Perspective

pubs.acs.org/Macromolecules

RAFT Agent Design and Synthesis

Daniel J. Keddie, Graeme Moad,* Ezio Rizzardo, and San H. Thang
CSIRO Materials Science and Engineering, Bag 10, Clayton South, Victoria, Australia

ABSTRACT: This Perspective reviews the design and synthesis of RAFT

agents. First, we briefly detail the basic design features that should be
considered when selecting a RAFT agent or macro-RAFT agent for a given
polymerization and set of reaction conditions. The RAFT agent should be
chosen to have an optimal Ctr (in most circumstances higher is better) while
at the same time it should exhibit minimal likelihood for retarding
polymerization or undergoing side reactions. The RAFT agent should also
have appropriate solubility in the reaction medium and possess the requisite
end-group functionality for the intended application. In this light we critically
evaluate the various methods that have been used for RAFT agent synthesis.
These methods include reaction of a carbodithioate salt with an alkylating
agent, various thioacylation procedures, thiation of a carboxylic acid or ester, the ketoform reaction, thiol exchange, radical
substitution of a bis(thioacyl) disulfide, and radical-induced R-group exchange. We also consider methods for synthesis of
functional RAFT agents and the preparation of macro-RAFT agents by modification of, or conjugation to, existing RAFT agents.
The most used methods involve esterification of a carboxy functional RAFT agent, azide−alkyne 1,3-dipolar cycloaddition, the
active ester−amine reaction, and RAFT single unit monomer insertion. While some of these processes are described as “click
reactions”, most stray from that ideal. The synthetic method of choice is strongly dependent on the structure of the desired
RAFT agent. Finally, we outline some of the current challenges in RAFT agent design and synthesis.

■ INTRODUCTION
RAFT (reversible addition−fragmentation chain transfer)
direct use of addition−fragmentation chain transfer agents to
provide living character to radical polymerization did not appear
polymerization, a reversible deactivation radical polymerization until the mid-1990s. The first RAFT agents (though that term
(RDRP),1 is one of the most effective and versatile methods for was not used at the time) were macromonomers of general
providing living characteristics to radical polymerization.2−9 structure 1. 19−21 The RAFT process making use of
RAFT provides reversible deactivation of propagating radicals thiocarbonylthio compounds 2 to control radical polymer-
by degenerate chain transfer1 for which a general mechanism is ization appeared in 1998.22−24 When the thiocarbonylthio
shown in Scheme 1.4 The chain transfer step has been termed compound is a xanthate (Z = O-alkyl), the process is also
known as MADIX (macromolecular design by interchange of
Scheme 1. Polymerization with Reversible Deactivation by xanthate).25
Degenerate Chain Transfer

The intention of this Perspective is to review and provide

guidance on the design and synthesis of thiocarbonylthio RAFT
agents (2). These compounds include dithioesters (Z = alkyl or
degenerate because the process involves an exhange of aryl), trithiocarbonates (Z = SR′), xanthates (Z = OR′), and
functionality and the only distinction between the species on dithiocarbamates (Z = NR′R″). The question of how to choose
the two sides of the equilibrium is molar mass. or design the right RAFT agent for the monomer(s), the
Reports of radical addition−fragmentation processes first reaction conditions, and the desired functionality in the product
appeared in the synthetic organic chemistry literature in the will be addressed. We will then critically assess the various
early 1970s.10,11 Well-known examples include allyl transfer available methods for RAFT agent (and macro-RAFT agent)
reactions with allyl sulfides12 and stannanes (the Keck synthesis. Finally, we will point to some of the remaining
reaction)13 and the Barton−McCombie deoxygenation process challenges in RAFT agent design and synthesis.
with xanthates.14 The use of (irreversible) addition−fragmen-
tation chain transfer agents, such as vinyl ethers and allyl Received: February 28, 2012
sulfides, to control molecular weight and end-group function- Revised: May 9, 2012
ality of polymers was reported in the 1980s.15−18 However, the Published: May 21, 2012

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Macromolecules

■
Perspective

RAFT AGENT DESIGN AND SYNTHESIS the rate constants ktr and k−tr are defined in terms of the rate
RAFT polymerization comprises the addition−fragmentation constants for radical addition, kadd and k−β, and a partition
equilibria shown in Scheme 2 plus all of the usual processes that coefficient (ϕ) as shown in eqs 1−3,32−34 where the various
rate constants are defined in Scheme 2.
Scheme 2. RAFT Equilibria kβ
k tr = kaddϕ = kadd
k −add + kβ (1)

k −add
k −tr = k −β(1 − ϕ) = k −β
k −add + kβ (2)

kβ
ϕ=
k −add + kβ (3)

The partition coefficient ϕ indicates the preference for the

intermediate radicals 3 (or 5) to fragment to products or return
to starting materials. For effective RAFT agents 2, R should be
a good homolytic leaving group with respect to the propagating
make up radical polymerization, most notably initiation and radical (i.e., ϕ should be >0.5). For macro-RAFT agents 4
termination.23 Note that radicals are neither formed nor destroyed formed in RAFT homopolymerization, where n and
by the RAFT steps. Thus, RAFT polymerization will not take m > 2, then Ctr = C−tr and ϕ will be ∼0.5.
place without an external supply of radicals from an initiator. The predicted dependence of the degree of polymerization
Therefore, like ideal chain transfer reactions, the RAFT equilibria and dispersity of the polymer formed on monomer conversion
need have no direct influence on the rate of polymerization and the transfer coefficient (Ctr = C−tr) for an ideal
beyond that caused by the reduction in molar mass and the polymerization (no termination) with reversible chain transfer
narrowing of the molar mass distribution. It should also be noted is shown in Figure 1.33 The predicted degree of polymerization
that radical−radical termination is not directly suppressed by the is simply the ratio of [monomer consumed]:[RAFT agent
RAFT process. Although the basic mechanism shown in Scheme 2 consumed]. A higher molecular weight than would be predicted
is generally not disputed, there is ongoing debate on the detailed with complete utilization of the transfer agent need not reflect
kinetics of the RAFT process, the rapidity with which the various some form of “hybrid behavior” as is suggested in some papers.
equilibria are established, and what side reactions might occur to It can simply indicate a low Ctr and that the initial RAFT agent
complicate the process in specific circumstances.26−30 If fragmen- is not fully converted to macro-RAFT agent.31 The character-
tation is slow, the intermediate species (3 or 5) is consumed in istics often associated with living polymerization, namely, the
side reactions, or reinitiation is slow or inefficient, and then straight line dependence of molar mass on conversion (and a
retardation or inhibition can result.31 low dispersity, Đ < 1.2), require a Ctr of at least 10. The more
Optimal control in RAFT polymerization requires choosing effective RAFT agents have Ctr > 100.
an appropriate RAFT agent (2) for the monomer(s) to be The rate of consumption of the initial transfer agent (2) is
polymerized and the reaction conditions. The Z and R given by eq 4:
groups both play critical roles in determining the outcome
of polymerization. By determining the rate of addition and d[2] [2]
≈ C tr
fragmentation, they control efficiency of chain transfer and the d[M] [M] + C tr[2] + C −tr[4]
likelihood of retardation or inhibition. [2]
The properties of RAFT agents 2 can be defined in terms of = C tr
two transfer coefficients Ctr (=ktr/kp) and C−tr (=k−tr/kiR) where [M] + C tr[2] + C −tr([2]0 − [2]) (4)

Figure 1. Predicted dependence of (a) the degree of polymerization and (b) the dispersity on conversion in polymerizations involving reversible
chain transfer as a function of the chain transfer coefficient (Ctr). Predictions are based on equations proposed by Müller et al.35,36 with
the concentration of active species = 10−7 M, Ctr as indicated and the ratio of monomer to transfer agent = 605. Experimental data points shown are for
methyl methacrylate (7.02 M) polymerization in presence of dithiobenzoate esters (0.0116 M) where R is −C(Me)2CO2Et (○) or −C(Me)2Ph (□).
Figures adapted from ref 33.

