Iodobenzene Dichloride in the Esterification and Amidation of Carboxylic Acids: In-Situ Synthesis of Ph3PCl2

Article abstract of DOI:10.1002/ejoc.201600714

A novel, in-situ synthesis of dichlorotriphenylphosphorane (Ph₃PCl₂) is accomplished upon combining PPh₃and the easily prepared hypervalent iodine reagent iodobenzene dichloride (PhICl₂). The phosphorane is selectively generated in the presence of carboxylic acid or alcohol residues to rapidly produce acyl chlorides and alkyl chlorides in high yields. Addition of EtOH, PhOH, BnOH, Et₂NH or CH₂N₂results in the direct synthesis of esters, amides and diazo ketones from carboxylic acids.

Full text of DOI:10.1002/ejoc.201600714

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Accepted Article
Title: Iodobenzene Dichloride in the Esterification and Amidation of Carboxylic acids:
In-Situ Synthesis of Ph3PCl2
Authors: Myriam S. Carle; Grace K. Shimokura; Graham K. Murphy
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201600714
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European Journal of Organic Chemistry
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Iodobenzene Dichloride in the Esterification and Amidation of
Carboxylic acids: In-Situ Synthesis of Ph3PCl2
Myriam S. Carle, Grace K. Shimokura, and Graham K. Murphy 0000-0002-8795-2404[a]*
Abstract: A novel, in-situ synthesis of dichlorotriphenylphosphorane
(Ph3PCl2) is accomplished upon combining PPh3 and the easily
prepared hypervalent iodine reagent iodobenzene dichloride, PhICl2.
The phosphorane is selectively generated in the presence of
carboxylic acid or alcohol residues to rapidly produce acid chlorides
and alkyl chlorides in high yield. Addition of EtOH, PhOH, BnOH,
Et2NH or CH2N2 results in the direct synthesis of esters, amides and
diazoketones from carboxylic acids.
toxic, moisture sensitive or environmentally undesirable.
Adapting the recyclable, hypervalent iodine-based chlorine gas
surrogate to the synthesis of Ph3PCl2 offers a mild and
operationally simple means to access organic chlorides. We
report here the in-situ synthesis of Ph3PCl2 from Ph3P and
PhICl2 that, in the presence of carboxylic acids and alcohols,
results in smooth conversion to acid and alkyl chlorides.
Introduction
The conversion of carboxylic acids to acid chlorides is among
the earliest transformations in organic synthesis, and remains a
fundamental reaction. For over a century and a half, chemists
have developed and employed organic (oxalyl chloride, (COCl)2)
and inorganic (PCl5, SOCl2, etc.) reagents to effect this
transformation. Curiously absent from the literature of acid
chloride synthesis is PhICl2 (1), the first hypervalent iodine
reagent ever reported.[1] This easily prepared iodane has broad
applicability in organic synthesis as an oxidant and chlorinating
agent, and, like many hypervalent iodine reagents since
reported, it enjoys
a broad reactivity profile and mild,
environmentally benign reaction conditions.[2] These favorable
characteristics have resulted in strong interest in the synthetic
community, with many new reports of its synthesis,[3] its use as
Figure 1. Esterification reactions based on hypervalent iodine / PPh3 reagent
mixtures.
an oxidant[3a,4,5] or
a
chlorinating agent,[6] and even its
recyclability[7] within the last decade.
In addition to developing PhICl2-mediated chlorination reactions
of diazo and hydrazone functional groups,[6b,c,g,h] we are also
interested in using it in developing deoxygenative chlorination
processes. Unlike oxalyl chloride, PCl5 or SOCl2, iodane 1 does
not engage in such chemistry; reactions with alcohols gives
aldehydes[8] or ketones,[9] and reactions with carboxylic acids
results in ligand metathesis on the iodane.[10] We were inspired
by the recent work of Zhang and co-workers who showed that
coupling reactions between carboxylic acids and alcohols or
amines could be effected by the combination of iodosodilactone
(2) and PPh3 (Figure 1, a)).[11,12] Because 1 is so readily able to
transfer chlorine to Lewis basic elements, we believed it should
also do so with triphenylphosphine, which would constitute a
novel synthesis of triphenylphosphine dichloride (3).[13] This
phosphorane is a versatile deoxygenative chlorinating reagent
popularized by Appel through the reaction that bears his
name.[14] Phosphorane 3 can be synthesized with Cl2, CCl4,
COCl2, (COCl)2 or C2Cl6 etc,[13] but these reagents are either
Results and Discussion
We began our investigation by determining the feasibility and
reaction rate of the chlorine transfer process in a time-lapse 31P
NMR experiment.[15] A mixture of PPh3 (1.0 equiv), and PhICl2
(1.2 equiv) was prepared in DCM; after 5 minutes we observed
complete conversion to the phosphorane. Given the rate of the
conversion, no competition was therefore expected from the
carboxylic acid reacting with the iodane; however, since
triphenylphosphine oxide was also observed so quickly,
preventative measures to exclude atmospheric moisture were
required.
[a]
M.S. Carle, G.K. Shimokura and G.K. Murphy*
Department of Chemistry
University of Waterloo
200 University Ave. W., Waterloo, ON, Canada, N2L3G1
E-mail: graham.murphy@uwaterloo.ca
https://uwaterloo.ca/murphy-lab/
Figure 2. 31P NMR of PPh3 (bottom) and Ph3PCl2 (top) prepared in situ with
PhICl2.
Supporting information for this article is given via a link at the end of
the document.

