Studies of hydrogen isotope scrambling during the dehalogenation of aromatic chloro-compounds with deuterium gas over palladium catalysts

Received: 18 June 2020

DOI: 10.1002/jlcr.3878

Revised: 23 July 2020

Accepted: 19 August 2020

R E S E A R C H A R T I C L E

Studies of hydrogen isotope scrambling during the

dehalogenation of aromatic chloro-compounds with

deuterium gas over palladium catalysts

William J.S. Lockley¹

| Niccolò A. E. Venanzi²

| Georgie J. Crane¹

¹Department of Chemistry, Faculty of

Engineering and Physical Sciences,

University of Surrey, Guildford, UK

²Department of Chemistry, University

College London, London, UK

Catalytic dehalogenation of aromatic halides using isotopic hydrogen gas is an

important strategy for labelling pharmaceuticals, biochemicals, environmental

agents and so forth. To extend, improve and further understand this process,

studies have been carried out on the scrambling of deuterium isotope with pro-

tium during the catalytic deuterodehalogenation of model aryl chlorides using

deuterium gas and a palladium on carbon catalyst in tetrahydrofuran solution.

The degree of scrambling was greatest with electron-rich chloroarene rings.

The tetrahydrofuran solvent and the triethylamine base were not the source of

the undesired protium; instead, it arose, substantially, from the water content

of the catalyst, though other sources of protium may also be present on the cat-

alyst. Replacement of the Pd/C catalyst with one prepared in situ by reduction

of palladium trifluoroacetate with deuterium gas and dispersed upon

micronised polytetrafluoroethylene led to much reduced scrambling (typically

0–6% compared with up to 40% for palladium on carbon) and to high atom%

abundance, regiospecific labelling. The improved catalytic system now enables

efficient polydeuteration via the dehalogenation of polyhalogenated precur-

sors, making the procedure viable for the preparation of MS internal standards

and, potentially, for high specific activity tritium labelling.

Correspondence

William J. S. Lockley, Department of

Chemistry, Faculty of Engineering and

Physical Sciences, University of Surrey,

Guildford GU2 7XH, UK.

Email: w.lockley@surrey.ac.uk

K E Y W O R D S

catalysis, halogen exchange, isotope scrambling, mechanism, palladium, palladium

trifluoroacetate, PTFE, reductive dehalogenation

1 | INTRODUCTION

powerful reductants such as samarium halides have been

optimised for the process.¹⁶

The dehalogenation of haloaromatics is a widely utilised

reaction, which is important in the preparation of

labelled compounds and in the detoxification of haloge-

nated waste. Both solution- and gas-phase procedures are

employed in the reaction, as are photochemical

procedures,^1,2metal hydrides,^3–5stannanes,^6,7hydrogen

gas^8,9and various transfer hydrogen donors.^10,11The use

of palladium complexes^12,13and palladium nanoparticle

catalysts^14,15have also been investigated, whereas other

Particularly relevant to the current work is a thor-

ough investigation of hydrodechlorination by Sajiki

et al.^8,17They studied the hydrodehalogenation of

4-chlorobiphenyl (and other chloroaromatics) with

hydrogen gas under catalysis by palladium on carbon and

noted the importance of the nature of the base to the effi-

ciency of the reaction. A range of amine bases, best exem-

plified by triethylamine, shared the ability to promote

rapid reaction, though some N-heteroaromatic bases

J Label Compd Radiopharm. 2020;1–22.

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LOCKLEY ET AL.

were strongly inhibitory. It had long been believed that

the role of the base was simply to neutralise the hydrogen

chloride generated in the reaction, but these workers

were able to show that the amine had a more significant

additional function with respect to facilitating the reac-

tion mechanism (see later).

For many decades, dehalogenation with isotopic

hydrogen gas, a palladium catalyst and triethylamine as

base, has been a productive, routine, facile and common

approach to labelling organic compounds with tritium.¹⁸

The reaction is site specific and proceeds in high yield.

Indeed, the procedure has been widely employed in

industrial research organisations and is currently offered

by all the main radiolabelling contract laboratories. Hun-

dreds of tritiated compounds have been prepared by this

approach.^19,20Moreover, the corresponding deuterium

labelling procedure has also been utilised for many

years,^21–23either using conventional hydrogenation with

deuterium gas or by transfer-hydrogenation with various

deuterium donors.^24,25

FIGURE 2 Structures of the dehalogenation substrates used

The dehalogenation of chloroaromatics, however,

generally gives low atom% abundance²⁶due to competing

isotopic scrambling reactions which introduce protium

instead of deuterium or tritium at the labelling site. The

presence of this undesired protium has been variously

ascribed to scrambling with protiated heteroatoms in the

substrate, or other protiated components of the

reaction,²⁷or with the solvent,^28,29especially alcohols.³⁰

We have studied several model deuterodechlorination

systems over several years with the intention of identify-

ing the nature of the scrambling processes and identify-

ing more efficient dehalogenation systems.^26,31,32Our

early studies utilised the dehalogenation of 2⁰-

chloroacetanilide (Figure 1) in conjunction with a defi-

ciency of deuterium gas, to model the typical conditions

of a tritiation reaction (Experimental Procedure A). Later

studies used an excess of deuterium to model the condi-

tions used in the preparation of deuterated materials for

tracer studies and MS internal standards (Experimental

Procedure B).

in the studies

6⁰-proton occasioned by deuterium substitution at the 2⁰-

position.³²This isotope effect also differentiates the 3⁰

and 5⁰positions in the ¹³C-NMR of 2⁰-labelled

acetanilides.

During the later stages of our studies, other substrates

and conditions were utilised to ensure that the broad

conclusions drawn were indeed general. The substrates

used throughout these studies are shown in Figure 2. We

now report the studies in detail.

2 | RESULTS AND DISCUSSION

Because nearly all literature dehalogenations with tritium

or deuterium gas have been carried out at room tempera-

ture and at ambient pressure (sometimes somewhat

lower for safety when using tritium), the reaction

between deuterium gas and 2⁰-chloroacetanilide was

studied at room temperature and with an initial deute-

rium pressure of 1 atm.

The 2⁰-chloroacetanilide model was particularly use-

ful because both the degree of reaction and the percent-

age deuterium at the reaction site can be easily

determined by ¹H-NMR due to a large isotope shift of the

2.1 | Catalyst selection

An initial evaluation of a wide selection of potential cata-

lysts was made, using the model system in Figure 1 to

select a suitable catalyst for our studies. This catalyst

would give a reasonable reaction rate whilst providing a

sufficiently low (but not untypical) deuterium abundance

in the product (Figure 3). On this basis, we excluded the

metal blacks and the catalysts based upon rhodium,

FIGURE 1 Deuteration and scrambling in the

deuterodehalogenation of 2⁰-chloroacetanilide (1)

LOCKLEY ET AL.

3

FIGURE 3 Reaction extent and degree of

scrambling (%H at the labelling site) found

during the dehalogenation of 2⁰-

chloroacetanilide by various active catalysts

using D₂gas, THF as solvent and triethylamine

as base

which, presumably because of the high degree of scram-

bling and low reactivity, are not used routinely for isoto-

pic dehalogenation reactions. Instead, we selected 5%

palladium on carbon as our model catalyst.

reaction volume was set at 2 ml, whereas the quantity of

substrate was set at 0.5 mmol (Section 4: Procedure A).

These conditions ensured that there would be a defi-

ciency of deuterium in the model system because the

remaining capacity of the 10 ml capacity reaction vessels

used would be 8 ml (approximately 0.3 mmol D₂allowing

for solvent vapour pressure). The use of a deficiency of

tritium with respect to the substrate is a common

approach to atom efficiency in labelling procedures. Next,

the amount of catalyst utilised was selected on the basis

of initial studies, which showed that the amount of

catalyst was negatively correlated with the percentage

deuterium achieved in the [2⁰-D]acetanilide product

(Figure 4); 30 mg of the catalyst was selected as a

reasonable amount.

Studies also showed that the percentage deuterium

was not substantially affected by the quantity of the base

(triethylamine) used, provided this was greater than

1 mol/mol of substrate.

A selection of solvents was examined, and THF was

chosen as a typical solvent (Figure 5). Under these condi-

tions, the reaction was complete after 2 h.

Like many Pd/C catalysts, this standard catalyst con-

tains added water. Such catalysts are described as “pas-

tes” though they are apparently dry, free-flowing

powders. The water was originally added to protect

against pyrophoricity, but it also ensures faster hydroge-

nation reactions, a phenomenon that has been ascribed

to the facilitation of proton-hopping mechanisms.³³

The chosen catalyst was supplied as containing

approximately 50% water, but the actual water content of

the dispensed catalyst varies according to humidity. Dry-

ing at 200^ꢀC showed a weight loss of only 23.5%, whereas

desiccation over activated silica gel or molecular sieve 4A

showed weight losses of 23.5% and 22.8%, respectively.