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Macromolecules Perspective

where [2]0 is the initial RAFT agent concentration and [2], [4], In these cases, the importance of canonical forms such as 10
and [M] are the actual concentrations of RAFT agent, macro- and 13 effectively reduces the contribution of 12 and 15,
RAFT agent, and monomer, respectively. This equation can respectively. The effectiveness of xanthates is similarly sensitive
be solved numerically to give estimates of Ctr and C−tr.32,34 to the nature of substituents on oxygen.39
However, most reported values for Ctr appearing in the Monomers can be considered as belonging to one of two
literature are apparent transfer coefficients (Ctrapp) being based broad classes. The “more activated” monomers (MAMs) are
on an assumption that C−tr and k−β are zero or negligible. For those where the double bond is conjugated to an aromatic ring
the more active RAFT agents, values of Ctrapp often under- (e.g., styrene (St), vinylpyridine), a carbonyl group (e.g., methyl
estimate Ctr by several orders of magnitude.34 methacrylate (MMA), methyl acrylate (MA), acrylamide (AM)),

■ ROLE OF THE Z GROUP

The Z group modifies both the rate of addition of propagating
or a nitrile (e.g., acrylonitrile (AN)). The “less activated”
monomers (LAMs) are those where the double bond is adjacent
to saturated carbon (e.g., diallyldimethylammonium chloride),
radicals (Pn•) to the thiocarbonyl of 2 and 4 and the rate of an oxygen, or nitrogen lone pair (e.g., vinyl acetate (VAc) or
fragmentation of the intermediate radicals 3 and 5. The rate N-vinylpyrrolidone (NVP)) or the heteroatom of a hetero-
constant kadd can be “adjusted” over some 5 orders of aromatic ring (e.g., N-vinylcarbazole (NVC)).
magnitude through manipulation of Z. Propagating radicals with a terminal more active monomer
The most reactive RAFT agents include the dithioesters and (MAM) unit are less reactive in radical addition (lower kp,
trithiocarbonates which have carbon or sulfur adjacent to the lower kadd), and one of the more active RAFT agents is required
thiocarbonylthio group. RAFT agents with a lone pair on for good control. The poly(MAM) propagating radicals are
nitrogen or oxygen adjacent to the thiocarbonyl, such as the relatively good homolytic leaving groups; therefore, retarda-
O-alkyl xanthates, N,N-dialkyldithiocarbamates, and N-alkyl-N- tion solely due to slow fragmentation is unlikely. The more
aryldithiocarbamates, have dramatically lower reactivity active RAFT agents such as the dithioesters, trithiocarbonates,
toward radical addition. Lower rate coefficients for addition and aromatic dithiocarbamates allow the preparation of low-
are predicted by molecular orbital calculations34,37,38 and can dispersity polymers from MAMs, whereas the N-alkyl-N-
be qualitatively understood in terms of the importance of aryldithiocarbamates and the O-alkyl xanthates typically have
the zwitterionic canonical forms 7 and 9 (Figure 2). The lower transfer constants and provide poor control.
Propagating radicals with a terminal less-activated monomer
(LAM) unit are highly reactive in radical addition (higher kp,
higher kadd). Accordingly, addition to less active transfer agents
such as the N-alkyl-N-aryldithiocarbamates and the O-alkyl
xanthates is sufficient that these RAFT agents have high transfer
constants in LAM polymerization. However, the poly(LAM)
propagating radicals are relatively poor homolytic leaving
groups. Thus, when more active RAFT agents, such as
dithioesters, are used in LAM polymerization, fragmentation
is slow and inhibition or retardation is likely.
General guidelines for selection of Z are shown in Figure 3.
Irrespective of the class of RAFT agent, the transfer constant
is generally enhanced by the presence of electron-withdrawing
Figure 2. Canonical forms of xanthates and dithiocarbamates. groups on Z and by the capacity of Z to stabilize an adjacent
radical center.34,37 However, these same factors generally can
also increase the likelihood of side reactions (see below).
interaction between the lone pair and the CS double bond The second important role of Z is to determine the stability
both reduces the double-bond character of the thiocarbonyl of the intermediate radicals 3 and 5. When Z is aryl, the
group and stabilizes the RAFT agent (2) relative to the RAFT- intermediate is stabilized, and the rate of intermediate radical
adduct radical (3).6,34,38,39 Dithiocarbamates where the nitro- fragmentation is slower than when connecting atom of Z is sp3
gen lone pair is not as available because it is part of an aromatic carbon, oxygen, or nitrogen or sulfur. There currently is some
ring system (such as a pyrrole in 11) or where a carbonyl (as in unresolved controversy as to whether for dithiobenzoates the
14) is α to the nitrogen lone pair (Figure 2) have reactivity rate of fragmentation is sufficiently slow to cause retardation
similar to that of the dithioesters and trithiocarbonates.34,40,41 directly or the rate of fragmentation is simply reduced to the

Figure 3. Guidelines for selection of the Z group of RAFT agents (ZC(S)SR) for various polymerizations. Addition rates decrease and
fragmentation rates increase from left to right. A dashed line indicates partial control (i.e., control of molar mass but poor control over dispersity or
substantial retardation in the case of LAMs such as VAc or NVP). Figure adapted from that in earlier reviews.2−5,8 HPMAM = N-(2-
hydroxypropyl)methacrylamide.

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Macromolecules Perspective

extent that side reactions such as combination or dispro- aryl.49,50 Similar design considerations apply in the case of
portionation involving 3 or 5 are more likely. A full dis- unsymmetrical trithiocarbonates (2, Z = SR′).51
cussion on this topic is beyond the scope of this Perspective, When Z is strongly electron-withdrawing, the thiocarbonyl
and the reader is referred to the recent literature.26−30 group may undergo a direct reaction with monomers. Thus,
Irrespective of mechanism, it is clear that aromatic dithioesters RAFT agents where Z is alkylsulfonyl or phenylsulfonyl group
give retardation. This is most apparent when higher RAFT Z = PhSO2− undergo direct reaction with (meth)acrylate
agent concentrations are used (to give lower molecular weight monomers (BA, MA, tBA, and MMA) under polymerization
polymers) and with faster propagating monomers (e.g., acrylates, conditions with consumption of the thiocarbonylthio group and
vinyl esters). ultimately little control over the polymerization.52 A hetero-
It was proposed by Coote and colleagues that RAFT agents Diels−Alder mechanism was suggested. Good control was
where Z is fluorine might perform as a “universal” RAFT achieved only with isobornyl acrylate where the side reactions
agent.42,43 In terms of the simple theories expounded above, the with monomer were suppressed by the bulky ester substituent.
high electronegativity of fluorine means that canonical forms The presence of electron-withdrawing groups on Z, which
analogous to 7 and 9 in which an electron is removed from Z lead to higher transfer coefficients, increases the likelihood
have little importance. The fluorine also provides little stability of side reactions such as hydrolysis or aminolysis2,53 and
to the intermediate radical. However, difficulties in synthesis participation in cycloaddition reactions54 such as the hetero-
of the so-called F-RAFT agents have meant that such RAFT Diels−Alder reaction with diene monomers52 and 1,3-dipolar
agents have not been fully tested. cycloaddition.55 This is an important consideration in some
We44−47 have adopted a different strategy in developing RAFT agent syntheses (e.g., method J, below), can be critical to
RAFT agents with more universal applicability and have the choice of RAFT agent for specific polymerization con-
designed new class of stimuli-responsive, switchable, RAFT ditions (e.g., in aqueous media or in emulsion polymerization)
agents that can be switched to offer good control over and determines the ease of end-group transformation processes
polymerization of both MAMs and LAMs. Our motivation has that may be required post-RAFT polymerization.
been to provide a more direct route to poly(MAM)-block-
poly(LAM). The N-(4-pyridinyl)-N-methyldithiocarbamates
(Scheme 3) behave as other N-aryl-N-alkyldithiocarbamates
■ ROLE OF THE R GROUP
The nature of R determines the partition coefficient ϕ (eq 3).
For optimal control of a polymerization, the R group of the
Scheme 3. N-(4-Pyridinyl)-N-methyldithiocarbamate RAFT agent (2, ZC(S)SR) must be a good homolytic
Switchable RAFT Agents leaving group with respect to Pn•, such that the intermediate 3,

