion-pairing in TBAF that

undergoes immediate salt metathesis in the presence of anili-

nium triates to aﬀord anilinium uorides.^12,63

Fig. 7 Hammett analysis of solution-phase degradation experiments

shown in Fig. 5, supporting the approximation that more electron-

deﬁcient ring substituents accelerate anilinium iodide degradation by

demethylation as the predominant pathway.

while 4-methyl (12a; 6 ꢁ 1%) was more stable than 1a. Halogen

substituents have inductive electron withdrawing eﬀects which

would destabilise the anilinium cation, but they also have the

competing ability to stabilise positive charge through resonance

donation;⁵⁹the trend in decreasing stability from 5a to 7a (4-F >

4-Cl > 4-Br) is consistent with decreasing resonance donation

down the halogen group. Conversely, 4-CF₃(15a; 79 ꢁ 0%)

shows that a strong inductive electron-withdrawing eﬀect

signicantly destabilises the anilinium salt versus the unsub-

stituted 1a. 2-Me (14a; 71 ꢁ 1%) shows high anilinium salt

degradation over 20 min, and can presumably be attributed to

the steric encumberment of the 2-Me and resulting destabili-

sation of the reactive quaternary nitrogen centre.

Beyond substitution eﬀects of the aromatic moiety on N,N,N-

trimethylanilinium iodide stability, we next investigated the

Fig. 9 Relative degradation of N,N,N-trimethylanilinium iodide 1a

Fig. 8 Degradation of 1a (X ¼ I), 1b (X ¼ Br), and 1c (X ¼ Cl) upon upon heating in DMSO-d₆(0.1 M) at 120 ^ꢀC for 20 min in the presence

heating in DMSO-d₆(0.1 M) at 120 ^ꢀC for 20 min. Results and errors are of 1 equiv. halide additive. Results and associated error bars taken from

taken from triplicate runs.

triplicate runs.

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Fig. 11 Relative degradation of N,N,N-trimethylanilinium cations

partnered with weakly coordinating (less nucleophilic) anions upon

heating in DMSO-d₆(0.1 M) at 120 ^ꢀC for 20 min.

Fig. 10 Attenuated degradation of anilinium iodides in the presence of

additive concentrations of water. N,N,N-Trimethylanilinium iodides

(0.1 M) heated in DMSO-d₆with 0, 10 or 20 v/v% D₂O, at 90 ^ꢀC for

120 min; maleic acid was used as an internal standard to calculate the

concentration of the anilinium salt before and after heating.

NMR degradation kinetics

We next sought to monitor the anilinium iodide degradation

reaction time course to gain a richer insight into the active

mechanism(s) of degradation. From a practical perspective, we

hypothesised that this additional insight could enable practi-

tioners to use anilinium salts as a controlled source of methyl

iodide generated in situ. Again, ¹H NMR spectroscopy was

employed to quantify reaction data. 4-Formyl-N,N,N-trimethy-

lanilinium iodide (3a), was selected as an appropriate salt to

exemplify reaction kinetics since its degradation was signi-

cantly advanced (approximately three half-lives over 16 hours)

to capture relevant mechanistic information in a feasible

timescale. Additionally, the formyl proton on 3a was easily

identiable in NMR spectra due its isolated downeld chemical

If ion-pairing indeed dictates preorganisation prior to anili-

nium degradation, data in Fig. 9 suggest that only the latter

three additives contribute signicant salt metathesis to form in

situ ion pairs more prone to degradation than the parent ani-

linium iodide, 1a.

Another contributing factor in the apparent banality of LiF

comes from its notably hygroscopic nature. In turn, this may

have led to the introduction of water into the degradation

mixture. A follow-up investigation showed that increasing water

concentration – in the presence and absence of TBAF – atten-

uated anilinium degradation (Fig. 10), likely due to a decrease

in halide nucleophilicity through more eﬃcient anion solvation

in water versus DMSO. Alternatively, the apparent decrease in

halide nucleophilicity could also emerge through changes in

the equilibrium, caused by enhanced solvation of ionic reac-

tants as opposed to electronically neutral methylhalide and

dimethylanilines.^60,64

Whereas the increased decomposition of the anilinium salts

to generate the parent aniline and methyl halide in situ may be

favourable for use in methylation chemistries, minimising

degradation is desired for use of anilinium salts in cross-

coupling reactions.^{8–11,34–37}Thus, we expanded our degradation

studies to include a range of substituted anilinium salts bearing

non-nucleophilic anions, including several anilinium partner

anions employed in cross-coupling methodologies.

The solution-phase thermal degradation of these non-halide

anilinium salts are shown in Fig. 11. Non-nucleophilic coun-

terions signicantly retarded the decomposition of anilinium

salts in solution, particularly when using tetrakis(3,5-

bis(triuoromethyl)phenyl)borate (BArF^ꢂ) salts which proved

even more thermally stable than the commonly-applied triate

salts.

Fig. 12 ¹H NMR time course for the degradation of 3a. Conditions: 3a

(0.1 M) in DMSO-d₆(0.6 mL), 1,2,4,5-tetramethylbenzene as internal

standard (0.06 M; not plotted) at 80 ^ꢀC. Lines are colour-coded

according to the proton shift followed, as indicated on the ﬁgure.

Methyl transfer and isotopic scrambling were trackable.

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shi. The concentration of various species were calculated with aniline formation (Fig. 12 green and purple), while the

against the internal standard (Fig. 12). TMSO-d₆,h₃intermediate and, in turn, DMSO-d₃product

The depletion of 3a could be monitored over time by formation displayed an induction period. This suggested that

following either the formyl, –NMe₃⁺, and 2-aryl protons. Simi- iodide-led degradation of anilinium cation is the major (though

larly, the evolution of 4-formyl-N,N-dimethylaniline could be not exclusive) precursor to methyl transfer to solvent. In short,

seen by following the analogous –NMe₂, formyl and 2-aryl methyl iodide forms directly, in the rst degradation step, not

protons. Furthermore, the evolution of methyl iodide (d₀) could later.

be observed in the same experiment. Interestingly, the calcu-

The proposed degradation pathway takes place via a series of

lated concentration of both the anilinium or aniline via two-electron closed-shell processes. In order to probe for the

aromatic and formyl protons, while being equal, were each possibility of radical degradation pathways, the degradation of

greater than the concentration calculated via the N-methyl 3a (4-CHO) was carried out separately under UV light and in

groups (orange vs. blue, and green vs. yellow lines in Fig. 12). darkness. Comparatively, the amount of 3a degraded in each

This is suggestive of isotopic scrambling of N–CH₃for N–CD₃case was almost identical, suggesting that photo-degradation

groups via interaction with the evidently non-innocent DMSO- mechanisms are not dominant (see Experimental ESI Section

d₆solvent. Deuterium scrambling is consistent with the emer- 15†). The absence of radical-mediated mechanisms is also

gence of trimethyl sulfoxonium (d₆,h₃) as a key intermediate, supported by additional control experiments in applied meth-

and DMSO-d₃as a nal product.

ylation chemistries (see Applications section below). It is plau-

Our combined mechanistic evidence to this stage led to the sible that the depletion of the anilinium salt could also occur

tentative proposal of the mechanistic pathways summarised in through an S_NAr-type displacement of trimethylamine by the

Fig. 13. Mass-calibrated diﬀusion-ordered NMR spectroscopy iodide counterion, however the corresponding aryl iodide was

(DOSY) analysis of various anilinium salts in DMSO at room not observed (see Experimental ESI Section 14†).