Rehydration of the dried catalyst by exposure to air at

98% humidity showed a weight uptake corresponding to

29%, which dropped back to approximately 24% at a

humidity of 50%. Hence, a portion of the water content is

easily removable and replaceable. It is possible, though,

that a further portion of the water is strongly retained,

maybe as chemisorbed species.

Once the standard conditions were defined, several

studies were carried out to investigate factors affecting

the degree of scrambling. Of these, the most revealing

were studies of the timing of substrate addition

(Figure 6). These data suggest that one or more compet-

ing isotope scrambling reactions are occurring in the

absence of the substrate.

The other reaction parameters were set to provide

conditions similar to those encountered in typical

tritiation reactions. However, the scale was increased to

enable accurate repeat analysis of the deuterium and pro-

tium in the products by spectroscopic techniques. The

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LOCKLEY ET AL.

FIGURE 4 Effect of catalyst amount on the

scrambling (%H at the labelling site) for [2⁰-D]

acetanilide (Procedure A)

FIGURE 5 Effect of solvent on the

reaction extent and isotopic scrambling in the

deuterodehalogenation of 2⁰-chloroacetanilide

FIGURE 6 Percentage deuterium in the

dehalogenated product versus time (minutes) at

which the substrate was added to the reaction

for substrates 2⁰-chloroacetanilide (1, Procedure

A) and 4-chlorobenzophenone (2, Procedure B)

To investigate these scrambling reactions further,

utilised two new chloro-substrates,

(3) and phenyl

scrambled) and phenyl [4-D]benzoate (only 8%

scrambled).

We hypothesised that the different degree of scram-

bling between the substrates probably reflected different

degrees of inhibition of the scrambling reactions by the

substrates.

we

4-chlorophenylsuccinimide

4-chlorobenzoate (4), which had similar rates of reaction

but which showed very different degrees of scrambling in

the deuterated products: [4-D]phenylsuccinimide (43%

LOCKLEY ET AL.

5

Further information was provided by a study of the

same two substrates under competitive conditions

(Figure 7), which showed that the dehalogenation rate of

has long been known^35–38and indeed has been exploited

for the large scale preparation of high-enrichment heavy

water.³⁹The nature of the exchange mechanism is a mat-

ter of debate, but studies suggest that a hydrated proton

intermediate, possibly H₃O⁺, may be a key intermedi-

ate.⁴⁰More recently, the exchange between O-deuterated

methanol and hydrogen gas over palladium on carbon

has been used for the preparation of deuterium gas on a

convenient and simple laboratory scale.¹⁷It seemed

likely, therefore, that a similar process might be

contributing to the scrambling reaction(s) during

dehalogenation. In support of this idea, carrying out the

dehalogenation reaction of 2⁰-chloroacetanilide (1) under

ordinary hydrogen gas (protium) in the presence of added

deuterium oxide resulted in acetanilide partially labelled

(21%D) with deuterium at the 2⁰-position.

4-chlorophenylsuccinimide

(3)

was

substantially

inhibited in this case, suggesting that the phenyl

4-chlorobenzoate (4) was achieving preferential access to

the reaction site, possibly by tighter binding.

The substrates 3 and 4 differ substantially in electron

availability. The chlorophenyl ring in substrate 3 is

electron-rich in comparison with that in substrate 4,

which is electron-poor (Page 1 of the Supporting Infor-

mation). Thus, the ZDO partial charges³⁴of the carbon at

the C–Cl reaction site for 3 is −0.069, whereas for 4, it is

−0.0285. To check if this electron availability difference

was predictive of interaction with the catalyst and hence

of the precedence of the more electron-poor substrate in

competitive reactions, two other pairs of compounds with

significant differences in ZDO partial charge were also

examined under competitive conditions. The results for

each pair confirmed the behaviour: in each case, the

more electron-poor substrate reacted faster and slowed

the reaction of the more electron-rich substrate (Page 2 of

the Supporting Information).

2.2.1 | The effect of solvent, base and

reaction product

We next undertook a series of studies of the gas-phase

component of the dehalogenation reaction. Initially, we

utilised phenylacetylene as a rapidly reduced surrogate to

report the degree of scrambling of the deuterium gas by

analysis of the styrene reduction product (Page 3 of the

Supporting Information). Subsequently, the results were

confirmed directly and further studies carried out, using

a residual gas analyser: a quadrupole mass spectrometer

that can sample and analyse small (200 μl) quantities of

isotopic hydrogen gas.

2.2 | Studies of the reaction parameters

affecting the degree of scrambling

The scrambling of isotope between protiated hydroxylic

solvents and deuterium gas over platinum group metals

Access to this technology allowed the effects of com-

ponents of the dehalogenation reaction upon the degree

of isotope scrambling to be separately evaluated by analy-

sis of the quantity of hydrogen, hydrogen deuteride and

deuterium in the gas above the reaction.

The results were clear (Figure 8) and showed that

scrambling took place with the solid catalyst alone, in the

absence of any THF solvent or triethylamine base. More-

over, treatment of the catalyst with deuterium gas, addi-

tion of THF/CDCl₃, filtration and analysis by D-NMR

showed the time-dependent generation of HOD (peak at

δ 3.4 ppm in THF).

Further, reaction components were then investigated

separately. This showed only minimal inhibition of the

scrambling by triethylamine (though triethylamine

deuterochloride was later shown to be somewhat more

effective as an inhibitor), whereas the THF solvent did

not inhibit the scrambling.

However, the scrambling was much reduced when

the catalyst was dried over molecular sieve 4A or silica

gel. Moreover, studies employing hydrogen (protium) gas

and palladium on carbon catalyst treated with deuterium

FIGURE 7 Reaction time-course for the

deuterodechlorination of 4-chlorophenylsuccinimide (3) and

phenyl 4-chlorobenzoate (4) either alone (0.1 mmol) or under

competitive conditions (0.05 mmol each) using Procedure B

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LOCKLEY ET AL.

FIGURE 8 Gas-phase analyses of

H₂, HD, D₂(m/z 2, 3, 4) of the effects

of the individual components of the

deuterodechlorination reaction. (A–D)

Time-course for the reaction (at 0,

10, 20 and 40 min) in the absence of

any dechlorination substrate. (E) Solid

catalyst alone, no solvent or base

present. (F) Catalyst plus

triethylamine, no THF solvent.

(G) Catalyst plus THF alone, no

triethylamine. (H) Catalyst plus THF

and triethylamine (spectra E–H were

all recorded at 30 min reaction time)

oxide showed rapid formation of hydrogen deuteride and

deuterium. Furthermore, this scrambling was increased if

the catalyst had been dried previously to remove

protiated water (Page 4 of the Supporting Information).

of interaction (binding or reaction) with the catalyst is an

important factor in the degree of scrambling experienced.

In this regard, the adsorption strength of the various

monohalobenzenes to palladium catalysts have been pre-

viously shown to be I>> Br > Cl, though this need not

transfer to overall reaction rate in any particular case as

fast reaction requires an optimum balance between

adsorption strength and carbon–halogen bond energy.¹⁰

The tight binding is particularly striking for iodo-

compounds and has been well characterised for

iodobenzene, where thermal desorption studies⁴¹have

shown facile binding plus reduction of the phenyl to

benzene by subsurface hydrogen. The palladium-bound

iodine from the deiodination process is strongly

bound and poisons the catalyst. Indeed, it was so tightly

bound that no iodine desorption was observed until

approximately 1000^ꢀC. The different binding strengths

between the halogens allows for selectivity between

dehalogenation sites, and this has been exploited in many

labelling studies.⁴²The issue has been briefly reviewed by

Filer,⁴³who noted that in competitive dehalogenations,

2.2.2 | The effect of the substrate on the

gas scrambling

Next, the effect of the dehalogenation substrate on the

extent of deuterium gas scrambling was examined, again

using substrates 3 and 4. The results are shown in

Figure 9, which shows the isotopic purity of the deute-

rium (%D/(D + H) against time. Both substrates inhibited

the scrambling reaction, but to different extents.

The degree of inhibition was then examined at two

substrate concentrations (Figure 10), which showed a

concentration-dependent inhibition that was more effec-

tive for substrate 4 than for substrate 3. This is in line

with the higher degree of scrambling for substrate 3 in

the dehalogenation reaction and suggests that the degree

LOCKLEY ET AL.

7

From the earlier gas-phase experiments, it was clear

that water content of the catalyst was an important

contributor to the scrambling reaction(s). As noted

earlier, carbon-based platinum group catalysts are

usually marketed with some added or residual water to

facilitate reductive reactions via ‘proton-hopping’³³

a

process that has been observed in real time on a catalytic

surface by atomic force microscopy.⁴⁴

The role of water and water-derived species on metal

surfaces has been extensively reviewed recently and the

situation is complex.⁴⁵Reactions are known in which

surface-oxidised catalyst can interact with water to give

OH⁻species, whereas multiply hydrated protonated spe-

cies H⁺(H₂O)_nmay be formed on surfaces exposed to

hydrogen, especially if Cl⁻is present. The actual hydro-

gen species present on a specific catalyst surface will

therefore reflect the preparation of the catalyst and its

storage, whereas the species present during

dehalogenation will reflect the actual reaction environ-

ment, the solvent, the substrate, the base, the product

and by-products.