and are effective in controlling the polymerization of LAMs formed by addition of Pn• to 2, both fragments rapidly and
but have relatively low transfer constants when used in MAM partitions in favor of 4 and R•. The expelled radical (R•) must
polymerization. However, in the presence of a strong protic or also be able to reinitiate polymerization efficiently (i.e., ki,R >
Lewis acid, the switched form of the RAFT agent provides kp); otherwise, retardation is likely.45 Radical stability is
excellent control over the polymerization of MAMs.44 important in determining fragmentation rates. Experimental
Very recently, the N-aryl-N-(4-pyridinyl)dithiocarbamates findings that the transfer coefficient and the value of ϕ increase
have been evaluated in polymerizations of MA, NVC, and in the series primary < secondary < tertiary and with the
VAc. These RAFT agents appear more effective (dispersities are introduction of substituents which are capable of delocalizing
lower) than the analogous N-methyl-N-(4-pyridinium)- the radical center are consistent with this view. However, other
dithiocarbamates (Scheme 3) with LAMs in the unswitched factors are of equal or greater significance.
(neutral) form and more active with MAMs in the switched It is not sufficient for R to be a monomeric analogue of the
(protonated) form.48 propagating radical because penultimate unit effects are
A final consideration is that Z should not cause any side substantial, particularly when R is tertiary. RAFT agents with
reactions. With xanthates (2, Z = OR′) it is important that R′ be R = 2-ethoxycarbonyl-2-propyl (17), which can be considered
a poor homolytic leaving group. Otherwise, fragmentation with as a monomeric model for a methacrylate chain (16), provide
loss of R′ (irreversible chain transfer) will compete with the only poor control over the polymerization of MMA and other
desired RAFT process. This requires that R′ be primary alkyl or methacrylates because R is a poor homolytic leaving group with

Figure 4. Guidelines for selection of the R group of RAFT agents (ZC(S)SR) for various polymerizations. Transfer coefficients decrease from left
to right. Fragmentation rates also decrease from left to right. A dashed line indicates partial control (i.e., control of molar mass but poor control over
dispersity or substantial retardation in the case of VAc, NVC, or NVP). Figure adapted from that in earlier reviews.2−5,8

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Macromolecules Perspective

Scheme 4. Processes for RAFT End-Group Transformation (R′• = Radical, [H] = Hydrogen Atom Donor, M = Monomer)
[Reproduced with Permission from Ref 67. Copyright 2011 Society of Chemical Industry]

respect to the PMMA propagating radical.33,56 For similar These considerations discussed above with respect to
reasons, RAFT agent with R = t-butyl (19) is poor with respect selection of R are also important in designing the synthesis of
to RAFT agent with R = t-octyl (18).33 These differences in block copolymers by RAFT polymerization. In the synthesis of
RAFT agent activity are attributed to steric factors. a block copolymer comprising segments of a 1,1-disubstuted
Polar effects are also extremely important in determining the monomer and a monosubstituted monomer the block
partition coefficient ϕ. Electron-withdrawing groups on R both comprising the 1,1-disubstuted monomer should be prepared
decrease rates of addition to the thiocarbonyl group and increase first.33 Similarly, in synthesizing a poly(MAM)-block-poly-
rates of fragmentation. The relatively high transfer constants of (LAM), using switchable RAFT,44,45 the poly(MAM) block
cyanoalkyl RAFT agents (Figure 4) vs similar benzylic RAFT should be made first because poly(LAM) propagating
agents is attributed to the influence of polar factors. radicals are relatively poor homolytic leaving groups, however,
Thus, control over the polymerization of methacrylates and poly(MAM) propagating radicals are slow to reinitiate LAM
methacrylamides (and other 1,1-disubsituted monomers which polymerization.

■
result in a tertiary Pn•) usually requires that R to be tertiary
(e.g., 2-cyano-2-propyl or cumyl)33 or secondary aralkyl (e.g., COMMERCIAL AVAILABILITY OF RAFT AGENTS
α-cyanobenzyl).57,58 However, polymerization of monomers
A range of RAFT agents including the carboxylic acid
with high propagation rate constants (kp) such as acrylates,
functional RAFT agents 20−22 are now commercially available
acrylamides, vinyl esters (e.g., vinyl acetate), and vinyl amides
in research quantities.60,61 The industrial scale-up has been
(e.g., N-vinylpyrrolidone) are best controlled with RAFT agents
announced of the xanthate, Rhodixan-A1, by Rhodia62 and
with primary or secondary R groups. Tertiary radicals, such as
trithiocarbonates, Blocbuilder DB and CTA-1, by Arkema63 and
2-cyano-2-propyl radical, are inefficient in reinitiating polymer-
Lubrizol,64 respectively.
ization since ki,R is often lower than kp.33
Guidelines to the selection of R are provided in Figure 4. The
order shown is based on measurements of Ctrapp for
dithiobenzoate RAFT agents in St and MMA polymerization33
■ RAFT AGENT FUNCTIONALITY
The thiocarbonylthio group is generally robust, and the RAFT
and seems general based on limited data for other classes of process is tolerant of a wide range of unprotected functionality
RAFT agent. The benzylic radicals and tertiary alkyl radicals on Z or R, which includes hydroxy, carboxylic acid, sulfonic
add to most LAMs very slowly (with reference to kp) and an acid, tertiary amine, and primary, secondary, tertiary, and
inhibition period is often observed with these R groups.59 quaternary ammonium.
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Macromolecules Perspective