1

temperature did not support the existence of observable

The same H NMR kinetics method was used to follow the

concentrations of higher order salt aggregates (see Experi- degradation time course of a wider range of trimethylanilinium

mental ESI Section 13†), though this does not directly rule out salts (Experimental ESI Section 11†). With the exception of 2a (2-

their transient existence. We proposed that the primary py) and 14a (2-Me), most salts appeared to reach equilibrium

pathway, via a relatively rapid approach to equilibrium, of an that did not involve full salt degradation, consistent with

approximately thermoneutral self-immolative degradation led a process that is approximately thermoneutral. Exploratory

by nucleophilic attack of iodide onto a N-methyl unit of the Swain–Lupton analysis⁶⁶was applied to solution-phase initial

anilinium cation, leading directly to the parent dimethylaniline rate data to delineate eld and resonance contributions of aryl

and methyl iodide. In the bulk solvent, we proposed that DMSO ring substituents to salt degradation. This analysis revealed

could act as a S-centred nucleophile^56,65and attack the methyl near equal eld (F) and resonance (R) contributions (52%

iodide in an S_N2 fashion, producing trimethylsulfoxonium Fversus 48% R; Fig. 14). The positive reaction constant (r ¼

iodide (TMSO-d₆,h₃iodide). The TMSO-d₆,h₃cation could then +3.71) was consistent with earlier observations that more

undergo the reverse reaction with the aniline or instead electron-decient anilinium salts degrade more quickly (cf.

undergo a self-immolative process to release d₃-methyl iodide.

The incorporation of CD₃in the anilinium cation, which could

remain present in the degradative aniline product, is consistent

with the diﬀerence in anilinium and aniline concentrations

calculated using ¹H NMR spectroscopy, assuming negligible

aromatic H/D exchange. In further support of this mechanistic

hypothesis, methyl iodide formed at an initial rate consistent

Fig. 14 Swain–Lupton analysis using initial rate values (not explicitly

Fig. 13 First proposed degradation pathway of N,N,N-trimethylanili- derived rate-constants) for anilinium iodide degradation. Modiﬁed

nium iodide salts in DMSO-d₆, with rate constants assigned to each Hammett substituent constants were derived from Swain–Lupton F

step. Minor deuterium scrambling steps have been omitted for clarity. and R constants such that s_SW¼ 0.52F + 0.48R.

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Fig. 16 Exemplar Eyring plot for the degradation of 3a between 50–

80 ^ꢀC, using simulated ﬁrst order rate constants, showing counterin-

tuitive positive entropy of activation. Inset: Explanatory cartoon model

citing reduced solvent demand as the root cause of the observed

entropy value. Similar conclusions from the Eyring plot with simulated

second order rate constants is available in the Experimental ESI

(Section 18).†

Fig. 15 Main plot: Initial concentration of 3a versus calculated initial

degradation rate showing apparent mixed order kinetics. Real data

(blue open circles) show agreement with simulated 1st + 2nd mixed

order kinetics (green dashed line) versus simulated ﬁrst order kinetics

(red dashed line). Inset: log–log plot showing apparent reaction order

of approximately 1.7 in [3a].

self-immolative degradation pathway at each temperature and

an Eyring plot was produced using this data (Fig. 16). The Eyring

analysis revealed the activation enthalpy and entropy of the

reaction as DH^‡¼ +127.0 ꢁ 4.0 kJ mol^ꢂ1and DS^‡¼ +34.8 ꢁ 11.7

J mol^ꢂ1K^ꢂ1. DH^‡and DS^‡values for reactions involving changes

in charge should be interpreted with caution as the values will

include solvation dynamics and selection of appropriate rate

constant from the mechanistic model(s). To cover this potential

calculation error, we estimated Eyring parameters using both

rst and second order models, and in all circumstances,

a positive entropy of activation was found. The positive activa-

tion entropy obtained in this case is hypothesised to be due to

a reduced solvation demand as the charged reactants proceed to

neutral products (see Computational section).⁶⁷This model is

also consistent with the reaction proceeding through ion pairs

wherein the translational entropy penalty of bringing electro-

phile and nucleophile together has largely been paid. The

overall DG^‡¼ +114.7 kJ mol^ꢂ1(+27.4 kcal mol^ꢂ1) derived from

these calculations is in good agreement with the related DFT-

calculated barrier of +116.7 kJ mol^ꢂ1(27.9 kcal mol^ꢂ1; see

below).

To gain further insight into the degradation mechanism,

a kinetic isotope eﬀect (KIE) study was conducted. A d₉-

analogue (Ar-N(CD₃)₃) of the 3-bromo anilinium iodide salt

(11a) was synthesised and subjected to an NMR degradation

experiment. The rates of degradation were determined by

independent experiments. While not conclusive on their own,

all data were consistent with there being no primary KIE

(approx. 1.18), thus ruling out mechanisms involving direct

deprotonation (i.e. ylide formation) on the anilinium cation N–

Me groups (see Experimental ESI Section 19†). These data are

also qualitatively consistent with the ꢃ90-times molar excess of

Fig. 5 and 7). Additional Swain–Lupton analysis using the

simulated k₁values based on the tentative reaction model

shown in Fig. 13 lead to similar conclusions (51% R versus 49%

F; r ¼ +0.89; see Experimental ESI Section 11†).

An important consideration when using a new reagent is the

concentration at which it is to be used. Our time course experi-

ments up until this point had been carried out with an anilinium

salt concentration of 0.1 M in DMSO-d₆for comparability. To

understand the dependence of anilinium degradation on

concentration, we carried out ve additional degradation moni-

toring experiments at various anilinium iodide starting concen-

trations, [3a]₀. Inspection of the data revealed a deviation from

linearity, providing evidence of greater than rst order reaction

order kinetics in [3a]₀(Fig. 15). This is not consistent with

a simple self-immolation mechanism involving a single ion pair

as the sole degradation mechanism, as suggested in Fig. 13.