FIGURE 9 Inhibition of D₂gas scrambling by dehalogenation

substrates 3 and 4

the iodoarene always reacts first, although its reaction

rate under noncompetitive conditions is often slower

than the other haloarenes. It was also suggested that the

strong adsorption of the iodoarene would exclude any

hydrogen transfer arising from the solvent (and presum-

ably from any other components of the reaction mixture)

but would not similarly exclude the small tritium mole-

cule from access to the active site, thus accounting for

the higher specific activity that is achieved in the

tritiodehalogenation of iodoarenes.

The studies reported earlier showed clearly that the

catalyst is one source of the protium for the scrambling

reaction(s). However, the other components of the reac-

tion might also supply protium; hence, we examined

these in turn.

2.2.3 | The solvent

The exchange of tritium from tritium gas into the reac-

tion solvent molecules during dehalogenation reactions

has been observed with polar solvents in the presence of

palladium oxide and palladium on barium sulphate cata-

lysts.⁴⁶It is also known that cyclic ethers such as dioxan

Our own studies have also shown a very powerful

inhibition of deuterium gas scrambling and inhibition of

dechlorination reactions by iodo-compounds (Page 5 of

the Supporting Information).

FIGURE 10 Inhibition of deuterium

scrambling by substrates 3 and 4 at two

concentrations

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LOCKLEY ET AL.

can act as hydrogen donors under catalysis by palladium

on carbon⁴⁷; hence, the solvent must be considered as a

potential protium source.

catalyst poisons. However, although the reaction is

indeed slow and often incomplete in the absence of a

base, this does not seem to be their only role.

To investigate this possibility, we studied the

dehalogenation of 1 under standard conditions but

replacing the THF solvent with [D₈]THF. This gave no

increase in the %D in the product [2⁰-D]acetanilide,

suggesting that the solvent was not the source of the pro-

tium. Moreover, no increase in the protium content of

the [D₈]THF was detected. Similarly, analysis by GC-MS

and D-NMR showed no deuterium above natural abun-

dance levels in the protiated THF from standard

deuterodehalogenation reactions.

We have examined an extensive range of inorganic

and organic bases (Figure 11) and found that the nature

of the base^8,9is indeed critical for the success of the reac-

tion and also for the %D achieved in the product. We find

that the open-chain monobasic trialkylamines are partic-

ularly effective in terms of the %D obtained at the

labelling site.

In our hands N,N-diisopropylethylamine (Hünig's

base, DIPEA) proved the most effective trialkylamine.

However, the aliphatic open chain trialkylamines

The fact that at least some of the scrambled protium

arises from water in the catalyst rather than the reaction

solvent is consistent with our previous collaborative

study with chemists at Janssen (Johnson & Johnson

N.V.). They exposed the solvents THF, dioxan, ethyl ace-

tate, DMA and DMF to tritium gas in the presence of a

palladium on carbon catalyst. Subsequent tritium-NMR

of the solvents in our laboratories showed only signals

from tritiated water. No tritiated solvent resonances nor

any other resonances other than HOT were detected.⁴⁸

(red) clearly form a favoured group (Page 6 of

the Supporting Information) for the delivery of high atom

% abundance labelling. Only in the case of bifunctional

trialkylamines with short linkers (N,N,N,N-tetramethyl

methylenediamine and N,N,N,N-tetramethylethylene

diamine) was deuterium abundance lowered or the reac-

tion inhibited, a behaviour likely to result from the

chelating ability of these systems.

From our results, it is possible that N-methyl N,N-

dialkylamines are somewhat anomalous. With the single

exception of diethylmethylamine, the use of N-

methylamines resulted in lowered %D. However, the

dehydrogenation of N-methylamines on palladium sur-

faces is a known process,⁵⁰and hence, this could contrib-

ute to the dilution of the isotope pool in these cases. It is

noteworthy that the pyridines investigated resulted in lit-

tle reaction or inhibited the reaction, a phenomenon pre-

viously reported^8,9and likely to result from strong

complexation to palladium active sites on the catalyst.

Because the base, solvent, substrate and product do

not appear to be the source of the isotopic scrambling,

the suspicion falls next upon the remaining players: the

deuterium gas itself, the catalyst, or adventitious water in

the apparatus. The deuterium gas cylinders used during

the studies were of 99.8% isotopic purity. Moreover, the

use of flame-dried apparatus and commercial super-dried

THF solvent again showed no reduction in the

scrambling.

2.2.4 | The substrate or product

Another potential source of protium could be via

exchange of the aromatic protons or the NH proton of

the substrate or product. However, there was no increase

in the percentage of deuterium in the [2⁰-D]acetanilide if

[amide-N-D]2⁰-chloroacetanilide was employed as sub-

strate, nor did the aromatic protons of the [2⁰-D]acetani-

lide or 2⁰-chloroacetanilide become labelled. D-NMR

showed only the expected deuterium at the 2⁰-position of

the [2⁰-D]acetanilide.

2.2.5 | The base

Because the triethylamine contains α-methylene protons,

and these are known to be prone to isotopic exchange,

particularly by labilisation on metal catalysts,⁴⁹we car-

ried out detailed MS and NMR studies with Et₃N, Bu₃N

and Hex₃N, which showed that they do not become deu-

terated during the reaction. Nor were any products

related to the amines (other than the deuterochlorides)

detected by D-NMR or GC-MS. Hence, if the base pro-

vides the protium, it is not via an exchange reaction or

via a dehydrogenation/reduction sequence.

2.2.6 | The catalyst

Thus, the only identified source of protium from our

studies was the catalyst, as noted earlier. Moreover, the

indications were that at least some of the scrambled pro-

tium arose from water. Drying of the catalyst by heating

under high vacuum did give improved deuterium abun-

dance in the dehalogenation product, but an unaccept-

able degree of scrambling remained. Of course, water

may not be the only catalyst source and it seems likely

Traditionally, it has been believed that the function of

the trialkylamine base in these reactions is to neutralise

the hydrogen halides released, because these latter are

LOCKLEY ET AL.

9

FIGURE 11 Reaction extent (% of

theoretical) and %D found for a series of bases

of varying structure using Experimental

Procedure A. Grey = reaction extent. Red = %D

with aliphatic open chain trialkylamines.

Green = %D with N-methylated cyclic

alkylamines. Black = %D with other bases

and none

therefore that there are further protium sources associ-

ated with the catalyst. In this regard, palladium hydride

phases have long been known⁵¹and are catalytically

active even in the absence of hydrogen gas.^52,53

2.3 | Experiments related to the

dechlorination reaction mechanism

The mechanism of dechlorination of variously

substituted aliphatic chlorides on palladium has been

investigated in detail and has been shown to be relatively

insensitive to substituent effects.⁵⁹However, our findings

relate to aromatic dehalogenation, an area for which

mechanistic information has been reviewed recently⁶⁰

and are broadly consistent with a published tentative

mechanism for the palladium-catalysed nonisotopic aro-

matic dechlorination reaction.⁹This mechanism involves

a single electron transfer (SET) from the tertiary amine to

the complexed chloroaromatic to give a trialkylaminium

radical cation and a chloroaromatic radical anion. Such

radical anions have been proposed as intermediates in

other related dechlorination systems.^61,62The radical

Palladium on carbon catalysts are generally prepared in

highly aqueous protiated environments often involving a

final high-temperature treatment with protium gas^54,55

;

hence, the nature of the protium species associated with the

metal and their migration and transformations are ill-

defined, though recently a proton-transfer mechanism

involving water has been shown by scanning tunnelling

microscopy to proceed via an H₃O⁺-like transition state.⁴⁴In

addition, the role of the carbon support in protium delivery

and transport is not well understood, though it is known to

be important in isotopic exchange processes via its participa-

tion in spillover mechanisms^49,56–58; hence, the support

cannot be excluded as an ancillary source of protium.

FIGURE 12 Literature mechanism of dechlorination

as modified for deuterodechlorination

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LOCKLEY ET AL.

anion then loses chloride ion to give an aryl radical

before picking up deuterium. Figure 12 demonstrates the

postulated process modified with respect to

deuterodehalogenation.

planar geometry and its stabilisation by substituents are

critically dependent on structure.^64,65For the monobasic

acyclic

trialkylamines

and

for

N,N,N,N-

tetramethylhexane-1,6-diamine, all of which have low

anodic oxidation potentials of around Ep. 0.7 V, the

achievement of planarity is facile. However, the shorter

chain bis-dimethylamino systems and the cyclic

alkylamines face greater steric constraints. The rather

poor performance of diaza[2,2,2]bicyclooctane (DABCO)

may be explained by a similar rationale. N-Met-

hylpyrrolidine, with more favourable geometry for pla-

narity around the nitrogen radical⁷¹and an Ep of 0.68 V,

shows intermediate behaviour.