A key feature of the RAFT process is that the thio- across an olefinic double bond (dithioesters); (G) radical
carbonylthio groups, present in the initial RAFT agent (2), are substitution of a bis(thioacyl) disulfide (dithioesters, trithiocar-
retained in the polymeric product (i.e., the polymeric products bonates, xanthates, dithiocarbamates); (H) radical-induced
of the process are also RAFT agents). They possess R group of R-group exchange (dithioesters, trithiocarbonates).
the initial RAFT agent at one end and Z−C(S)− group The thiocarbonylthio group is moderately robust such that a
at the other. In designing functional RAFT agents and polymer wide variety of chemistries can be performed in its presence.
architectures, it will normally be preferable to introduce that Thus, we will also consider methods for making RAFT agents
functionality through substituents on R. Any groups on by modification of existing RAFT agents or other thiocarbo-
Z may be lost if the thiocarbonylthio group is degraded or nylthio compounds. This includes the synthesis of macro-
removed. RAFT agents by end-group modification of non-RAFT
The Z−C(S)− may also be transformed post-RAFT polymers such as biopolymers: (I) esterification of a carboxy
polymerization and a wide variety of processes for effecting functional RAFT agent; (J) active ester−amine reaction; (K)
this have been described. Recent reviews on thiocarbonylthio azide−alkyne 1,3-dipolar cycloaddition; (L) thiol reaction
end-group transformation/removal include those by Willcock (Michael reaction, disulfide formation); (M) RAFT single
and O′Reilly,65 Moad et al.,66,67 and Barner and Perrier.68 unit monomer insertion.
Thiocarbonylthio groups undergo reaction with nucleophiles A. Reaction of a Carbodithioate Salt with an
and ionic reducing agents (e.g., amines, hydroxide, borohy- Alkylating Agent. The preparation of thiocarbonylthio
dride) to provide thiols. Thermolysis69−72 and radical-induced compounds 2 is most commonly and simply achieved by
reactions (e.g., addition−fragmentation transfer,73 addition− reaction of a carbodithioate salt 24 with an alkylating agent
fragmentation coupling74,75) are also widely used. A summary (RX) (Scheme 5). Variants of this technique are ubiquitous in
of these processes is provided in Scheme 4.67
The choice of Z can dictate the applicability of these Scheme 5. Preparation of RAFT Agents Using
processes. In general, the RAFT agents with the highest transfer Carbodithioate Salts
constants are also most reactive in end-group transformation/
removal processes. It is also important to note that while the
thiocarbonylthio end group is robust, degradation can occur.
For example, polymers prepared from methyl trithiocarbonates
become odorous after a short period of storage due the
liberation of trace amounts of methanethiol. The design of Z
determines the nature of byproducts from thiocarbonylthio
transformation (or unintended end-group degradation) and can the literature pertaining to RAFT agent synthesis. The method
also facilitate their removal.76 Thus, trithiocarbonates should is applicable to all forms of RAFT agents (i.e., dithioesters,
preferably be derived from a nonvolatile thiol.

■
trithiocarbonates, xanthates, and dithiocarbamates) but is mainly
used for preparation of RAFT agents containing primary and
RAFT AGENT SYNTHESIS secondary R groups. RAFT agents with tertiary R are more
Since the advent of the RAFT process, the preparation of a cumbersome to prepare via this method as nucleophilic sub-
vast suite of RAFT agents has been described. In this section stitution on tertiary halides is relatively slow, which results in
we review the various methods for preparing RAFT agents. lower yields of the desired product, requires extended reaction
For each method we highlight some perceived advantages and times (e.g., Tables 1 and 2), and elimination is a potential
possible drawbacks and indicate potential (or actual) side complication.85 Nonetheless, acceptable yields (70−80%) have
reactions. Synthetic routes to thiocarbonylthio compounds been reported for some tertiary trithiocarbonates.86−90
substantially predate the discovery of RAFT (and MADIX), Alkyl and aryl carbodithioates as dithioester precursors are
with initial reports dating as far back as the early 1900s.77−79 typically produced from the reaction of a Grignard reagent with
There are also a number of existing reviews on the synthesis of carbon disulfide (some examples are provided in Table 1).91
dithioesters and other thiocarbonyl compounds in a non-RAFT However, sodium salts and trialkylammonium salts have also
context.80−83 The examples described in these publications been used.85 Alkyllithiums are reported to provide lower
often lack the specific nuances of chemical structure that yields.83 In the example shown in Scheme 6, phenylmagnesium
underpin the requirements for an effective RAFT agent (e.g., bromide 25 is reacted with carbon disulfide in dry THF at
good homolytic leaving groups). Nonetheless, the synthetic 40 °C to give the phenyldithioate salt 26 which, upon reaction
techniques described are, for the most part, applicable to the with benzyl bromide at 50 °C for 1 h, produces benzyl
preparation of RAFT agents. This Perspective has been illus- dithiobenzoate 27 in 62% yield.33
trated by examples within a RAFT context. Methods for RAFT Aryldithioate salts can also be accessed by oxidative
agent synthesis are also briefly covered in some of our previous sulfuration of benzylic halides or similar species, for example,
reviews of the RAFT process.2,3,5,84 the reaction of benzyl chloride with sodium methoxide and
Eight basic methods for RAFT agent synthesis (and the class elemental sulfur33,95,96 (Scheme 7, left), or by the reaction of
of thiocarbonylthio compound that the method has generally (trichloromethyl)benzene with potassium sulfide (Scheme 7,
been applied to) are: (A) reaction of a carbodithioate salt with right).97
an alkylating agent (dithioesters, trithiocarbonates, xanthates, For the synthesis of asymmetric trithiocarbonates (Z =
dithiocarbamates); (B) thioacylation reactions (trithiocarbon- S-alkyl or S-aryl, Z ≠ R), xanthates (Z = O-alkyl or O-aryl),
ates, xanthates, dithiocarbamates); (C) thiation of a carboxylic and dithiocarbamates (Z = N,N-dialkyl, N-alkyl-N-aryl, or
acid or ester (dithioesters); (D) the ketoform reaction (tri- N,N-diaryl), carbodithioate formation usually involves reaction
thiocarbonates, xanthates, dithiocarbamates); (E) thiol exchange of the precursor Z−H (i.e., the corresponding thiol, alcohol, or
(dithioesters, trithiocarbonates); (F) addition of a dithioic acid amine, respectively) with carbon disulfide, in the presence of a
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Macromolecules Perspective

Table 1. Synthesis of Dithioesters from Grignard Reagents

a
Reaction conditions for reaction with carbodithioate salt. RT = room temperature. bUnder reflux.

base. For example, the synthesis of n-butylphenylethyltrithio- Scheme 7. Preparation of Phenyldithioate Salts from
carbonate (28) is obtained in quantitative yield from n- Halogenated Precursors33,95−97
butanethiol, carbon disulfide, and (1-bromoethyl)benzene, with
triethylamine as base (Scheme 8).70
As alcohols and amines are less acidic (higher pKa) than
thiols of similar structure,98 the preparation of xanthates
and dithiocarbamates generally requires use of stronger bases,
such as sodium hydroxide99−101 or sodium hydride,39,102−104 to
Table 2. Influence of the R-Group on the Synthesis of
promote formation of the carbodithioate salt. The synthesis of
Dodecyltrithiocarbonates87
the 2,2,2-trifluoroethylxanthate (29) is an example (Scheme 9).39
Some simple carbodithioates, such as potassium ethylxanthogen- entry thiol halide reaction time (h) yield (%)a
ate (30) and sodium N,N-diethyldithiocarbamate (32), are com- 1 C12H25SH (CH3)CH(CN)Br 2 71
mercially available allowing for synthesis of RAFT agents, such as the 2 C12H25SH (Ph)CH(CO2Et)Br 2 73
azide functional xanthate 31105 or benzyl dithiocarbamate (33),34 as 3 C12H25SH (CH3)2C(CO2H)Br 13 83
shown in Schemes 10 and 11, respectively. 4 C12H25SH (N-phthalimido)CH2Br 0.5 59
A recent article by Skey and O’Reilly87 further illustrated the a
Reaction conditions: acetone, K3PO4, room temperature.
utility of this technique for RAFT agent synthesis, making use
of non-nucleophilic inorganic bases such as potassium
phosphate, for preparation of trithiocarbonates (see Table 2 times than those which used primary or secondary halides (cf.
and entry 1, Table 3) and aromatic dithiocarbamates (see entry 2, entries 1, 2, and 4, Table 2).
Table 3) or cesium carbonate for synthesis of xanthates and Dithiocarbamates prepared from aryl amines, such as 34 and
aliphatic dithiocarbamates (see entries 3−5, Table 3). Reaction 36, require stronger bases than do aliphatic amines to achieve
conditions were varied depending on acidity of the ZH moiety acceptable yields. In this case complete deprotonation of the
and the reactivity of the alkyl halide toward nucleophilic NH bond must be facilitated, as the low nucleophilicity of the
substitution. While some examples using tertiary alkyl halides aryl-NH free base slows the reaction with CS2 considerably.
were found to give acceptable yields of the desired products We have found that in the synthesis of the switchable
(entry 3, Table 2), these required substantially longer reaction dithiocarbamate RAFT agents44,45,107 the use of butyllithium as