Consistent with data reported in Fig. 11, analysis of degradation

of the BArF salt of [3a] via in situ NMR kinetics revealed that the

background rate of degradation exclusively via the DMSO

pathway (in the absence of nucleophilic iodide) was negligible at

80 ^ꢀC (see Experimental ESI Section 12†). While DOSY NMR

revealed no appreciable concentration of aggregates beyond the

simple anilinium iodide ion pair at room temperature under the

range of concentrations studied, the presented data (most

notably Fig. 15) remain consistent with the possibility of degra-

dation of the anilinium iodide salt via a transient dimeric ion

pair or alternative higher order reaction.⁶³Dimeric degradation

pathways were later considered computationally (below, and

Computational ESI, Section 3†).

To estimate thermodynamic activation parameters, we con-

ducted NMR monitoring studies between 50–80 ^ꢀC. Rate

constants were estimated for a simplied rst order iodide-led

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Fig. 18 Partition of anilinium salts accordingly to their thermal

degradation and O-methylation behaviours. Non-iodide salts are

indicated where appropriate. The dotted lines are included solely as

a guide for the eye.

Fig. 17 Screen of O-methylation capability enabled by anilinium salts.

The anilinium iodide salt most reactive for methylation was

shown to be 11a (3-Br), giving near-quantitative conversion to 16

with minimal variance (Fig. 18). We were surprised to see that

salt 10a (3-Cl), which has a similar degradative prole to 11a

(Fig. 5, 7 and 14), was considerably less reactive to methyl

transfer under the applied conditions. More expectedly, 7a (4-

Br) gave high conversions in comparison to the 5a (4-F) and 6a

(4-Cl) analogues, the latter two presenting as more stable to

thermal degradation. 14a (2-Me), the only salt identied as

prone to degradation due to steric bulk, gave an average of 85 ꢁ

11% conversion to the methylated product under the conditions

tested. Salt 14a presents a viable alternative to 11a where

methylation (or cross-coupling) reactions might be compro-

mised by the presence of the 3-Br substituent in 11a. Surpris-

ingly, 2a (2-Py), 3a (4-CHO), and 4a (4-Bz) anilinium iodide salts,

each gave a relatively low conversion to 17 despite being the

most thermally unstable salts in solution-phase. On closer

inspection, it was found that S_NAr products 18–20, were formed

from use of the most resonance withdrawing anilinium iodide

salts (Fig. 17). The S_NAr reactivity presumably arises from 4-^tBu-

phenoxide displacing trimethylamine from the respective ani-

linium salt.^6,65Our own calculations remain consistent with the

concerted S_NAr mechanisms previously reported separately by

DiMagno¹²and Jacobsen.⁶⁵See the Computational analysis

section (Fig. 23).

The trend in methylation ability for the halide salt series 1a–

c correlated with extent of thermal degradation in solution, with

the chloride salt giving higher conversions to methylated

product than the analogous bromide and iodide salts. The tri-

ate salt (1e) was comparative in methylating ability to the

iodide salt (1a). Our mechanistic degradation studies showed

that methyl iodide was produced upon heating the anilinium

iodide salts in DMSO, raising the question of whether methyl-

ation of 16 occurs from reaction of the phenoxide nucleophile

directly with the anilinium cation, from a methyl halide

generated in situ, or both. The shared trend in anilinium

[CD₃] versus [CH₃] groups present in solution, and with DFT-

calculated KIE range of 1.29–1.47 covering 4 major mecha-

nistic hypotheses (see below).

Applications of mechanistic analysis in methylation

chemistries

Applying our new mechanistic data, we examined the broader

use of anilinium salts as methylating reagents. Degradation

analysis revealed the range of thermal and additive stabilities

(knowledge applicable to both cross coupling and process safety

strategies). We hypothesised that those anilinium salts pre-

senting as thermally unstable would, in turn, release methyl

iodide in situ most readily, and also be more susceptible to

direct nucleophilic attack, thus behaving as a viable methyl

iodide replacement. For a comparative application in methyla-

tion, phenol O-alkylation was chosen as it remains one of the

most used reactions in the pharmaceutical industry.^68,694-^tBu-

Phenol (16) was selected as a suitable substrate for initial

exploratory study. The conversion of 16 to 4-^tBu-anisole (17) was

calculated from the reaction mixture aer 3 h via ¹H NMR

spectroscopy, and the average conversion of each salt from

triplicate experiments is shown in Fig. 17.

From these experiments, the hypothesised trend of thermally

unstable anilinium salts leading to more eﬃcient methylation

did not hold. Indeed, three of the most thermally unstable ani-

linium iodides 2a–4a and 15a – all carrying strong electron-

withdrawing aryl substituents – led to measurable quantities of

S_NAr products (18–21) and poor yields of desired methylation

products. Indeed, analysis of thermal degradation versus O-

methylation eﬃciency within the anilinium salt library revealed

that only those unstable salts bearing no resonance withdrawing

aryl substituents served as eﬃcient methylating reagents.

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Table

1 Comparative methylation with anilinium salt 11a versus

common electrophilic methylating reagents

Entry

Methylating reagent

Yield (%)

1

2

3

4

5

6

7

11a

MeI

MeOTf

MeOTs

98

79

2

62

29

0

Me₂SO₄

Dimethyl carbonate

Dimethyl carbonate (+10 mol% DBU)

0

degradation and phenol methylation reactivity (1c > 1b > 1a)

suggests that decomposition to the methyl halide is important

for reactivity. However, the comparable methylating ability of 1a

(X ¼ I) and 1e (X ¼ OTf), despite the large diﬀerence in stability

(see Fig. 9 and 13), indicates that attack directly onto the ani-

linium salt also occurs, assuming negligible degradation of the

triate salt to produce methyl triate in situ (Fig. 11). We

propose that a combination of direct reaction with the anili-

nium salts and indirect reaction (via methyl iodide generation)

in the phenol methylation both occur under the reaction

conditions employed. This proposal is further elaborated in

discussion below.

To compare the eﬀectiveness of methylating reagent 11a to

common electrophilic methylating reagents, the methylation of

phenol 16 was carried out using methyl iodide, methyl triate,

methyl tosylate, dimethylsulfate, and dimethylcarbonate under

our chosen reaction conditions (Table 1).

Fig. 20 Conversion of 2⁰,4⁰-dihydroxyacetophenone to 35a–c using

11a or methyl iodide, demonstrating the possibility of exploiting

diﬀering methylation product selectivities. In both cases, no 35b was

formed.