The SET nature of the reaction was inferred from

inhibition studies with the known SET inhibitors

tetracyanoethylene (TCNE) and tetracyanoquino-

dimethane (TCNQ), and indeed, we have confirmed the

very powerful inhibitory effect of TNCE in the

dehalogenation of 1. However, it should be noted that

TCNE possesses metal chelation properties in addition to

its radical scavenging ability and that, in addition, some

stable-radical scavengers are inappropriate tools for

investigating palladium-based systems because they react

rapidly with palladium hydrides.⁶³

The by-product of the proposed SET reaction is a ter-

tiary aminium radical cation, a well-characterised species

produced in a range of chemical and electrochemical

reactions^64,65and involved also in metabolic

demethylations.⁶⁶A similar SET mechanism involving

formation of the triethylaminium radical cation is known

to occur in the reduction of quinones where the products

form a close ion-pair.⁶⁷Moreover, the SET reduction of

aryl halides by SmI₂, a one electron donor, is well known.

In that case, the hydrogen arises via aryl radical abstrac-

tion from the THF solvent.⁶⁸There is, therefore, reason-

able, but not unequivocal, background support for the

proposed SET mechanism.

Of relevance to the formation of triethylaminium

cations is the observation that triethylamine can react

with palladium on carbon to give a palladium hydride

species.⁶⁹In this reaction, an initial coordination of the

triethylamine to Pd(0) is followed by insertion of palla-

dium into an α-CH bond leading to a hydridic palladium

hydride coordinated to an iminium cation (Figure 13).

Such a species might be able to promote dehalogenation,

as it is postulated to be the reactive agent in conjugate

reduction of double bonds. Precedent for the formation of

such species with palladium is known.⁷⁰

With respect to our observations of the role of the

trialkylamine bases, a correlation might be expected

between %D and the propensity of the amine base for

SET. However, the interpretation of amine oxidation

potentials (Ep) is complex. Both the ability of the incipi-

ent aminium radical cation to achieve the necessary

There are, however, arguments against the proposed

SET mechanism, at least as far as it implies a stoichio-

metric process. One is the absence of cleavage products

of the quaternary Schiff base, derived from the aminium

radical cation by the facile loss of a proton and an elec-

tron. The formation of this species from the aminium ion

is known to be rapid, yet no trace of the expected alde-

hyde or secondary amine hydrolysis products could be

1

detected by GC-MS or H-NMR for the trialkylamines

Et₃N, Bu₃N or Hex₃N, even when extra water was added

to the reaction. Hence, the SET aspect of the reaction

could well be an initiation process rather than an overall

stoichiometric reaction.

A further objection is that from all the reactions that

we have studied, we have been unable to identify any

biphenyl-like radical-coupling products, though such

products have been observed in a related palladium

deuterodechlorination system where calcium metal was

incorporated with the palladium catalyst to provide

electron-donation.⁷²It may be that in the case of palla-

dium on carbon, the strong adsorption of the substrate

on the catalyst and the presence of surface and subsur-

face active hydrogen species leaves little chance for the

aryl radicals to migrate and couple.

Nor have we been able to facilitate the reaction by

employing radical initiators, photosensitisers, ultraviolet

light of 245 and 360 nm wavelengths or visible light.

Indeed, the reaction proceeds well in the dark as previ-

ously demonstrated.⁹

We noted earlier the preference of the palladium on

carbon catalyst for reaction with electron-poor chlo-

roarenes over electron-rich systems, a fact that has been

ascribed, for other palladium systems, to the ability of

chloroarenes to accept back-donation from Pd(0) to form

reasonably stable pre-reactive complexes.⁷³This prefer-

ence for electron-poor haloarenes is typical of reactions

involving oxidative addition of

a chloroarene to

palladium(0) species.^74,75Moreover, such an oxidative-

addition mechanism has been advanced for the dechlori-

nation of chloroarenes by a Pd(0) catalyst produced by

FIGURE 13 Putative formation of hydridic palladium species

by reaction of triethylamine with palladium on carbon

LOCKLEY ET AL.

11

borohydride reduction of palladium (phenanthroline)

dichloride.⁷⁶It therefore seemed worthwhile to investi-

gate the similarity between the Pd/C dehalogenation and

a typical oxidative-addition system. We chose the

Suzuki–Miyaura reaction as our model, because it is a

typical oxidative-addition system that is compatible with

our substrates and reaction conditions.^77,78Although het-

erogeneous palladium catalysts have been used for

Suzuki–Miyaura and similar reactions^79–81chloroarenes

have generally shown low reactivity.⁸²Indeed, we found

that our palladium on carbon catalyst showed little activ-

ity in a trial reaction between methyl 4-chlorobenzoate

and phenylboronic acid carried out in THF in the pres-

ence of potassium carbonate. Fortunately, however, the

catalyst showed greatly enhanced activity once it had

been activated with deuterium gas.

We further investigated the similarities between

the reactions using an ester, 4-chlorophenyl

4-chlorobenzoate (7) and an amide, N-(4-chlorophenyl)-

4-chlorobenzamide (12), both of which possess electron-

poor and electron-rich chloroarene rings within the same

molecule. Initially we studied the deuterodechlorination

of the compounds. These showed the expected preference

for deuteration at the electron-poor chloroarene ring.

The results from both compounds were very similar. In

the case of the ester 7, (Figure 14) only around 1% of the

dechlorination took place via the electron rich ring,

whereas compound 12 showed only traces (approxi-

mately 0.1%) of the reaction via the electron rich site at

the earliest time point and none thereafter (Page 7 of the

Supporting Information).

selectivity ratio between the electron-poor ring and

electron-rich ring dechlorination routes had reduced

from approximately 90:1 to approximately 5:1, presum-

ably as a result of the increase in temperature from room

temperature of approximately 18^ꢀC to 65^ꢀC. Interestingly

however, the Suzuki–Miyaura phenylation reaction,

which was occurring in parallel, also gave a similar selec-

tivity (7:1 ratio) between phenylation at the electron-poor

and electron-rich rings (Figure 15). The two reactions

therefore do share very similar behaviour in that (i) both

require that the catalyst is activated with hydrogen,

(ii) both have a preference for electron-poor chloroarenes

and (iii) both give similar ratios of products from the two

routes, one via an electron-poor ring and one via an

electron-rich ring. It therefore seems possible that a simi-

lar, or even the same, catalytic site is involved in both

reactions and that oxidative-addition forms a component

of the reaction mechanism.

The literature provides many examples of proposed

dehalogenation reaction mechanisms⁶⁰and single elec-

tron, ionic or oxidative-addition/reductive-elimination

processes are all represented. Moreover, the heteroge-

neous nature of the catalyst has not been definitely con-

firmed in many, perhaps most, cases.⁸¹Consequently, at

this stage, it is not possible to confirm a definitive mecha-

nism for the trialkylamine/palladium(0) catalysed

deuterodechlorination reaction.

It is noteworthy that the deuterodechlorination reac-

tion progresses (though less efficiently) in the absence of

trialkylamines (Figure 11). As such, it may be that the

actual mechanism of the dechlorination reaction is

defined by the specific reagents and reaction conditions:

in the current case by the use of trialkylamines as base

and by the requirement for catalyst activation by hydro-

gen. It may even be the case that more than one mecha-

nism is in operation or that the trialkylamine SET

Subsequently,

we

carried

out

the

deuterodechlorination under the conditions of the

Suzuki–Miyaura reaction (i.e., in the presence of phe-

nylboronic acid and potassium carbonate at 65^ꢀC) and

analysed all the products by GC-MS. We found that the

FIGURE 14 Reaction time course of the

deuterodechlorination of 4-chlorophenyl

4-chlorobenzoate (7)

12

LOCKLEY ET AL.

FIGURE 15 Competitive dechlorination

and Suzuki–Miyaura phenylation of

4-chlorophenyl 4-chlorobenzoate (7)

process merely acts as one step in the overall mechanism

(as an initiator?). Further studies of this important reac-

tion are therefore warranted.

competitive with the scrambling reaction(s). We therefore

studied the effect of additives, because admixtures with

other catalytic metals have been shown to improve label-

ling outcomes for the rhodium black system^83,84and for

deuterium exchange over palladium and platinum.^85,86

The effect of adding, Crabtree's catalyst, (PPh₃)₃RuCl₂,

Ag triflate, PtCl₂, PtO₂, RuO₂, IrO₂, Au₂O₃was investi-

gated but unfortunately none led to an improvement in

either the extent of reaction or the %D achieved and most

led to a significant reduction, possibly by increasing the

H₂O/D₂exchange reaction. An alternative would be to

promote the SET mechanism. Unfortunately, the addition

of AIBN and/or irradiation with ultraviolet light

(360 nm) showed no clear enhancement of either the

degree of reaction or of deuteration level. Similarly,

360-nm irradiation in the presence of the photosensitisers

benzophenone or rhodamine 6G only resulted in reduced

extent of reaction and degree of labelling (Page 8 of the

Supporting Information).