Scheme 6. Preparation of Benzyl Dithiobenzoate from Phenyl Grignard Reagent33

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Macromolecules Perspective

Scheme 8. Synthesis of Butylphenylethyltrithiocarbonate70

Scheme 9. Synthesis of 2,2,2-Trifluoroethylxanthate (29)39

Scheme 10. Synthesis of Azide-Functional Xanthate 31105 Scheme 12. Synthesis of the “Switchable” Cyanomethyl
Methyl(pyridin-4-yl)dithiocarbamate44,107

Scheme 11. Synthesis of Benzyl-N,N-diethyldithiocarbamate

(33)34

disulfide in the presence of a base. In the case of hydroxide as

base, the reaction proceeds via production of trithiocarbonate
anion (CS32−) (see Scheme 14),108−110 which can be
subsequently reacted with an alkylating agent.
Table 3. Influence of the Z Group on the Synthesis of Trithiocarbonate syntheses, including those reported above,
Phenylethyl and Benzyl RAFT Agents87 are typically carried out with a 2−3-fold excess of carbon
disulfide. Aoyagi et al.111,112 have found that it is possible to
entry ZH halide reaction conditions yield (%)
carry out the reaction with stoichiometric carbon disulfide and
1 PhCH2SH (Ph)CH(CH3)Br acetone, K3PO4, 4 h 91 still obtain near-quantitative yields. However, selection of the
2 imidazole (Ph)CH(CH3)Br acetone, K3PO4, 4 h 78 reaction solvent and the base is critical.
3 CH3CH2OH (Ph)CH(CH3)Br ethanol, Cs2CO3, 4 h 73 A wide variety of reaction conditions for this process have
4 (i-Pr)2NH PhCH2Br acetone, Cs2CO3, 61 been reported. Some methods employ biphasic media under
10 min
phase transfer conditions,70,113 while others use polar organic
5 (Ph)(CH3)NH PhCH2Br ethanol, Cs2CO3,106 70
4h solvents, such as N,N-dimethylformamide or acetonitrile.112
Several other variations on the general procedure appear in the
Table 4. Influence of Base Strength of Dibenzyltrithio- literature.114−116 Production of the trithiocarbonate anion from
carbonate112 carbon disulfide is dependent on base strength as indicated by
the yields of dibenzyl trithiocarbonate (38) obtained with
base (M2CO3) time (h) yield of 38 (%)
various bases (see Scheme 15 and Table 4).112
Li2CO3 24 <1 The yield of the RAFT agent prepared from carbodithioate
Na2CO3 24 <1 salts is dictated on the structure and reactivity of the reagents
K2CO3 12 44 used and the reaction conditions. The nucleophilicity of the
Cs2CO3 12 99 species which must undergo reaction with carbon disulfide
(Z− in Scheme 5) is of particular importance. When Z− is a
base can give rise to colored byproducts and when applied poor nucleophile (e.g., phenoxide, thiophenoxide), this reaction
to the synthesis of the N,N-dipyridyldithiocarbamate (37, can be problematic in that the equilibrium favors starting
Scheme 13) gave negligible yields (0−5%) of the desired RAFT materials and other synthetic protocols (e.g., method B below)
agent and a largely intractable product. Use of a strong non- become necessary.
nucleophilic base, potassium tert-butoxide (KOtBu), in place of It should also be noted that the reactions described in this
n-BuLi, resulted in a higher (45%) yield.48 section generally make use of carbon disulfide as a reagent.
Symmetrical trithiocarbonates, such as 38, can be simply Carbon disulfide is volatile (bp 46.2 °C),117 and toxic and
prepared by reaction between an alkyl halide and carbon appropriate care should be taken.
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Macromolecules Perspective

Scheme 13. Synthesis of the Cyanomethyl Di(pyridin-4-yl)dithiocarbamate48

Scheme 14. Formation of Trithiocarbonate Anion from Carbon Disulfide109

Scheme 15. Synthesis of Dibenzyltrithiocarbonate from Scheme 16. Synthesis of Benzyl Fluorodithioformate,
Benzyl Bromide and Carbon Disulfide112 F-RAFT, from Thiophosgene43

benzyl mercaptan provided benzyl chlorodithioformate (41),

B. Thioacylation Reactions. Thiophosgene (40) and which was reacted with potassium fluoride (KF) in the presence
thiophosgene equivalents, e.g., 1,1′-thiocarbonyldiimidazole of 18-crown-6 to furnish 42 in moderate yield (50%). Other
(43), can provide an alternative route to RAFT agents for examples of this strategy include preparation of sulfonyldithio-
the case where Z− does not readily form carbodithioate salts by formates.52
reaction with CS2 such that displacement chemistry (method A It is possible to use, 1,1′-thiocarbonyldiimidazole (43) rather
above) is unsuccessful or inefficient. For example, the synthesis than thiophosgene in this process (Scheme 17). The preparation
of RAFT agents with Z = phenoxy or thiophenoxy by displace-
ment chemistry provides, at best, only low yields because of Scheme 17. Preparation of Dithiocarbamates 44 and 45 from
the low nucleophilicity of the phenoxide or thiophenoxide ion 1,1′-Thiocarbonyldiimidazole86,118
and because the equilibrium in the reaction with carbon
disulfide lies substantially on the side of starting materials.
An alternate strategy for synthesizing such compounds is via
the aryl chlorothionoformates or equivalent species. Some
aryl chlorothionoformates are commercially available. Thus,
S-benzyl (75% yield)34 and S-2(-phenylethyl)-O-phenylxan-
thate86 were prepared from the commercial phenyl chloro-
thionoformate. Chlorothionoformates and chlorodithionofor-
mates can be synthesized through the reaction of the phenol or
thiophenol with thiophosgene. The chlorothionoformate or
chlorodithionoformate generally does not need to be isolated
such that the reaction of the phenol or thiophenol (ZH) of benzyl 1-imidazolyldithiocarbamate (44) by reaction with
with thiophosgene, and the subsequent reaction with a thiol benzyl mercaptan was reported in a CSIRO patent,118 and its
(R−SH), can be performed as parts of a “one-pot” process. use as a RAFT agent was subsequently published.40 Phenylethyl
Examples include the synthesis of S-benzyl-O-pentafluorophe- 1-imidazolyldithiocarbamate (45) has been prepared by the
nylxanthate (25% yield)34 and a series of benzylaryltrithiocar- same method. 86 Bicciocchi et al.51 showed that use of 43
bonates (39) with Z = (pentachlorophenyl)thio (44% yield), allowed for a convenient route to substituted arylbenzyl
(4-pyridyl)thio (37% yield), and (4-trifluoromethylphenyl)thio trithiocarbonates 39.
(23% yield).51 Perrier and co-workers have used this methodology for the
synthesis of a range of trithiocarbonates (46, 47, and 49),
dithiocarbamates (48 and 51), and the xanthate 50 achieving
moderate to high yields (Scheme 18).119 To use this reagent, Z
must be a better nucleophile than imidazole. Thiophosgene has
advantages in this context since chloride ion is a better leaving
group than imidazolide anion. However, the higher reactivity
and toxicity of thiophosgene make it a more difficult reagent to
Barner-Kowollik and co-workers43 used a related strategy in handle.
their preparation of the benzyl fluorodithioformate (F-RAFT, While the use of thiophosgene (40) or 1,1′-thiocarbonyldi-
42) (Scheme 16). In this case, reaction of thiophosgene with imidazole (43) allows for the synthesis of RAFT agents with Z
5329 dx.doi.org/10.1021/ma300410v | Macromolecules 2012, 45, 5321−5342
Macromolecules Perspective