We next investigated the ability of 11a (3-Br) to methylate

a range of phenols and related nucleophiles under our applied

reaction conditions (Fig. 19, see Experimental ESI Section 20†

for optimisation). A range of substituents and structural

complexities around the phenol ring were tolerated in these

methylation reactions, and most with good to excellent isolated

yields (17, 22–31, 34). Additionally, thiophenol and benzoic acid

could be methylated under the applied conditions to give thi-

oether 32 and ester 33 with good 77% and 80% yields, respec-

tively. Notably, having used the earlier mechanistic study to

guide choice of reagent (Fig. 17), no S_NAr product was observed

in any of our reactions using 11a as a methylating reagent. 14a

(2-Me) was explored as an alternative methylating reagent for

cases where a 3-Br substituent could cause undesired reactivity,

and was shown to be eﬀective in the formation of 17 (86%), 31

(62%) and 34 (84%). Using the same subset of substrates, NMP

was shown to be a viable alternative solvent, enabling the

synthesis of 17, 31, and 34 in 96, 94, and 84% yield, respectively.

We also investigated whether or not 11a could provide any

uniquely applicable regiochemical control when multiple

nucleophilic phenol sites are present on a substrate. To probe

this, 2⁰,4⁰-dihydroxyacetophenone was subjected to methylation

with 11a and methyl iodide under our standard conditions,

showing exploitable diﬀerences in reactivity and regioselectivity

(Fig. 20). A deeper analysis of this synthetic application is the

subject of future investigation.

Experimental mechanistic analysis of active methylation

species in solution using anilinium salts

Fig. 19 Methylation of phenols, thiophenol and benzoic acid using

11a. Yields in parentheses obtained with 14a (2-Me) as the methylating

reagent (left number) or for 8 h in NMP as solvent (right number), under

otherwise identical conditions.

Having demonstrated the potential of N,N,N-trimethylanili-

nium (primarily iodide) salts to act as competent methylating

reagents, we next aimed to understand the plausible

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To investigate this further, we ran the same methylation

reactions with TMSO salts in the place of anilinium salts.

TMSOI formed 17 in 76% yield (entry 4). We were able to

demonstrate through NMR analysis that TMSOI decomposes

thermally to give DMSO and methyl iodide at 80 ^ꢀC, the reverse

reaction was also shown to occur (Experimental ESI Section

22†). This nding raised the question as to whether TMSO⁺acts

directly as a source of methyl group (Path B), or if the methyl-

ation is simply occurring from methyl iodide produced via its

thermal decomposition (Path A). TMSO–PF₆and TMSO–BArF

were synthesised and subsequently used in methylation reac-

tions to aﬀord the anisole 17 in 57% (entry 5) and 53% yield

(entry 6), respectively. While this suggests that the TMSO⁺

cation is capable of methylating phenols, it does not rule out the

possibility that nucleophiles can directly attack the anilinium

cation to form the methylated product (Path D). To investigate

the ability of the anilinium cation to directly methylate the

substrate, the ability to generate TMSO⁺in the reaction mixture

would also have to be removed. Accordingly, we ran the meth-

ylation reactions in N-methyl-2-pyrrolidone (NMP). Anilinium

iodide 11a was used to methylate 16, giving 88% of the meth-

ylated product (entry 7).

We then repeated the reaction using anilinium PF₆salt 11d

as the methylating reagent, which gave only 11% yield of 17,

strongly suggesting that the degradation of the anilinium

iodide to release methyl iodide in situ is a key contributor to the

reaction (Path C); computational studies reveal that the barriers

for degradation and direct reaction are close such that reaction

ux through each pathway likely depends on the details of

concentration, temperature and the identity of the anilinium

salt. Furthermore, additive experiments (entries 9 and 10)

probing the presence of radical-centred degradation and

methylation mechanisms were carried out. These data

remained consistent with experimental and theoretical

evidence that anilinium iodide degradation was primarily via

closed shell pathways, and that the principle self-immolative

degradation pathway was faster than degradation via DMSO

participation (see Fig. 9, 11 and 12).

Fig. 21 Sources of electrophilic methylation reagent when employing

an anilinium iodide in DMSO. The dotted boxes highlight the source of

“Me⁺” at each side of the connected equilibria. Competing S_NAr

reactivity for the anilinium salt is also shown.

mechanism(s) by which these O-methylation reactions occur.

Our understanding of anilinium thermal degradation in DMSO-

d₆suggested multiple possible methylation pathways: Path A:

from methyl iodide generated from TMSO–I degradation, Path

B: from TMSO–I that forms in situ through methylation of the

non-innocent DMSO solvent by methyl iodide, Path C: via

methyl iodide generated from the anilinium iodide degrada-

tion, and Path D: direct attack of the nucleophile onto an N-

methyl group of the anilinium cation (Fig. 21).

To address the question of whether or not substrate meth-

ylation comes solely from the anilinium degradation-led

generation of methyl iodide (Path C), we carried out the meth-

ylation of 16 under our chosen (loosely-optimised) reaction

conditions using 3-bromo-N,N,N-trimethylanilinium PF₆(11d)

and BArF (11f) salts (Table 2). In these reactions where methyl

iodide could not be generated, 17 was formed in 45% (entry 2)

and 50% (entry 3) yield, compared to 98% yield when using

iodide salt 11a (entry 1). This showed that the generation of

methyl iodide likely accompanies eﬃcient methylation of

phenoxide substrates, but is not a necessity for the reaction to

occur under the chosen conditions. Given the knowledge that

anilinium PF₆and BArF salts can partially decompose in DMSO-

d₆to give the TMSO cation (see Fig. 11), it is possible that

methylation could occur in these reactions from the anilinium

directly (Path D) or the TMSO cation itself (Path B).

Table 2 Mechanistic experiments investigating the conversion of 16 to 17 with various methylating reagents in DMSO and NMP. Conditions: 16

(1 mmol, 1 equiv.), methylating reagent (1.2 equiv.), K₂CO₃(4 equiv.), additive (various equiv.), solvent (2 mL), 80 ^ꢀC, 3 h

Methylating

Entry

reagent

Anion

Solvent

Additive (equiv.)

O-Methylation yield (%)

1

2

3

4

5

6

7

8

9

11a

11d

11f

TMSO–I

TMSO–PF₆

TMSO–BArF

11a

11d

11a

I

DMSO

NMP

—

98

45

50

76

57

53

88

11

65

PF₆

BArF

I

PF₆

BArF

I

PF₆

I

NMP

DMSO

TEMPO (3)

10

11a

I

DMSO

86 (no consumption of additive)

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ESI.† Generally, the implicit solvation calculations are reported

unless noted.