2.4 | Developing a better catalytic system

Given the complexity of the palladium on carbon system,

the issue for isotope chemists therefore becomes how to

achieve a catalytic system that gives less scrambling

and which therefore increases the quality of the

labelled compounds prepared and opens the possibility

of routes that are currently obviated by scrambling (e.g.,

polydeuterodechlorination or polytritiodechlorination).

We confirmed (Figure 16) that intensive drying of the

catalyst was only partially effective in this regard, as

previously noted by other workers.⁴⁸It seemed unlikely

that scrambling by such catalysts could be improved

unless the dechlorination reaction were made more

FIGURE 16 Degree of scrambling in [4-D]

phenylsuccinimide (from 0.1 mmol of 3) with

palladium on carbon, dried palladium on carbon

and Pd(0) generated in situ from palladium

trifluoroacetate

LOCKLEY ET AL.

13

Because palladium on carbon proved intransigent in

varying the quantity of palladium trifluoroacetate and

PTFE powder. A suitable combination was obtained

when palladium trifluoroacetate (4 mg) was treated with

micronised PTFE (20 mg) in THF (2 ml) and deuterium

gas (8 ml). Under these conditions (Procedure C in

Section 4), 0.1 mmol of the scrambling-prone

4-chlorophenylsuccinimide was completely dehaloge-

nated in 3 h, and the amount of scrambling in the [4-D]

phenylsuccinimide product was <6%.

Isolation of the solid phase from the reaction and

investigation by Raman and FTIR showed no significant

changes in the spectra of the PTFE support (Page 9 of the

Supporting Information) though the material (now grey-

black) showed fluorescence in the Raman. Microscopy

showed that the micronised PTFE granules (approxi-

mately 2–5 μm in size) aggregated to form clumps, which

were now decorated by small islands of black palladium

trifluoroacetate-derived material, probably Pd(0) gra

nules, (approximately 1–10 μm in size) from which the

fluorescence was derived (Page 10 of the Supporting

Information).

With this new catalytic system in hand, the generality

of the procedure (Experimental Procedure C) was

checked with a range of dehalogenation substrates of

varying structure. The results were encouraging for all

the substrates. They are shown in Figure 18.

Because the new catalytic system clearly reduces the

isotopic scrambling, the polydehalogenation of

polychloro-substrates (and presumably of polyiodo- and

polybromo-substrates) becomes a viable option for pre-

paring polydeuterated internal standards or possibly of

polytritiated ligands. Some initial work in this area was

therefore carried out with deuterium.

this regard, we decided to prepare a heterogeneous palla-

dium catalyst by in situ reduction of Pd(II) within and

during the dehalogenation reaction.

For this screen, we utilised substrate 3 because it was

reactive but prone to a high degree of scrambling. With a

single exception, screening a number of Pd(II) systems

showed either no activity, or little reactivity with a high

degree of scrambling. The exception was palladium

trifluoroacetate, a catalyst precursor of Pd(0) that had

previously shown exceptional activity for benzylic isotope

exchange labelling.⁸⁷Interestingly, the trifluoroacetate

anion can coordinate to phosphine Pd(0) complexes in

the presence of triethylamine, facilitating the oxidative

addition of phenyl iodide to give anionic phenyl

trifluoroacetate complexes rather than the expected

phenyl iodide addition products.⁸⁸

Although the reactivity of the palladium

trifluoroacetate precursor was low, the degree of

scrambling was also gratifyingly very low.

The reduction of Pd(II) salts and complexes to

Pd(0) can be accomplished by various reductants, includ-

ing hydrogen, and the ready formation of a particulate

black deposit certainly suggests that the reduction to the

metal occurred in this case. However, the heterogeneous

nature of the reaction has not yet been demonstrated,

and the formation of low valent palladium, palladium

nanocluster, colloidal palladium species or even species

with different cooperating palladium oxidation states⁸⁹is

still possible.

Notwithstanding, the low activity of the catalyst still

needed substantial improvement. Hence, the effect of

adding a catalyst support was investigated. To minimise

any scrambling arising from water in the support, a selec-

tion of dry or hydrophobic materials was used Figure 17.

All the supports gave results that were much better

than palladium on carbon. But clearly the best support

material was micronised polytetrafluoroethylene (PTFE).

This support was therefore investigated further by

Two

2,3,4-trichloroanisole (8), which would provide an

internal standard for anisole analysis, and

polychloro-substrates

were

investigated:

2,4,6-trichlorophenyl 4-chlorobenzoate (11), which

allowed comparison with the chlorinated phenyl benzo-

ates studied previously.

FIGURE 17 Degree of scrambling in [4-D]

phenylsuccinimide (from 0.1 mmol of 3) when

Pd(0) was prepared from palladium

trifluoroacetate in the presence of various

support materials

14

LOCKLEY ET AL.

FIGURE 18 Comparison of the degree of

scrambling (%H/(H + D)) in the deuterated

products from the dechlorination of a range of

substrates using 5% palladium on carbon or a

palladium catalyst generated in situ from

palladium trifluoroacetate and

micronised PTFE

We were pleased to find that the new catalytic system

overall isotopic scrambling observed, and this exchange

was inhibited by the halogenated substrate. The inhibi-

tion was concentration dependent and was greatest for

substrates with electron-poor chloroarene rings.

Study of a range of bases showed that the aliphatic

trialkylamines formed a favoured set, providing the

highest degree of reaction and the highest abundance of

isotope in the labelled product.

provided [2,3,4-D₃]anisole with good deuterium content

(96.5% D₃) and with an unlabelled compound content of

<0.01% making the compound suitable for use as an

internal standard for GC-MS assay (Page 11 of the

Supporting Information). The corresponding labelled

compound prepared using palladium on carbon had an

unlabelled anisole content of 4.7% rendering it useless for

this application; 2,4,6-trichlorophenyl 4-chlorobenzoate

was studied to investigate the course of the

deuterodechlorination process. Halting the dechlorina-

tion of this substrate prior to the completion of the

reaction enabled GC-MS analysis of the dechlorination

intermediates. All the intermediates had a base peak at

106 (D-C₆H₄-CO + ion) showing that the dehalogenation

occurred first at the electron-deficient 4-chlorobenzoate

moiety. Subsequent dechlorinations resulted in [2,4,6-D₃]

phenyl [4-D]benzoate with a deuterium content of 87%

D₄, corresponding to a scrambling of 3.35% per chloro-

substituent replaced, and a D₀content of <0.065% (Page

12 of the Supporting Information).

Competitive reaction studies have shown that the

dehalogenation reaction has similarities with the heterog-

enous Suzuki–Miyaura reaction, and hence, the active

site(s) of both reactions could be similar and oxidative

addition of the chloroarene to a Pd(0) may be involved in

the mechanism. However, we have confirmed the inhibi-

tion of the reaction by the radical scavenger

tetracyanoethylene,⁸and hence, the involvement of sin-

gle electron species in the reaction mechanism still seems

likely.

Replacement of the Pd/C catalyst with one prepared

in situ from palladium trifluoroacetate and dispersed

upon micronised polytetrafluoroethylene led to much

reduced scrambling and to high atom % abundance,

regiospecific labelling for a range of halo substrates. The

new catalytic system was applicable to debromination

and deiodination and was also suitable for the prepara-

tion of high-quality labelled compounds via the

deuterodechlorination of polychlorinated precursors. It

may also have applications to the preparation of

multitritiated ligands by polytritiodehalogenation.

3 | CONCLUSIONS

The

study

of

the

deuterodechlorination

of

2⁰-chloroacetanilide and other chloroarenes over 5% pal-

ladium on carbon in tetrahydrofuran solution identified

catalyst-bound water as a major contributor to the scram-

bling of isotope during the reaction, though other sources

of protium may be present on the catalyst or the catalyst

support. The tetrahydrofuran solvent and the

triethylamine base were not sources of the protium

involved in the scrambling. The degree of isotopic scram-

bling was greatest for substrates with electron-rich

chloroarene rings. Isotopic exchange between the donor

deuterium gas and catalyst water was important in the

4 | EXPERIMENTAL

4.1 | Equipment

The deuterodehalogenation reactions were carried out

using a low dead-volume stainless steel gas-transfer

LOCKLEY ET AL.