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We investigated the feasibility of reacting the in situ-generated
Ph3PCl2 and carboxylic acids by screening a variety of reaction
conditions using p-tolylacetic acid (4a) as the model substrate
(Table 1).
As the acid chloride was difficult to isolate, we
trapped it by adding ethanol, giving ethyl p-tolylacetate (5a). The
initial reaction combined phosphine, iodane and carboxylic acid
in an equimolar ratio in DCM, which was stirred for 30 minutes at
reflux, and afforded 5a in 81% yield (entry 1). Using a slight
excess of the phosphorane caused the yield to increase to 92%
(entry 2), and using a slight excess of 1 relative to phosphine
and carboxylic acid gave a minor increase in product yield (entry
3). Maintaining this ratio of reagents and decreasing the
temperature decreased product yield (entry 4); however when
the reaction was repeated at reflux and terminated (by the
addition of EtOH) after 10 minutes, the product was again
recovered in excellent yield (entry 5). We tested the reaction in
various common solvents and found that the reaction proceeded
in high yield in toluene, THF, CHCl3 and DCE, and proceeded
poorly in DMF (entries 6-10). The rate and good to excellent
yields observed demonstrate the ease and efficacy of the
reaction, and confirm that there are no competitive side
reactions between 1 and 4a.
Table 1. Optimization of the acid chloride synthesis.[a]
Entry
Solvent
PPh3
(equiv)
PhICl2
(equiv)
Temp
°C
Time
(min)
Yield [b]
1
2
DCM
DCM
DCM
DCM
DCM
toluene
CHCl3
DCE
1
1.2
1
1
40
40
40
rt
30
30
81%
92%
94%
84%
93%
83%
86%
77%
84%
48%
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
3
30
4
1
30
5
1
40
40
40
40
40
40
10
6
1
30
7
1
180
120
30
Scheme 1. Substrate scope of esterification, amidation and diazoacylation
reactions. [a] Isolated yields. [b] NMR yield based on internal standard
HMDSO (O[Si(CH3)3]2). c 1.2 equiv of PPh3 used.
8
1
9
THF
1
10
DMF
1
30
and diesterification in 87% yield. The aryl carboxylic acids (4h-j)
all performed well when trapped with EtOH, Et2NH or PhOH.
Because PhICl2 readily chlorinates alkenes, we were not
surprised to find minor amounts of alkene chlorination product
when excess 1 was used with 4k.14 Using an equimolar mixture
of 1 and PPh3 obviated this adventitious reactivity, and gave the
esterification and amidation products (5k) in 72 – 81% yield.
[a] Reaction conditions: 1, PPh3 and 4a are added to DCM and immersed in a
40 °C bath. The reaction is quenched by the addition of EtOH (1.5 mL). [b]
Isolated yield.
We expanded the substrate scope of the reaction to investigate
various carboxylic acid precursors and nucleophiles (Scheme 1).
The aliphatic carboxylic acids (4a-d) all performed well in the
reaction, whether they were trapped with EtOH, Et2NH, BnOH,
PhOH or even (for 4a) diazomethane. Pivalic acid (4e) was
lower yielding, presumably due to steric hindrance. Two
dicarboxylic acids were used in the reaction, and while 4f was
only moderately effective, 4g underwent acid chloride formation
Two additional carboxylic acids were investigated to determine
the relative reactivity of alcohols and carboxylic acids (eq. 1, 2).
Acid chloride formation on mandelic acid (4l) proceeded poorly,
presumably due to competition with the alcohol. Conversely,