Computational analysis of anilinium salt degradation and

methylation mechanisms

A key rst step was to establish the likely speciation of the

anilinium salts, as either separated ions and/or as ion pairs. The

latter was supported by our DOSY NMR measurements (Exper-

imental ESI Section 13†). Two geometries were considered for

the ion-pair, one with the halide placed as an extension of the

ipso-C_aromatic–N bond, and the other with the halide between the

N-methyl groups and the ortho C–H position. The latter was

found to be energetically preferred in all cases investigated (see

Computational ESI Section 2†). Calculations at 353 K (80 ^ꢀC)

Further mechanistic insight for both anilinium salt degradation

and methylation was sought from computational studies. The

computations were all performed at the M06-2X/6-31+G** level

of theory and with IEF-PCM for DMSO as the solvation model,

all performed in Gaussian09.⁷⁰M06-2X was designed to be

a preferred method for the investigation of reaction barriers,

and so is appropriate for this task. Vibrational and standard

state corrections were implemented using Goodvibes (with

concentration values 1 M and 14.1 M respectively for solutes

and DMSO; a frequency cut-oﬀ of 100 cm^ꢂ1was used).⁷¹In

exploring competition between rst and second order reactions,

the role of specic interactions between solvent and solute was

explored by placing DMSO molecules such that their oxygen was

in positions expected to be favoured for such interactions,

namely: between the methyl groups of anilinium or TMSO,

between the ortho-hydrogens and the methyl groups of an ani-

linium, and, in the case of 3a (4-CHO), adjacent to the formyl

hydrogen with methyl groups of the DMSO solvent molecules

placed so as to interact with the carbonyl group. The lowest free

energy guides selection of the preferred solvation geometry (and

explicit solvent molecules are excluded when they involve an

increase in free energy). The solvation free energy of DMSO

itself (in either implicit or explicit solvation regimes) is assumed

to be approximately 0 kJ mol^ꢂ1in line with the thermodynamic

analysis of Lai et al. and so gas phase values are employed.⁷²The

details of all calculations are provided in the Computational

predicted all of the iodide salts to have a small (3–16 kJ mol^ꢂ1

,

or 0.8–3.8 kcal mol^ꢂ1) preference to be ion-paired (see

Computational ESI Section 5†). The bromides are computed to

have a mix of preferences, with 4-CHO and 3-Br showing

ꢃ2 kJ mol^ꢂ1(or ꢃ0.5 kcal mol^ꢂ1) preferences to be ion pairs,

while 2-Me and 2-pyridyl show preferences to be separate ions.

Chloride salts were computed to all have an energetic prefer-

ence of 0.8–11.7 kJ mol^ꢂ1(or 0.2 to 2.8 kcal mol^ꢂ1) to be sepa-

rated ions apart from for 3-Cl and 3-Br.

Reaction proles were computed for each of the anilinium

salts in which both degradative reactions (MeI formation and

reaction with solvent) and productive reactions (S_N2 and S_NAr

with phenolate) are compared. An example is given for 3a in

Fig. 22 where:

State A ¼ the reactant anilinium salt (as an ion-pair)

State B ¼ methyl transfer to solvent DMSO

Fig. 22 DFT-derived free energies for transition states and intermediates for the reaction of 3a with the reference state at 0 kJ mol^ꢂ1being a tight

anilinium iodide ion pair (in this case). Experimentally-consistent mechanisms for anilinium iodide degradation and anilinium-mediated O-

methylation are shown and described further in the text. Energies shown are free energies in kJ mol^ꢂ1, with kcal mol^ꢂ1values shown in

parenthesis. Method: M06-2X/6-31+G**/IEFPCM (DMSO). T ¼ 353.15 K (80 ^ꢀC).

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Fig. 23 DFT-computed comparison of S_NAr and S_N2 barriers for

reaction of phenolate with anilinium cation. Method: M06-2X/6-

31+G**/IEFPCM (DMSO). T ¼ 353.15 K (80 ^ꢀC).

Fig. 24 Four anilinium salt degradation mechanisms for which DFT-

computed solutions were found.

with phenoxide of 120.4 kJ mol^ꢂ1(28.8 kcal mol^ꢂ1), and thus all

three processes might be expected to be operating experimen-

tally. While the calculations are not able to explicitly corrobo-

rate 11a (3-Br) as the experimentally optimum methylating

reagent, they are suggestive of this salt as having a good balance

between the likely degree of degradation and the selectivity

between S_N2 and S_NAr reactions, thus providing an eﬀective and

safer ‘slow bleed’ alternative to methyl iodide.

State C ¼ self-immolative methyl transfer to halide (i.e. MeI

is formed)

State D ¼ S_N2 methylation of phenolate, and

State E ¼ S_NAr reaction.

Some features are consistent for each of the iodide salts.

First, the reaction of the anilinium iodide with DMSO is

kinetically and signicantly disfavoured (Fig. 22, A / B). The

formation of MeI (Fig. 22, A / C) is close to thermoneutral and

has a barrier that is readily accessible at the elevated tempera-

tures employed in the experimental studies. Electron donating

groups disfavour formation of MeI. The reverse reaction in

which anilinium reforms is also accessible. The barrier for

methyl iodide to react with DMSO is 89.3 kJ mol^ꢂ1(or

21.3 kcal mol^ꢂ1). These calculations are consistent with the

observed delay in sulfoxonium formation coming only aer

methyl iodide formation, the intermediate formation of both

methyl iodide and sulfoxonium, the induction period in the

observed formation of DMSO-d₃, and the observed positions of

H/D scrambling (Fig. 12).

Fig. 24 shows three alternative modes of anilinium iodide

self-immolation in ion-pairs, beyond the simple rst order self-

reaction, that were all considered computationally. In this case,

explicit DMSO molecules were included around the anilinium

(or formyl groups in 3a) for any instances where such explicit

solvation was computed to have a negative free energy of asso-

ciation. Of all 4 mechanisms of degradation (A–D), A and C were

consistently calculated to be the most accessible across calcu-

lations involving salts 1a, 3a, and 11a; thus, at high concen-

ꢀ

trations and at 80 C, second order contributions to anilinium

iodide degradation are computed to be accessible. This is

consistent with the observed deviation from linear concentra-

tion dependence reported in Fig. 15. At rst sight, this sugges-

tion appears inconsistent with the lack of sensitivity to addition

of excess iodide revealed in Fig. 9. However, it should be kept in

mind that the temperature dependence of the second order

reactions (that involve the entropic penalty of bringing together

two reactants) will be markedly diﬀerent from that for the rst

order reaction. The calculations support a remarkably ne

balance between a number of alternative modes of reactivity

that can be selected between with careful choice of concentra-

tions, temperatures, and reagents.