15

manifold. This enabled either high vacuum or deuterium

gas to be applied to the sealed reaction tubes via a

22 gauge Luer needle, which penetrated the reaction tube

septum. The manifold could be used both to evacuate the

reaction tubes under high vacuum and to supply deute-

rium gas to the tubes from a 200-ml capacity syringe. The

reaction tubes used were thick-walled test tubes of 10-ml

capacity sealed with 20-mm PTFE lined aluminium

crimp septa. These tubes (10-ml capacity “Discover”

tubes) and septa were obtained from CEM Microwave

Technology Ltd, 2 Middle Slade, Buckingham Industrial

Estate, Buckingham, MK18 1WA.

NMR spectra were recorded on a Bruker AVIII500

NMR spectrometer in CDCl₃at 500 MHz for ¹H,

100 MHz for ¹³C and 61 MHz for D and analysed by

Bruker TopSpin software. Raman spectra were measured

on crystalline samples supported on glass microscope

slides using a ThermoScientific DXR Raman Microscope

at laser frequencies of either 532 or 780 nm. Infrared

spectra were recorded for crystalline samples on a

sapphire anvil using an Agilent Resolutions Pro

spectrometer. GC-MS analysis was performed using

1.0-μl injections of solutions at approximately 1 mg/ml

in dichloromethane using an Agilent 6890N gas

chromatograph coupled to a 5973 mass selective detector

House, Templars Way, Sharnbrook, Bedfordshire

MK441PY, UK. Graphite Powder Kasp K30050 was

obtained from Carl Kammerling International Ltd,

Glanydon Industrial Estate, Pwllheli LL53 5LH, UK,

via Amazon.co.uk. Other general reagents were

obtained from regular chemical supply houses and

were used as received.

4.3 | Catalysts

The stock catalyst used throughout the studies was 5%

palladium on carbon (Aldrich Item 27,670-7) and was

purchased from Merck (Sigma-Aldrich Company Ltd),

The Old Brickyard, New Road, Gillingham, Dorset SP8

4XT, UK This catalyst was supplied containing, nomi-

nally, 50% added water but showed a loss on drying at

200^ꢀC of only 23.5% by weight. The catalyst was stored in

bulk in a tightly sealed container, and samples were dis-

pensed rapidly into reaction tubes to ensure that the

water content did not change as a result of equilibration

with atmospheric moisture.

The catalysts used for comparison purposes were 10%

palladium on carbon (Aldrich Item 20,569-9), rhodium

black (Aldrich Item 267341), platinum black (Aldrich

Item 20,591-5), palladium black (Aldrich Item 520810),

platinum(IV) oxide (Aldrich Item 20,603-2), Lindlar

catalyst (Aldrich Item 20,573-07), 5% palladium on

calcium carbonate (Aldrich Item 21,435-3), 5% palladium

on barium sulphate (Aldrich Item 27,799-1), 5% rhodium

on alumina (Aldrich Item 21,2857-1G), 5% rhodium on

carbon (Aldrich Item 206164-1G), dry 5% palladium

on carbon (Aldrich Item 20. 568-0), 5% palladium on

carbon (Engelhard item batch code 5096, BASF, Earl

Road, Cheadle Hulme, Cheadle, Cheshire SK8 6QG, UK),

palladium(II) oxide (Avocado Item 11895/c1485A,

Alfa Aesar, Shore Road, Port Of Heysham Industrial

Estate, Heysham, Morecambe LA3 2XY, UK), 1% palla-

dium on carbon (Johnson Matthey Item 103585),

Johnson Matthey 1% palladium on alumina (ATHENA

The

column

was

a

Phenomenex

ZB-5MS,

30 m × 0.25 mm, used with a temperature profile: 50^ꢀC

(held for 3 min), ramp at 10^ꢀC per minute to 250^ꢀC and

held for 2 min, or, in the case where high molecular mass

compounds may be present, an injection volume of 1.0 μl

at 50^ꢀC (held for 3 min), ramping to 325^ꢀC at 25^ꢀC/min

(held for 6 min). The carrier gas was helium at

1.0 ml/min. Hydrogen, hydrogen deuteride and deute-

rium analyses were carried out using an EcoSys P

residual gas analyser, ESS Ltd, Northwich CW9 7LU,

UK. The molecular formulae for the labelled compounds

were determined at the National Mass Spectroscopy

Facility, University of Swansea, using an LTQ Orbitrap

XL operating in APCI or NSI modes.

consortium

experimental

formulation,

EPSRC

4.2 | General reagents

GR/R54576/01).

The tetrahydrofuran reaction solvent (>99.5%, Item

186562) and triethylamine base (Item 471283) were

obtained from Merck (Sigma-Aldrich Company Ltd),

The Old Brickyard, New Road, Gillingham, Dorset SP8

4XT, UK. Other solvents were of high quality (classi-

fied as anhydrous) and were obtained from either

Merck (address above) or Fisher Scientific (Fisher

Scientific UK Ltd, Bishop Meadow Road, Loughbor-

ough LE11 5RG, UK). Micronised PTFE powder was

obtained from Hagen Automation Ltd, Greybern

4.4 | Deuterated reagents

The deuterium gas (99.8% D) used was obtained from CK

Isotopes Ltd, Office 6, Newtown Grange Farm Business

Park, Leicestershire LE9 9FL, UK. [D₈]Tetrahydrofuran

(Item 1133640001) and [D₄]methanol (Item 151947-25G)

were obtained from Merck (Sigma-Aldrich Company

Ltd), The Old Brickyard, New Road, Gillingham, Dorset

SP8 4XT, UK.

16

LOCKLEY ET AL.

4.5 | Dechlorination substrates

99/101, 85, 75, 63; ν_max(sapphire) 3102, 3080, 2920, 1742,

1591, 1481, 1400, 1263, 1201, 1170, 1160, 1070, 1009,

870, 846, 799, 747, 678, 660, 628, 530 cm⁻¹; Raman

(780-nm excitation) 3080, 1744, 1593, 1260, 1193, 1161,

2⁰-Chloroacetanilide (1), 4-chlorobenzophenone (2), ethyl

4-chlorophenylacetate (6), 4⁰-chlorobutyrophenone (9)

and 2,3,4-trichloroanisole (8) were obtained from Merck

(Sigma Aldrich, Ltd, UK), The Old Brickyard, New Road,

Gillingham, Dorset SP8 4XT, UK. The precursors for the

preparation of the other dehalogenation substrates were

also purchased from this source. The following

dehalogenation substrates were prepared as below.

1098, 1069, 872, 812, 738, 628, 475, 344, 284, 267, 178 cm⁻¹

.

4.6.3 | 4-t-Butylphenyl 4-chlorobenzoate, 5

¹H-NMR (500 MHz, CDCl₃) 1.34 (s, 9H), 7.12 (d, 2H),

7.41 (d, 2H), 7.46 (d, 2H), 8.13 (d, 2H) ppm; ¹³C-NMR

(100 MHz, CDCl₃) 31.5, 120.9, 126.4, 128.1, 128.9, 131.6,

140.1, 148.4, 148.9, 164.5 ppm; m/z 290/288, 275/273,

141/139. 113/111, 91, 75, 65; ν_max(sapphire) 2963, 2910,

2860, 1744, 1590, 1509, 1398, 1366, 1257, 1199, 1172,

4.6 | Preparation of chlorine-substituted

phenyl benzoates

These were prepared using the following general

procedure:

1087, 1077, 1011, 873, 846, 811, 749, 681, 556 cm⁻¹

;

Raman (532-nm excitation) 3081, 2973, 2932, 2909, 1760,

1745, 1598, 1267, 1213, 1177, 1095, 1074, 886, 820,

The substituted phenol (3 mmol) was dissolved in dic-

hloromethane (10 ml) in a 20-ml glass reaction vial and

triethylamine (500 μl) was added. The substituted ben-

zoyl chloride (3 mmol) was then added in four portions

allowing the small exotherm to subside before the next

addition. After 1 h, saturated sodium bicarbonate solu-

tion (5 ml) was added, the vial shaken and the aqueous

layer discarded. This process was repeated with 4-M

hydrochloric acid (5 ml) and then with water (3 × 5 ml).

The resulting organic layer was filtered, dried with anhy-

drous magnesium sulphate, filtered and evaporated

under a stream of dry nitrogen to give a crystalline prod-

749, 635) cm⁻¹

.

4.6.4 | 2,4,6-Trichlorophenyl

4-chlorobenzoate, 11

¹H-NMR (500 MHz, CDCl₃) 7.42 (s, 2H), 7.51 (d, 2H),

8.17 (d, 2H) ppm; ¹³C-NMR (100 MHz, CDCl₃)

126.3, 128.7, 129.2, 129.4, 129.7, 131.9, 132.3, 141.0, 143.0,

162.2 ppm; m/z 334/336/338/340, 299/301/303, 236/238,

195/197/199, 167/169/171, 139/141, 111/113, 97, 75; ν_max

(sapphire) 3090, 2930, 2850, 1746, 1591, 1565, 1487, 1447,

1401, 1386, 1256, 1223, 1174, 1142, 1072, 1045, 1010,

852, 844, 838, 819, 806, 767, 715, 626 cm⁻¹; Raman

(532-nm excitation) 3086, 1754, 1599, 1265, 1241, 1183,

1

uct, which was analysed by GC-MS and H-NMR. The

procedure gave highly pure products in all cases.