Scheme 18. Use of 1,1′-Thiocarbonyldiimidazole for the Synthesis of Trithiocarbonates, Dithiocarbamates, and Xanthates119

Scheme 19. Mechanism of Thiation with Lawesson’s Reagent125

group substitution that may be difficult to prepare via alkylation transformed to the dithioester in reasonable yield (66%) by
of a carbodithioate salt, this technique suffers from some refluxing with LR 52 in toluene (Scheme 20).33
limitations. Some desirable R groups, such as cyanomethyl or
2-cyano-2-propyl, are not easily accessed by this method because Scheme 20. Thiation of Benzoyl Thioloester with Lawesson’s
the required thiols are commercially unavailable and difficult to Reagent33
handle when prepared.120−122
C. Thiation of Carboxylic Acids and Esters. Thiation of
carbonyl compounds to form thiocarbonyl compounds can be
facilitated by the use of phosphorus pentasulfide, Lawesson’s
reagent (LR, 52),123 and other tetrathiophosphates, such as
Davy reagent.124 A proposed mechanism125 with LR involves
reaction of the reactive dithiophosphine ylide 53 with the
carbonyl group of the substrate and subsequent cleavage of Sudalai et al.127 reported use of P4S10 for preparation of
a four-membered heterocycle as shown in Scheme 19. A dithioesters from carboxylic acids and either thiols or alcohols.
comprehensive review of the rich chemistry of LR has been The reaction is suggested to proceed by formation of an
provided by Jesberger et al.125 activated carboxylic acid derivative by reaction with P4S10, which
An example of the use of LR in a RAFT context are the can be readily attacked by a thiol (which was added directly to
synthesis of phenylethyl dithiobenzoate126 and tert-butyl the reaction mixture or formed in situ from P4S10 and an
dithiobenzoate (55).33 Treatment of benzoyl chloride with alcohol), as shown in Scheme 21 (top). Thiation of the carbonyl
tert-butyl mercaptan gave the thioloester 54 (50%), which was group then proceeds similarly to that described above for 52.
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Macromolecules Perspective

An example of such a reaction is the production of benzyl Reaction of carbon disulfide, chloroform, a ketone (acetone in
4-methoxydithiobenzoate, 56 (see Scheme 21, bottom). most examples, although others have been used), and sodium
hydroxide in the presence of a phase transfer catalyst (PTC)
Scheme 21. Mechanism and Example of the Formation of furnishes symmetrical trithiocarbonates (e.g., Scheme 23).
Dithioesters from Carboxylic Acids with Thiols/Alcohols
and P4S10127 Scheme 23. Synthesis of Tertiary Carboxyl-Functional RAFT
Agents via the Ketoform Reaction

Inclusion of a thiol, amine, or alcohol in the reaction mixture

allows asymmetric trithiocarbonates, dithiocarbamates, or
xanthates to be prepared respectively (see lower portion of
Scheme 23 for examples). The technique has been successfully
implemented by a number of research groups133−139 with
reported yields varying from ∼35% to quantitative. Lubrizol has
successfully developed the process to produce the trithiocar-
Dureault et al.128 have prepared di- and trifunctional RAFT
bonate 23 in multiton quantities.140
agents from the corresponding di- and tricarboxylic acids and
The advantage of this technique is that it allows synthesis of a
benzyl mercaptan by a similar technique.
variety of RAFT agents containing tertiary carboxylic acid R
Dureault et al.129 also formed RAFT agents in situ from
groups in a single preparative step. As the reaction medium is
carboxylic acids in St polymerization. In this process a
biphasic (part aqueous), carbodithioate salts derived from
phenylethyl R group is incorporated, by Markovnikov addition
intermediates not compatible with water (e.g., those derived
of the dithioic acid to St (section F).
from anilines)132 need to be prepared in a separate step.
Some drawbacks of this technique include the limited
Attention must be paid to stoichiometry and reagent volatility
availability of some desired carbonyl and thiol/alcohol
and toxicity (acetone, chloroform, carbon disulfide).
precursors. In their report, Sudalai et al.127 indicate the
E. Thiol Exchange. Thioglycolic acid-based dithioesters
occurrence of side reactions in some examples, such as
have been used as precursors to other RAFT agents.141−143
Friedel−Crafts alkylation of the toluene solvent when alcohol
They undergo facile reaction with other thiols to provide new
precursors were used. This suggests that the method may not
dithioesters. For example, the reaction of 61 with benzylmer-
be tolerant to some functional groups. It is not clear how
captan provides benzyl dithiobenzoate (27) in high yield
universal the protocol is as to date only dithioesters have been
(Scheme 24).144 In a RAFT context, the scope of the process is
prepared using this technique.
limited by the ready availability of thiols of appropriate structure.
D. RAFT Agents Prepared via the Ketoform Reaction.
Lai and co-workers have adapted the ketoform reaction130 as
a method to prepare trithiocarbonates,131 dithiocarbamates, Scheme 24. RAFT Agent Synthesis by Thiol Exchange144
and xanthates132 containing tertiary carboxyl groups. The pro-
posed mechanism (Scheme 22) involves ring-opening of a

Scheme 22. Proposed Mechanism of the Ketoform

Reaction130,131

When the reaction can be carried out in aqueous solution,

and product solubility is such that the desired dithioester
separates from the reaction medium, the equilibrium is shifted
to the product side, resulting in complete transesterification.
For reactions carried out in organic solvents, treatment of the
reaction mixture with aqueous alkali preferentially removes the
thioglycolic acid byproduct, again resulting in near-quantitative
conversion to the required dithioester.141
F. Addition of a Dithioic Acid across an Olefinic
dichloroepoxide intermediate with a nucleophile,131 in this case Double Bond. The reaction of a dithioic acid with a variety
a carbodithioate salt, as a key step. Subsequent hydrolysis of the of electron-rich alkenes was reported to provide quantitative
acyl chloride produced provides the acid functional RAFT yields of the Markovnikov addition product.145 The olefins
agent. used included St, α-methylstyrene, VAc, vinyl ethers, and vinyl
5331 dx.doi.org/10.1021/ma300410v | Macromolecules 2012, 45, 5321−5342
Macromolecules Perspective