The reactions with phenolate, S_N2 (Fig. 22, C / D) and S_NAr

(Fig. 22, A / E) have barriers that are low and largely irre-

versible. For salts 2a (2-Pyr), 3a (4-CHO), and 4-Bz (4a), the

barrier for S_NAr is computed to be the most lowered versus S_N2

(Fig. 23), qualitatively corresponding to the observation of S_NAr

product dominating the product mixture (Fig. 18). More

electron-donating substituents are computed to have a prefer-

ence for S_N2 but this is accompanied by an overall higher barrier

for reaction; thus, iodide salts predicted to be selective for

methylation over arylation are also predicted to react more

slowly. Although the 4-CHO salt (3a) has barriers for direct

reaction of phenolate with salt that are signicantly lower than

those for formation of MeI (77.7 kJ mol^ꢂ1for S_NAr vs.

116.5 kJ mol^ꢂ1for S_N2), this is not the case for all anilinium

salts universally. For instance, the unsubstituted iodide salt, 1a

(Computational ESI Section 3†), is computed to have a barrier to

formation of MeI of 125.2 kJ mol^ꢂ1(29.9 kcal mol^ꢂ1), a barrier

to S_NAr of 124.6 kJ mol^ꢂ1(29.8 kcal mol^ꢂ1), and a barrier to S_N2

Limitations of mechanistic analysis

Our mechanistic analysis – both experimental and computational

– is consistent with at least two operative mechanisms of anili-

nium iodide degradation. The rst and most dominant is simple

rst order self-immolation; one ion-pair degrades to one molecule

of dimethylaniline and one molecule of methyl iodide. The

second mechanism, accessible at higher concentrations of

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commonly applied DFT methods, this investigation also provides

a powerful data set on ionic reactivity that can actively inform new

computational approaches to studying the impact of solvent and

counterions on reactivity.⁷³

Conclusions

We have presented solid and solution phase thermal degrada-

tion analyses, kinetic studies, isotopic labelling, and computa-

tional modelling showing that N,N,N-trimethylanilinium salts

are likely to degrade in a self-destructive process. Taken

together, the mechanistic experiments forced a partial revision

of our initial mechanistic hypothesis from Fig. 13, as displayed

in Fig. 26. Increasing the anilinium counter-anion nucleophi-

licity, solution concentration, electron-withdrawing aryl

substituent power, soluble non-iodide halides, and solution

temperature were all found to increase the rate of salt degra-

dation. The minimal impact of solvent-led degradation path-

ways was supported by computational modelling of the two

degradation pathways. A range of N,N,N-trimethylanilinium

salts was tested as O-methylation reagents, with aryl-

substitution and counterion species shown to aﬀect methyl-

ating ability. 3-Br-N,N,N-Trimethylanilinium iodide (11a) was

shown to be an eﬀective methylating reagent for a variety of

phenols in DMSO and NMP. Mechanistic studies suggest that in

situ generated methyl iodide is likely to be the main methylating

reagent in these reactions. From a practical standpoint, should

these anilinium salts be made accessible without rst using

methyl iodide, we thus envisage that carefully selected anili-

nium iodide salt could function as a safer, crystalline, and

storable ‘slow bleed’ alternative to using carcinogenic and low-

boiling methyl iodide directly.⁴²

Fig. 25 Relative change in measured solution conductivity relative to

changes in 3a salt concentration during degradation. Conditions: 3a

(0.1 M) in DMSO-d₆(0.6 mL), 1,2,4,5-tetramethylbenzene as internal

standard (0.06 M; not plotted) at 80 ^ꢀC.

The same studies have highlighted the most stable anili-

nium salt congurations, and those salts for which concerted

S_NAr at the ipso carbon of the parent anilinium salts presents

dominant reactivity, both key considerations for chemists

aiming to exploit these same salts for cross-coupling as opposed

to methylation reactivity.

Fig. 26 Revised mechanistic model for anilinium iodide degradation,

consistent with all available experimental and computational mecha-

nistic evidence.

Beyond advancing popular O-alkylation strategies,⁶⁹it is

clear that varied applications of trimethylammonium salts is, at

the time of writing, on the rise.⁷⁴As such, the implications of

the above results on a broader range of chemistries involving

trimethylanilinium salts is also worth delineating. In our esti-

mation, the fundamental understanding of the structural

parameters aﬀecting anilinium salt degradation hold implica-

tions for: (i) the design of anilinium-derived ionic liquids used

as solvents, electrolytes, and in electropolymerisation strate-

gies,^75,76(ii) the design and understanding of anilinium-derived

compounds used in antibacterial technologies,^77,78(iii) under-

standing the reaction conditions and range of anilinium

substitution patterns amenable to metal-catalysed chemistries

(including but not limited to arylation, alkynylation, silylation,

and ortho-methylation),^{7,8,23,29,31,79}(iv) understanding substrate

design for ¹⁸F radiolabelling mediated by S_NAr chemistries on

anilinium cores,^12,80and (v) a fuller understanding of the range

of anilinium structures applicable to ion-pair directed regio-

control of C–H activation methods.²

anilinium iodide, is proposed to be (at least in part) second order

with respect to the anilinium iodide ion pair. Further microkinetic

analysis remains consistent with both rst and second order

processes being operative (see Experimental ESI Section 17†). The

main unavoidable assumption in all mechanistic analysis, is that

these reactions proceed in an unchanging medium that presents

unchanging physical properties as the main reactions proceed. In

reality, an unchanging medium is highly unlikely, especially for

such reactions proceeding from charged reactants to neutral

products. Conductivity measurements (Fig. 25, and Experimental

ESI Section 25†) and scans of solvent model dielectric constant

versus DG (Computational ESI, Section 5†) show that the physical

properties of the reaction medium change with time. The

temperature variation of the nature of both the medium and the

solvation thermodynamics are also unlikely to be universally

consistent for the diﬀerent structural variations of anilinium

iodide. As a result of the identied subtleties of these very

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9 E. Wenkert, A.-L. Han and C.-J. Jenny, J. Chem. Soc., Chem.

Commun., 1988, 975–976.

Author contributions

10 J. T. Reeves, D. R. Fandrick, Z. Tan, J. J. Song, H. Lee,

N. K. Yee and C. H. Senanayake, Org. Lett., 2010, 12, 4388–

4391.

11 S. B. Blakey and D. W. C. MacMillan, J. Am. Chem. Soc., 2003,

125, 6046–6047.

12 H. Sun and S. G. DiMagno, J. Fluorine Chem., 2007, 128, 806–

812.

13 N.-U. H. Khan, B. C. Lee, S.-Y. Lee, Y. S. Choe, C.-H. Jun and

D. Y. Chi, J. Labelled Compd. Radiopharm., 2002, 45, 1045–

1053.