4.6.1 | Phenyl 4-chlorobenzoate, 4

1098, 1058, 871, 723, 635, 391 cm⁻¹

.

¹H-NMR (500 MHz, CDCl₃), δ 7.21 (d, 2H), 7.28 (t, 1H),

7.44 (t, 2H), 7.49 (d, 2H), 8.13 (d, 2H) ppm; ¹³C-NMR

(100 MHz, CDCl₃) 121.6, 126.0, 128.0, 129.0, 129.5, 131.5,

140.1, 150.7, 164.3 ppm; m/z 232/234, 139/141 (bp),

111/113, 75, 65; ν_max(sapphire) 3100, 3075, 3070, 3050,

1729, 1589, 1482, 1398, 1267, 1190, 1174, 1159, 851, 742,

Preparation of 4-halosuccinimides

The 4-haloaniline (1.5 mmol) and succinic anhydride

(1.5 mmol) were ground together in the bottom of a

10-ml capacity heavy-walled pressure tube and the tube

capped with a septum and heated at 140^ꢀC for 30 min.

Methanol was then added, the melt broken up and the

solution refluxed until only a small insoluble residue

remained. The supernatant was separated, allowed to

crystallise on ice for 30 min and the supernatant

removed. The crystals were dried in air overnight to pro-

vide the 4-halophenylsuccinimide.

721, 692, 682 cm⁻¹

; Raman (532-nm excitation)

3102, 3087, 3083, 3067, 3052, 1735, 1595, 1274, 1203,

1176, 1164, 1099, 1084, 1012, 869, 824, 768, 731, 636, 623,

594 cm⁻¹

.

4.6.2 | 4-Chlorophenyl 4-chlorobenzoate, 7

4.6.5 | 4-Chlorophenylsuccinimide;

1-(4-chlorophenyl)pyrrolidine-2,5-dione, 3

¹H-NMR (500 MHz, CDCl₃), δ 7.16 (d, 2H), 7.39 (d, 2H),

7.48 (d, 2H), 8.12 (d, 2H); ¹³C-NMR (CDCl₃, 100 MHz)

123.00, 127.64, 129.02, 129.60, 131.45, 131.55, 140.38,

149.22, 164.10 ppm; m/z 266/268, 139/141, 111/113,

This was prepared as above but the crystalline material

isolated was shown by ¹H-NMR to contain a small

LOCKLEY ET AL.

17

amount an impurity (N,N⁰-(4-chlorophenyl)succinic

diamide) This was removed by treating the dry solid with

a mixture of dichloromethane (1.0 ml) and tetrahydrofu-

ran (125 μl) in which the impurity was insoluble. The

resulting suspension was filtered, and the filtrate evapo-

rated under a stream of dry nitrogen to give the pure

245, 219, 203, 146, 132, 118, 90, 76, 63, 55; ν_max(sapphire)

3086, 2927, 1695, 1483, 1388, 1294, 1184, 1164, 1011,

922, 822, 711, 670 cm⁻¹; Raman (780-nm excitation)

3071, 3007, 2929, 1764, 1583, 1483, 1391, 1261, 1229,

1166, 1055, 1011, 923, 721, 634, 565, 483, 346, 221 cm⁻¹

.

1

crystalline product. H-NMR (500 MHz, CDCl₃), δ 2.89

(s, 4H), 7.26 (d, 2H), 7.45 (d, 2H) ppm; ¹³C-NMR

(100 MHz, CDCl₃) 28.38, 127.67, 129.41, 130.35, 134.44,

175.84 ppm; m/z: 209/211, 181/183, 164/166, 157, 155,

154, 153, 146, 138, 127/129, 111/113, 90, 75, 63, 55; ν_max

(sapphire) 3098, 3058, 2987, 2947, 1703, 1491, 1378, 1164,

4.6.8 | 4-Chloro-N-(4-chlorophenyl)

benzamide, 12

4-Chloroaniline (1 mmol) was dissolved in dic-

hloromethane (20 ml) and triethylamine (500 μl) was

added. 4-Chlorobenzoyl chloride (1 mmol) was added in

four portions over a minute, after which white crystals

precipitated from the solution. After an hour, the crystals

were filtered under vacuum and washed with sodium

bicarbonate solution (5 ml), then with hydrochloric acid

(4 M, 5 ml) and then with water (3 × 5 ml) and dried in

air. GC-MS indicated that the product was pure.

1089, 1014, 924, 829, 741, 711, 659, 586, 577, 450 cm⁻¹

;

Raman (780-nm excitation) 3078, 2978, 2944, 1771, 1592,

1432, 1382, 1266, 1176, 1091, 1013, 925, 744, 642, 580,

415, 351, 241 cm⁻¹

.

4.6.6 | 4-Bromophenylsuccinimide,

1-(4-bromophenyl)pyrrolidine-2,5-dione, 13

¹H-NMR (500 MHz, [D₆]DMSO), δ 7.41 (d, 2H), 7.61

(d, 2H), 7.81 (d, 2H), 7.95 (d, 2H), 10.43 (s, NH); m/z

265/267, 139/141, 111/113, 99, 75; ν_max(sapphire) 3300,

3250, 3200, 3140, 3100, 1645, 1602, 1527, 1327, 1290,

1263, 1230, 1087, 1012, 821, 735, 684, 661 cm⁻¹; Raman

(532-nm excitation) 3087, 3063, 1652, 1602, 1578, 1499,

1410, 1338, 1299, 1272, 1249, 1184, 1099, 1022, 913, 743,

637 cm⁻¹.

¹H-NMR (500 MHz, CDCl₃) 2.89 (s, 4H), 7.20 (d, 2H),

7.60 (d, 2H) ppm; ¹³C-NMR (100 MHz) 28.4, 122.5, 127.9,

130.9, 132.4, 175.8 ppm; m/z: 255/253, 227/225, 199/197,

173, 171, 157/155, 146, 128, 118, 90, 77, 76, 73, 63, 65;

ν_max(sapphire) 3100, 2990, 2940, 1695, 1654, 1587, 1522,

1487, 1393, 1329, 1294, 1276, 1182, 1163, 1068, 1012,

822, 667, 640, 586 cm⁻¹; Raman (532-nm excitation)

3083, 3015, 3000, 2938, 1773, 1595, 1495, 1432, 1410,

1398, 1301, 1270, 1236, 1193, 1170, 1074, 1020, 1011,

General Procedure A: For the deuterodehalogenation of

2⁰-chloroacetanilide

930, 734, 646, 573, 500 cm⁻¹

.

Palladium on carbon catalyst (30 mg) was weighed into a

10-ml capacity thick-walled test tube equipped with a

magnetic stir bar. The 2⁰-chloroacetanilide (0.5 mmol)

and the appropriate base (1 mmol) in dry THF (2 ml)

were added and the tube sealed with a 20-mm alumin-

ium PTFE lined septum and attached to the gas transfer

manifold via a 22 gauge Luer needle, which penetrated

the septum. The tube was stirred and then evacuated via

the needle until the solvent boiled and then briefly filled

with deuterium gas before being again evacuated. After

refilling with deuterium gas, the tube was detached from

the gas manifold needle and the reaction stirred at room

temperature for 3 h. The reaction mixture was filtered

free of catalyst and the filtrate partitioned between

dichloromethane (10 ml) and hydrochloric acid (2 M,

10 ml). The dichloromethane layer was then washed with

saturated sodium hydrogen carbonate solution (5 ml)

and then twice with water (5 ml, each time). After drying

and evaporation, the quality of the product and the

4.6.7 | 4-Iodophenylsuccinimide;

1-(4-iodophenyl)pyrrolidine-2,5-dione, 10

The above one-pot procedure proved inefficient for

the preparation of the iodophenylsuccinimide. Instead,

the material was prepared in two steps via acylation of

the aniline (1.5 mmol) with succinic anhydride

(1.5 mmol) in dichloromethane (10 ml) containing

triethylamine (2 mmol) at room temperature. After wash-

ing with hydrochloric acid (4 M, 5 ml), water (5 ml), dry-

ing (MgSO₄) and evaporation, the isolated acid was

cyclised to the succinimide in a mixture of tetrahydrofu-

ran (6 ml) and acetic anhydride (1 ml) at 50^ꢀC for 4 h.

The reaction mixture was partitioned between dic-

hloromethane (10 ml) and a saturated solution of sodium

bicarbonate (5 ml). Drying (MgSO₄) and evaporation gave

the crystalline 4-iodophenylsuccinimide, pure by GC-MS.