sulfones. We found the reaction of dithiobenzoic acid (62) with G. Reaction of Radicals with Bis(thioacyl) Disulfides.
α-methylstyrene in CCl4 provided cumyl dithiobenzoate (63) Radical-induced decomposition of bis(thioacyl) disulfides, such
in relatively low yield (33%) after purification (Scheme 25).6 as 67, by radicals derived from azo-initiators is arguably the
most effective technique for the synthesis of functional tertiary
Scheme 25. Synthesis of Cumyl Dithiobenzoate by RAFT agents (see Scheme 27 and Table 5).66,149,150 The
Markovnikov Addition of a Dithiobenzoic Acid to method has been applied to each of the most common forms of
α-Methylstyrene6 RAFT agent (dithioesters, trithiocarbonates, xanthates, and
dithiocarbamates). The usual radical source is an excess of an
azo-compound initiator,66,149,150 and the main contaminants in
the product are the byproducts of azo-compound decom-
position (e.g., tetramethylsuccinonitrile when azobis-
(isobutyronitrile) (AIBN) is used).
In our work, the bisthioacyl disulfide has usually been
prepared by oxidation of the carbodithioate salt with molecular
iodine which generally proceeds in quantitative yield.66,73
Alternate methods include oxidation of a carbodithioate salt
with potassium ferricyanide and the reaction of carbodithioate
salt with p-toluenesulfonyl chloride.151
A related process has been reported by Wager et al.154 and
Kwak et al.155 in which an ATRP initiator (a secondary or
tertiary alkyl halide and a copper catalyst) is used as the radical
The similar methodology has also been applied to prepare source. The latter group termed the process atom transfer
cumyl dithioacetate (45% yield),34 cumyl phenyldithioacetate, radical addition−fragmentation (ATRAF).155 For dithioesters
64 (36% yield),146 cumyl pyrrolocarbodithioate, 65 (28% reported yields were generally high (82−92%), but lower yields
yield),147 2-phenylethyl dithiobenzoate (43% yield),33 and were observed for dithiocarbamate (65%) and xanthate (43%)
2,4,4-trimethylpent-2-yl dithiobenzoate (32% yield).33 examples.155 Wager et al.154 also demonstrated the preparation
Kanagasabapathy et al.126 have published on the regiose- of macro-RAFT agents from ATRP-synthesized polymers using
lectivity of addition of thiols and thiobenzoic acids to St. In this strategy.
contrast to the behavior seen with dithioic acids, in the absence H. Radical-Induced R-Group Exchange. A useful
of an acid catalyst these reagents react with St and other technique for the preparation of RAFT agents involves
substrates to give predominantly (>94% for St) anti- R-group exchange by placing a RAFT agent in the presence of
Markovnikov addition. Only in the presence of a Lewis acid a radical source such as a thermal initiator. For the process to be
(montmorillonite K10) was the Markovnikov product obtained effective, the R group of the precursor RAFT agent should be a
with a high degree of regioslelectivity. The thionoester formed good homolytic leaving group with respect to that of the desired
by reaction of thiobenzoic acid to St was converted to the RAFT agent.156 Thus, tertiary R groups cannot be efficiently
dithioester phenylethyl dithiobenzoate through treatment with introduced through reaction of tertiary radicals with RAFT agents
Lawesson’s reagent (method C).126
possessing primary or secondary R groups.
Much has been published on retardation mechanisms in
An early example was the preparation the 2-cyano-2-propyl
RAFT polymerization, and much of this literature relates to
dithiobenzoate from cumyl dithiobenzoate by heating the latter
polymerizations with cumyl dithiobenzoate.26 Monteiro and
in the presence of AIBN as a source of 2-cyano-2-propyl
co-workers148 have suggested that the purity of cumyl
dithiobenzoate as formed by this process and, in particular, radicals.33 The same process was used to prepare 2-cyano-2-
the presence of dithiobenzoic acid, may be responsible for the propyl dithioacetate from cumyl dithioacetate.34 Alberti et al.156
retardation and indicated the inadequacy of silica chromatog- further developed this methodology when they employed a
raphy for purification. In our work6 we used chromatography “RAFT agent” 69 which has a triphenylmethyl R group for the
on neutral alumina to provide a product which retained preparation of the 2-cyano-2-propyl phosphoryldithioformate
effectiveness for >2 years when stored in the refrigerator. (70, Scheme 28). The corresponding bis(thioacyl) precursor
With electron-poor olefins, such as (meth)acrylates, (meth)- (for method G) could not be prepared.156 The same process
acrylamides, or (meth)acrylonitrile (e.g., MMA; Scheme 26), was used to prepare 2-cyano-2-propyl dithiobenzoate156 and
2-cyano-2-propylpyridin-4-ylcarbodithioate.157 The driving force
Scheme 26. Michael Addition of Dithioacetic Acid to Methyl of the reaction is the production of a stable triphenylmethyl
Methacrylate145 radical.
The use of macro-RAFT agents in this process has been
developed as a method for end-group removal and for
regenerating a (low molecular weight) RAFT agent.74 Thus,
PMMA with dithiobenzoate ends was heated with a 20-fold
excess of AIBN to both cleave the end group (the PMMA
propagating radicals undergo radical−radical termination) and
produce 2-cyano-2-propyl dithiobenzoate.74 Many additional
the Michael addition (or anti-Markovnikov product) predom- examples of the use of this method for end-group removal have
inates.145 The primary alkyl radicals are poor homolytic leaving been reported.6 While the method was stated to have general
groups. Consequently, compounds such as 66 do not have applicability to RAFT-synthesized polymers,74 it appears
utility as RAFT agents. inefficient, often giving incomplete end-group removal, when
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Macromolecules Perspective

Scheme 27. Synthesis of a Tertiary RAFT Agent from a Bis(thioacyl) Disulfide149

Table 5. Synthesis of RAFT Agents by Reaction of Azo- by RAFT polymerization that possesses functionality to
Compounds R−NN−R with Bis(thioacyl) Disulfides facilitate conjugation post-RAFT polymerization. It should be
[ZC(S)S]2 noted in this context that a number of processes for forming
block copolymers post-RAFT polymerization are based on
reaction yield
Z R conditionsa (%)b ref direct modification of the thiocarbonylthio end-group.
Ph C(CH3)(CN) A 68 149, 152 Processes for RAFT end-group transformation are mentioned
CH2CH2CO2H briefly below but are more fully detailed in our recent review of
Ph C(CH3)(CN) A 87 153 that topic.67
CH2CH2CO2C6F5 I. Esterification or Amidation of Acid Functional RAFT
Ph C(CH3)(CN) B 46 33, 149 Agent. One of the most common methods to introduce new
CH2CH2CH2OH
Ph C(CH3)2(CN) A 69 149, 150
functionality into a RAFT agent or form a macro-RAFT agent
Ph C(CH3)2(CO2CH3) D 65 150 is to react a hydroxy or amino functional substrate with a
CH3S C(CH3)2(CN) C 47 34, 149 carboxy functional RAFT agent. Standard synthetic protocols
CH3(CH2)11S C(CH3)(CN) A 87 66 for the synthesis of esters and amides, such as the acid chloride
CH2CH2CO2H route166,167 or carbodiimide coupling reaction,168−172 are
CH3(CH2)11S C(CH3)2(CN) A 60 73 compatible with the thiocarbonylthio group and generally
C2H5O C(CH3)2(CN) A 94 149, 150 give very high yields. Acid functional RAFT agents used in this
C2H5O C(CH3)(CN) E 77 150 context include 20, 22, and 71−75. Some representative
CH2CH2CO2H
examples of process are provided in Tables 6 and 7, and many
(N-pyrrole) C(CH3)2(CN) B 61 34, 149
additional examples can be found in our previous reviews.2,3,5
C(CH3)2N C(CH3)2(CN) C 93 149, 150
a
J. Active Ester−Amine Reaction. The active ester−amine
Reaction conditions: (A) reflux, ethyl acetate, 18 h; (B) degas, ethyl reaction has been used to prepare of functional RAFT agents
acetate, 70 °C, 24 h; (C) reflux, benzene, 24 h; (D) reflux,
from substrates bearing amine functionality (Scheme 29). A
cyclohexane; (E) reflux, dioxane/cyclohexane. bIsolated yield after
purification. variety of RAFT agents bearing active-ester functionality have
been prepared, including pentafluorophenyl ester (76),153
N-hydroxylsuccimidyl ester (77),174,175,186 and 2-mercaptothia-
applied to styrenics and acrylates75 and does not work with zoline ester (78).176,187 Some examples appear in Table 6. The
poly(LAM).67 strategy has been widely used for biopolymer conjugation. The
Macro-RAFT Agent Synthesis. In this section we address the sensitivity of the thiocarbonylthio group to aminolysis means
synthesis of macro-RAFT agents or functional RAFT agents by that care must be taken in selecting reaction conditions and
modification of other RAFT agents. In particular, we consider stoichiometry (the amine should not be used in excess).67
the synthesis of macro-RAFT agents based on oligomers or A specific example is the synthesis of the biotin macro-RAFT
polymers that are not formed by RAFT polymerization. Two agent 80 from RAFT agent 79 (Scheme 30).186
areas that have recently attracted much attention are the
production of biopolymer (peptide, protein, siRNA, poly-
saccharide) conjugates158−163 for biomedical applications and
block copolymers containing fully conjugated segments164 (e.g.,
a poly(3-hexylthiophene segment165) for optoelectronic
applications.
There are two basic strategies for forming such structures
that are relevant to this section. The first involves formation of
a biopolymer based macro-RAFT agents which is then used in
RAFT polymerization. The second involves forming a polymer