European Journal of Organic Chemistry
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COMMUNICATION
acid chloride formation on 4-hydroxybenzoic acid (4m)
proceeded well, and gave 5m in 95% yield.
Experimental Section
General procedure for acid chloride formation and trapping with
EtOH: To an oven-dried 10 mL round bottom flask was added the
carboxylic acid (1.0 eq) and dry DCM (1.5 mL), and the resulting solution
was heated to reflux under nitrogen. PPh3 (1.0 eq) was added, followed
by PhICl2 (1.2 eq), and the reaction was stirred for an additional 10
minutes at reflux. To this was then added ethanol (~10 eq) drop wise
over 2 minutes, and the reaction was stirred for 30 minutes, by which
time TLC analysis indicates the consumption of starting material. The
crude reaction mixtures were concentrated by rotary evaporation and
purified by column chromatography.
Acknowledgements
This work was supported by the Natural Sciences and
Engineering Research Council (NSERC) of Canada and the
University of Waterloo.
We also carried out chlorination reactions on benzylic and
aliphatic alcohols (eq. 3-6). Both benzyl and p-methoxybenzyl
alcohol reacted more slowly than did the carboxylic acids, but
their conversion to the corresponding chlorides was clean and
high yielding. Ethyl mandelate was converted to the chloride in
excellent yield, supporting our suspicion that competition from
the alcohol led to the decreased yield of 5l, and (–)-menthol was
converted to menthyl chloride in 72% yield.
Keywords: acid chloride • hypervalent iodine • Appel reaction •
esterification • amidation
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In conclusion we have developed a novel, in-situ synthesis of
Ph3PCl2 from Ph3P and the hypervalent iodine reagent PhICl2. A
time-lapse 31P NMR experiment showed the chlorine transfer
from iodane to phosphine to be rapid, though highly sensitive to
atmospheric moisture. When synthesized in the presence of
both saturated and unsaturated carboxylic acids, the ensuing
acid chlorides underwent high-yielding esterification, amidation
and diazoacylation reactions. Finally, when the phosphorane
synthesis was carried out in the presence of benzylic alcohols,
benzyl chlorides were observed in high yield.

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European Journal of Organic Chemistry
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Acid chloride synthesis
Myriam S. Carle, Grace K. Shimokura
and Graham K. Murphy*
Page No. – Page No.
Iodobenzene Dichloride in the
Esterification and Amidation of
Carboxylic acids: In-Situ Synthesis of
Ph3PCl2
Text: An in situ synthesis of dichlorotriphenylphosphorane (Ph3PCl2) was achieved via a chlorine
transfer reaction between iodobenzene dichloride (PhICl2) and PPh3. When carried out in the presence
of carboxylic acids, the resulting acid chlorides could be trapped with various nucleophiles. When
carried out in the presence of alcohols, alkyl chlorides were produced.