¹H-NMR (500 MHz, CDCl₃) 2.90 (s, 4H), 7.0 (d, 2H),

7.8 (d, 2H) ppm; ¹³C-NMR (CDCl₃, 100 MHz), 28.38.

94.03, 128.21, 131.57, 138.35, 175.69 ppm; m/z 301, 273,

1

extent of reaction were determined by GC-MS, H-NMR

and TLC (silica gel F₂₅₄, ethyl acetate/dichloromethane

1:3 v/v gave [4-D]acetanilide

=

R_f0.4 and 2⁰-

chloroacetanilide = R_f0.7).

18

LOCKLEY ET AL.

General Procedure B: For the deuterodehalogenation of

substrates using 5% palladium on carbon catalyst with

an excess of deuterium

4.6.9 | Phenyl [4-D]benzoate

¹H-NMR (500 MHz, CDCl₃) 7.22 (d, 2H), 7.27 (t, 1H),

7.43 (t, 2H), 7. 51 (d, 2H), 8.21 (d, 2H) ppm; D-NMR

(CHCl₃, 61 MHz) s, 7.70 ppm, no other resonances; ¹³C-

NMR (100 MHz, CDCl₃) 121.7, 125.9, 128.5, 129.5, 129.6,

130.2, 133.0 (t, 1:1:1, J = 25 Hz), 151.0, 16 5.2 ppm; m/z

199 (3%), 116 (1%), 106 (100%), 93 (1%), 78 (40%), 65 (4%);

C₁₃H₁₀DO₂(M + H) requires 200.0816 amu, found

5% Palladium on carbon catalyst (15 mg) was weighed

into a 10-ml capacity thick-walled test tube equipped

with a magnetic stir bar. The substrate (0.1 mmol)

and triethylamine (20 μl) in dry THF (2 ml) were added,

and the tube sealed with a 20-mm aluminium PTFE lined

septum and attached to the gas transfer manifold via a

22 gauge Luer needle, which penetrated the septum. The

tube was stirred and then evacuated via the needle until

the solvent boiled and then briefly filled with deuterium

gas before being again evacuated. After refilling with deu-

terium gas, the tube was detached from the gas manifold

needle and the reaction stirred at room temperature for

3 h. The products were isolated as follows: the reaction

mixture was filtered free of catalyst and the filtrate

partitioned between dichloromethane (10 ml) and

hydrochloric acid (2 M, 10 ml). The dichloromethane

layer was then washed with saturated sodium hydrogen

carbonate solution (5 ml) and then twice with water

(5 ml, each time). After drying and evaporation, the

purity, degree of reaction and the % deuterium content

were determined by GC-MS.

200.0817 amu, C₁₃H₁₃DO₂N (M

+ NH₃) requires

217.1082 amu, found 217.1084 amu, C₁₃H₉DO₂Na

(M + Na) requires 222.0636 amu, found 222.0637 amu;

ν_max(sapphire) 3070, 1729, 1597, 1589, 1482, 1455, 1312,

1261, 1245, 1191, 1178, 1073, 1022, 1001, 918, 852,

817, 759, 747, 689, 675, 573, 506 cm⁻¹; Raman (532-nm

excitation) 3078, 1734, 1602, 1269, 1202, 1173, 1028,

991, 621 cm⁻¹

.

4.6.10 | 4-t-Butylphenyl [4-D]benzoate

¹H-NMR (500 MHz, CDCl₃) 1.34 (s, 9H), 7.14 (d, 2H),

7.43 (d, 2H), 7.50 (d, 2H) 8.2 (d, 2H) ppm; D-NMR

(CHCl₃, 61 MHz) s, 7.69 ppm, no other resonances; ¹³C-

NMR (100 MHz, CDCl₃) 31.5, 34.5, 114.8, 121.0, 126.3,

128.5, 129.7, 130.2, 133.2 (t, 1:1:1, J = 24 Hz), 148.7,

165.4 ppm; m/z: 255 (4%), 240 (1%), 134 (1%), 106 (100%),

91 (4%), 78 (24%), 65 (1%); C₁₇H₁₈DO₂(M + H) requires

256.1442 amu, found 256.1443 amu, C₁₇H₂₁DO₂N

(M + NH₃) requires 273.1078 amu, found 273.1079 amu,

C₁₇H₁₇DO₂Na (M + Na) requires 278.1262 amu, found

278.1261 amu; ν_max(sapphire) 3050, 2962, 2923, 2860,

1732, 1594, 1507, 1288, 1409, 1370, 1261, 1203, 1169,

1113, 1968, 1025, 1015, 908, 874, 864, 830, 806, 771,

695, 675, 650 cm⁻¹; Raman (532-nm excitation) 3079.

2979, 2438, 1737, 1603, 1450, 1271, 1212, 1181, 1081,

General Procedure C: For the deuterodehalogenation of

substrates using palladium trifluoroacetate and

micronised PTFE powder

Palladium trifluoroacetate (4 mg, 0.018 mmol) and

PTFE powder (20 mg) were weighed into a 10-ml

capacity thick-walled test tube equipped with a mag-

netic stir bar. The substrate (0.1 mmol) and

triethylamine (20 μl) in dry THF (2 ml) were added

and the tube sealed with a 20-mm aluminium PTFE

lined septum and attached to the gas transfer manifold

via a 22 gauge Luer needle, which penetrated the sep-

tum. The tube was stirred and then evacuated via the

needle until the solvent boiled and then briefly filled

with deuterium gas before being again evacuated. After

refilling with deuterium gas, the tube was detached

from the gas manifold needle and the reaction stirred

at room temperature for 3 h. The reaction mixture

became black within 10 min. The products were

isolated as follows: the reaction mixture was filtered

free of catalyst and the filtrate partitioned between

dichloromethane (10 ml) and hydrochloric acid (2 M,

10 ml). The dichloromethane layer was then washed

with saturated sodium hydrogen carbonate solution

(5 ml) and then twice with water (5 ml, each time).

After drying and evaporation, the quality of the product

was determined by GC-MS and characterised by

spectroscopic methods. The characterisation data are

given below:

993, 884, 815, 738, 703 cm⁻¹

.

4.6.11 | [2⁰-D]Acetanilide; N-

(2-deuteriophenyl)acetamide

¹H-NMR (500 MHz, CDCl₃) 2.16 (s, 3H), 7.08 (t, 1H),

7.27–7.31 (cm, 2H), 7,52 (d, 1H), 7.95 (broad s. 1H) ppm;

D-NMR (CHCl₃, 61 MHz) s, 7.57 ppm, no other reso-

nances; ¹³C-NMR (100 MHz, CDCl₃) 24.5, 119.7 (weak, t,

1:1:1, J = 26 Hz), 120.0, 124.2, 128.8, 128.9, 138.1,

168.7 ppm; m/z 136 (27%), 94 (100%), 93 (11%), 92 (5%),

78 (5%), 67 (13%), 66 (15%); C₈H₈DONNa (M + Na)

requires 159.0639 amu, found 159.0637 amu; ν_max(sap-

phire) 3287, 3251, 3195, 3127, 2970, 2920, 2851, 1659,

1606, 1590, 1547, 1431, 1366, 1318, 1291, 1259, 1014,

770, 743, 640 cm⁻¹: Raman (532-nm excitation) 3068,

LOCKLEY ET AL.

19

2934, 2278, 1669, 1599, 1541, 1481, 1375, 1299, 1268,

1236, 1167, 1130, 1059, 993, 874. 843, 669, 618, 351 cm⁻¹

Niccolò A. E. Venanzi https://orcid.org/0000-0001-7528-

2450

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4.6.12 | [4-D]Phenylsuccinimide;

1-(4-deuteriophenyl)pyrrolidine-2,5-dione

(from 4-chlorophenylsuccinimide)

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¹H-NMR (500 MHz, CDCl₃) 2.90 (s, 4H), 7.29 (d, 2H),

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7.47 (d, 2H, broadened by ortho-D coupling) ppm; ¹³C-

NMR (100 MHz, CDCl₃) 28.42, 126.47, 128.37 (weak, t,

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excitation) 3067, 2974, 2935, 1775, 1592, 1431, 1391, 1232,

1175, 987, 926, 703, 624, 462 cm⁻¹

4.6.14 | Ethyl [4-D]phenylacetate; ethyl

2-(4-deuteriophenyl)acetate

¹H-NMR (500 MHz, CDCl₃) 2.27 (t, 3H), 3.60 (s, 2H), 4.15

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2919, 2850, 1732, 1500, 1417, 1367, 1335, 1251, 1218,

1027, 770, 660, 640, 620 cm⁻¹

.

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Studies of hydrogen isotope scrambling during the dehalogenation of aromatic chloro-compounds with deuterium gas over palladium catalysts

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