JBW – data curation; formal analysis; investigation; method-

ology; validation; visualization; writing – original dra. MA –

data curation; formal analysis; investigation; methodology;

validation; visualization; writing – original dra. CY – data

curation; formal analysis; investigation; methodology; valida-

tion; visualization. DM – data curation; formal analysis; inves-

tigation; methodology; validation; visualization. VJ – data

curation; investigation; visualization. AGL – supervision; data

curation; formal analysis; investigation; methodology; valida-

tion; writing – original dra; writing – review & editing. SEB –

supervision; writing – review & editing. MR – conceptualization;

formal analysis; project administration; supervision; validation;

writing – original dra; writing – review & editing.

14 R. Richarz, P. Krapf, F. Zarrad, E. A. Urusova, B. Neumaier

and B. D. Zlatopolskiy, Org. Biomol. Chem., 2014, 12, 8094–

8099.

15 X. Huang, R. J. Gillies and H. Tian, J. Labelled Compd.

Radiopharm., 2015, 58, 156–162.

16 G. F. Silbestri, M. T. Lockhart and A. B. Chopra, ARKIVOC,

2011, 210–220.

Conﬂicts of interest

There are no conicts to declare.

17 Y.-T. Wang, B.-B. Gao, F. Wang, S.-Y. Liu, H. Yu, W.-H. Zhang

and J.-P. Lang, Dalton Trans., 2017, 46, 1832–1839.

18 B.-B. Gao, M. Zhang, X.-R. Chen, D.-L. Zhu, H. Yu,

W.-H. Zhang and J.-P. Lang, Dalton Trans., 2018, 47, 5780–

5788.

Acknowledgements

MR thanks the Leverhulme Trust for fellowship funding (ECF-

2016-264). JBW thanks GlaxoSmithKline for funding. MR, DM,

CY, and JBW thank Drs John Liggat and Len Berlouis for helpful

discussions during the course of solid-state thermal degrada-

tion investigations. MR thanks the ARCHIE-WeSt High Perfor-

mance Computer service (www.archie-west.ac.uk) based at the

University of Strathclyde. MR and JBW thank the EPSRC for

funding via Prosperity partnership EP/S035990/1. AGL and MA

would like to acknowledge AstraZeneca for funding, and also

the assistance given by Research IT and the use of the

Computational Shared Facility at The University of Manchester.

´

19 J. Martınez, F. de la Cruz-Martınez, M. A. Gaona, E. Pinilla-

˜

´

Penalver, J. Fernandez-Baeza, A. M. Rodrıguez, J. A. Castro-

´

Osma, A. Otero and A. Lara-Sanchez, Inorg. Chem., 2019,

58, 3396–3408.

20 S. P. Desai, M. Mondal and J. Choudhury, Organometallics,

2015, 34, 2731–2736.

21 F. Sadegh, O. Bagheri, M. Moghadam, V. Mirkhani,

S. Tangestaninejad and I. Mohammadpoor-Baltork, J.

Organomet. Chem., 2014, 759, 46–57.

22 A. Chen, G. Er, C. Zhang, J. Tang, M. Alam, H. T. Ta,

A. G. Elliott, M. A. Cooper, J. Perera, S. Swi, I. Blakey,

A. K. Whittaker and H. Peng, J. Polym. Sci., Part A: Polym.

Chem., 2019, 57, 1908–1921.

23 A. W. Rand and J. Montgomery, Chem. Sci., 2019, 10, 5338–

5344.

24 Y. I. Park, O. Postupna, A. Zhugayevych, H. Shin, Y.-S. Park,

B. Kim, H.-J. Yen, P. Cheruku, J. S. Martinez, J. W. Park,

S. Tretiak and H.-L. Wang, Chem. Sci., 2015, 6, 789–797.

Notes and references

1 S. E. Denmark, N. D. Gould and L. M. Wolf, J. Org. Chem.,

2011, 76, 4260–4336.

2 H. J. Davis, M. T. Mihai and R. J. Phipps, J. Am. Chem. Soc.,

2016, 138, 12759–12762.

3 K. Brak and E. N. Jacobsen, Angew. Chem., Int. Ed., 2013, 52,

534–561.

4 N. A. Shamsutdinova, I. D. Strelnik, E. I. Musina, 25 Y. Ma, L. Zhang, Y. Luo, M. Nishiura and Z. Hou, J. Am.

T. P. Gerasimova, S. A. Katsyuba, V. M. Babaev,

Chem. Soc., 2017, 139, 12434–12437.

D. B. Krivolapov, I. A. Litvinov, A. R. Mustana, 26 Q. Chen, F. Gao, H. Tang, M. Yao, Q. Zhao, Y. Shi, Y. Dang

A. A. Karasik and O. G. Sinyashin, New J. Chem., 2016, 40,

9853–9861.

5 P. H. J. Carlsen, K. Liberkova, R. Harrex, J. Røe, K. Rissanen,

and C. Cao, ACS Catal., 2019, 9, 3730–3736.

27 L. G. Xie and Z. X. Wang, Angew. Chem., Int. Ed., 2011, 50,

4901–4904.

W. Shi, S. Styring, C. Tommos, K. Warncke and B. R. Wood, 28 Z.-X. Wang and B. Yang, Org. Biomol. Chem., 2020, 18, 1057–

Acta Chem. Scand., 1997, 51, 343–344.

1072.

6 D. Wang, Z. Yang, C. Wang, A. Zhang and M. Uchiyama, 29 C. Wang, Chem. Pharm. Bull., 2020, 68, 683–693.

Angew. Chem., Int. Ed., 2018, 57, 3641–3645.

7 D. Y. Wang, X. Wen, C. D. Xiong, J. N. Zhao, C. Y. Ding,

30 H. Chen, H. Yang, N. Li, X. Xue, Z. He and Q. Zeng, Org.

Process Res. Dev., 2019, 23, 1679–1685.

Q. Meng, H. Zhou, C. Wang, M. Uchiyama, X. J. Lu and 31 L. Liu, W.-Q. Yu, T. Huang and T. Chen, Tetrahedron Lett.,

A. Zhang, iScience, 2019, 15, 307–315. 2020, 61, 151647.

8 T. Uemura, M. Yamaguchi and N. Chatani, Angew. Chem., Int. 32 B. W. H. Turnbull, J. Chae, S. Oliver and P. A. Evans, Chem.

Ed., 2016, 55, 3162–3165.

Sci., 2017, 8, 4001–4005.

Chem. Sci.

View Article Online

Edge Article

Chemical Science

33 X.-Q. Zhang and Z.-X. Wang, J. Org. Chem., 2012, 77, 3658– 64 E. M. Arnett and D. R. McKelvey, J. Am. Chem. Soc., 1966, 88,

3663. 2598–2599.

34 J. Hu, H. Sun, W. Cai, X. Pu, Y. Zhang and Z. Shi, J. Org. 65 E. E. Kwan, Y. Zeng, H. A. Besser and E. N. Jacobsen, Nat.

Chem., 2016, 81, 14–24. Chem., 2018, 10, 917–923.

35 H. Zhang, S. Hagihara and K. Itami, Chem.–Eur. J., 2015, 21, 66 C. Gardner Swain and E. C. Lupton, J. Am. Chem. Soc., 1968,

16796–16800. 90, 4328–4337.

36 X.-Q. Zhang and Z.-X. Wang, Org. Biomol. Chem., 2014, 12, 67 J. T. Burns and K. T. Leﬀek, Can. J. Chem., 1969, 47, 3725–

1448–1453. 3728.

37 F. Zhu, J.-L. Tao and Z.-X. Wang, Org. Lett., 2015, 17, 4926– 68 S. D. Roughley and A. M. Jordan, J. Med. Chem., 2011, 54,

4929. 3451–3479.

38 R. W. Hoﬀmann, Angew. Chem., Int. Ed., 2000, 39, 2054–2070. 69 D. G. Brown and J. Bostrom, J. Med. Chem., 2016, 59, 4443–

39 M. Burns, S. Essa, J. R. Bame, S. P. Bull, M. P. Webster, 4458.

S. Balieu, J. W. Dale, C. P. Butts, J. N. Harvey and 70 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,

¨

V. K. Aggarwal, Nature, 2014, 513, 183–188.

M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone,

B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato,

X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng,

J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota,

R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,

O. Kitao, H. Nakai, T. Vreven, J. J. A. Montgomery,

J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd,

E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi,

J. Normand, K. Raghavachari, A. Rendell, J. C. Burant,

S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam,

M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo,

J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev,

A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski,

R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth,

P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels,

O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski and

D. J. Fox, 2009.

¨

40 H. Schonherr and T. Cernak, Angew. Chem., Int. Ed., 2013, 52,

12256–12267.

¨

41 E. J. Barreiro, A. E. Kummerle and C. A. M. Fraga, Chem. Rev.,

2011, 111, 5215–5246.

42 M. Butters, D. Catterick, A. Craig, A. Curzons, D. Dale,

A. Gillmore, S. P. Green, I. Marziano, J.-P. Sherlock and

W. White, Chem. Rev., 2006, 106, 3002–3027.

43 K. Endo and T. Shibata, Synthesis, 2012, 44, 1427–1452.

44 J. Kim and S. H. Cho, Synlett, 2016, 27, 2525–2529.

45 R. Giri, S. Thapa and A. Kae, Adv. Synth. Catal., 2014, 356,

1395–1411.

¨

46 G. Lamoureux and C. Aguero, ARKIVOC, 2009, 2009, 251–264.

47 J. Macgee, J. Anal. Chem., 1970, 42, 421–422.

48 D. G. Bailey, J. Chromatogr., 1975, 11, 305–311.

49 L. Hevesi, Tetrahedron Lett., 1976, 17, 1389–1390.

50 J. L. Day, P. Grenier and L. Harold, J. Chromatogr. A, 1979,

177, 118–121.

51 J. Hartenstein and E. Fritschi, US Pat., US4425350A, 1980.

52 C. A. Francis, US Pat., US20050261500A1, 2004.

53 G. Noonan and A. G. Leach, Org. Biomol. Chem., 2015, 13,

2555–2560.

71 G. Luchini, J. V. Alegre-Requena, I. Funes-Ardoiz and

R. S. Paton, F1000Research, 2020, 9, 291.

72 J. T. W. Lai, F. W. Lau, D. Robb, P. Westh, G. Nielsen,

C. Trandum, A. Hvidt and Y. Koga, J. Solution Chem., 1995,

24, 89–102.

54 A. L. Dunn, A. Payne, P. R. Clark, C. McKay, G. D. Williams, 73 Y. Nieves-Quinones and D. A. Singleton, J. Am. Chem. Soc.,

K. Wheelhouse, K. Arendt, F. Dixon and S. Shilcrat, J. Chem.

Educ., 2021, 98, 175–182.

55 J. P. Lewicki, D. Todd, P. Redon, J. Liggat and L. Gibson, MRS

Online Proc. Libr., 2007, 1047, 1047-Y04-05.

2016, 138, 15167–15176.

74 A conservative Scopus search of 1610 chemistry-focussed

research articles containing “trimethylammonium” in the

title and/or abstract shows an increase of 40 articles per

year to over 100 articles per year in the period 2000–20.

75 M. E. Abdelhamid, T. Murdoch, T. L. Greaves,

A. P. O'Mullane and G. A. Snook, Phys. Chem. Chem. Phys.,

2015, 17, 17967–17972.

76 B. Baker, C. J. Cockram, S. Dakein, J. M. DeMaria,

D. M. George, K. R. Malyk, M. J. F. Sarno and

A. J. P. Cardenas, J. Mol. Struct., 2021, 1225, 129122.

˜

´

56 E. Avella-Moreno, N. Nunez-Dallos, L. Garzon-Tovar and

A. Duarte-Ruiz, J. Sulfur Chem., 2015, 36, 535–543.

57 Z. Shen, S. Zhang, H. Geng, J. Wang, X. Zhang, A. Zhou,

C. Yao, X. Chen and W. Wang, Org. Lett., 2019, 21, 448–452.

58 Y. Chen, Chem.–Eur. J., 2019, 25, 3405–3439.

59 P. Storoniak and J. Rak, J. Therm. Anal. Calorim., 2000, 60,

927–941.

60 R. F. Rodewald, K. Mahendran, J. L. Bear and R. Fuchs, J. Am. 77 S. Chakraborty, R. Barman and S. Ghosh, J. Mater. Chem. B,

Chem. Soc., 1968, 90, 6698–6700. 2020, 8, 2909–2917.

61 W. M. Weaver and J. D. Hutchison, J. Am. Chem. Soc., 1964, 78 O. Bulut, H. A. Oktem and M. D. Yilmaz, J. Hazard. Mater.,

86, 261–265.

2020, 399, 122902.

62 P. S. Pregosin, Magn. Reson. Chem., 2017, 55, 405–413.

63 E. V. Dalessandro and J. R. Pliego, Theor. Chem. Acc., 2020,

139, 27.

79 D.-Y. Wang, K. Morimoto, Z. Yang, C. Wang and

M. Uchiyama, Chem.–Asian J., 2017, 12, 2554–2557.

80 C. N. Neumann, J. M. Hooker and T. Ritter, Nature, 2016,

534, 369–373.

Chem. Sci.

Article Doi

Trialkylammonium salt degradation: Implications for methylation and cross-coupling

DOI: 10.1039/d1sc00757b

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Article abstract of DOI:10.1039/d1sc00757b

Full text of DOI:10.1039/d1sc00757b

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