Scheme 28. Synthesis of Tertiary RAFT Agents by Radical-Induced R-Group Exchange

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Macromolecules Perspective

Table 6. Examples of Functional RAFT Agents Formed from Acid Functional RAFT Agents

a
DCC = N,N′-dicyclohexylcarbodiimide, DMAP = 4-(dimethylamino)pyridine, DPTS = 4-(N,N-dimethylamino)pyridinium-p-toluenesulfonate,
EDC = N-(3-(dimethylamino)propyl)-N′-ethylcarbodiimide hydrochloride, and HOBT = 1-hydroxybenztriazole. bYield not reported. cProcess
involves formation acid chloride with reagent indicated.

Table 7. Examples of Macro-RAFT Agents Formed from Scheme 29. Active Ester−Amine Reaction and the Structure
Acid Functional RAFT Agents of Some Common Active Esters
acid RAFT block Aa
agent (end group) reagentsb yield (%) ref
22 PLA (OH end) oxalyl chloridec 93 167
71 PDMS (OH end) DCC −d 168
20 PEG (OH end) DCC/DMAP 88−100 96, 172, 184
73 PEG (OH end) DCC 94 169
75 P3HT (OH end) DCC/DMAP 94 185
22 peptide (NH2 end) DIC/NMI 100 170
20 peptide (NH2 end) DCC 76 171
a
P3HT = poly(3-hexylthiophene), PLA = polylactide, PDMS =
poly(dimethylsiloxane), PEG = poly(ethylene glycol). bDCC = N,N′- cycloaddition (Scheme 31).188−193 Many of these deal with the
dicyclohexyl carbodiimide, DPTS = 4-(dimethylamino)pyridinium-4- formation of an alkyne or azide functional polymer through the
toluenesulfonate, DIC = N,N′-diisopropyl carbodiimide, NMI = use of a RAFT agent with the corresponding functionality.
N-methylimidazole. cProcess involves formation acid chloride with
reagent indicated. dYield not reported.
A wide range of alkyne or azide functional RAFT agents have
been reported (for some examples see Table 6). Ladmiral
et al.194 have pointed out that azides can undergo 1,3-dipolar
K. Azide−Alkyne 1,3-Dipolar Cycloaddition. There have cycloaddition with many common monomers (MMA, MA,
been many papers on the use of RAFT polymerization in N-isopropylacrylamide (NIPAM), and St were studied) and
combination with copper-catalyzed azide−alkyne 1,3-dipolar that this can occur under polymerization conditions. The use of
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Macromolecules Perspective

Scheme 30. Synthesis of a Biotin Functional RAFT Agent via the Active Ester−Amine Reaction186

Scheme 31. Copper-Catalyzed Azide−Alkyne 1,3-Dipolar reactions have not generally been considered as a suitable
Cycloaddition method for preparing RAFT agents because of the likelihood of
side reactions. However, such methods have been successfully
used to prepare macro-RAFT agents through conjugation to
cystein functionality in bovine serum albumin (BSA).
Thus, Sumerlin and co-workers used the thio Michael reac-
tion of a maleimide functional RAFT agent to prepare a BSA
macro-RAFT agent as shown in Scheme 32.182,197 The possibility
lower reaction temperatures during polymerization can minimize of side reactions (e.g., thiol exchange; cf. method E above) was
this problem. The importance of protecting alkyne functional reduced by using the RAFT agent in very large (20×) excess
RAFT agents (or monomers) as the trimethylsilyl derivative has over BSA thiol residues which were quantitatively converted.
been regarded as important by some authors.105 However, in Boyer et al.198 used disulfide coupling to prepare a BSA macro-
other cases reagents with unprotected alkyne functionality have RAFT agents from a RAFT agent with pyridyl disulfide
been used with apparently minimal (no reported) side reactions, functionality (Scheme 33). Again, the process involved using
which is attributed to the alkyne being much less reactive toward the RAFT agent in very large excess over BSA thiol functionality
radical addition than a (meth)acrylate double bond. to quantitatively convert those groups and avoid side reactions.
RAFT agents having a triazolinylmethyl R group have been M. Single Unit Monomer Insertion. New thiocarbonyl-
synthesized by a copper-catalyzed 3 + 2 cycloaddition reaction thio compounds with the general structure 85 can be prepared by
between an azide and a propargyl thiocarbonylthio com- the addition of a single monomer unit to a preprepared RAFT
pound.195 The triazolinyl trithiocarbonates 81 and 82 were agent 84, as illustrated in Scheme 34. Single unit monomer
effective in controlling polymerizations of St and butyl acrylate
(BA) while the triazolinyl xanthate 83 was able to control Scheme 34. Single Unit Monomer Insertion into a
polymerizations of NVP and VAc. Thiocarbonylthio RAFT Agent

insertion is favored by using equimolar monomer and RAFT

L. Thiol Reactions. Modification of RAFT agent function- agent. A high Ctr for the RAFT agent and a high rate of addi-
ality by reaction with a thiol using so-called “thiol-click” tion of the radical (R•) to monomer relative to further pro-
reactions,196 such as the Michael thiol−ene reaction or disulfide pagation are also important. This ensures that less than one
formation, has been widely exploited in modification of monomer unit is incorporated per activation cycle. The value
RAFT-synthesized polymers post polymerization.67 These of Ctr is determined by the relative rate of addition to the

Scheme 32. Preparation of a RAFT Agent by the Michael Reaction (BSA = Bovine Serum Albumin)

Scheme 33. Preparation of a RAFT Agent by the Disulfide Coupling (BSA = Bovine Serum Albumin)

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Macromolecules Perspective

RAFT agent vs monomer and the way the intermediate radical Scheme 36. “Attached To” Process for “Grafting From” with
partitions between starting materials and products.32,33 Thus, to a R-Connected RAFT Agent
ensure a high rate of addition, the RAFT agent needs to be
chosen for the monomer to be inserted.6,34 Typically this will
mean use of xanthates or dithiocarbamates should be preferred
for LAMs and trithiocarbonates, dithioesters, or the more
active form of switchable RAFT agents44−47 for more activated
monomers (MAMs). Under these conditions “selective initializa-
tion”199−203 occurs, and the initial RAFT agent starting material
84 is converted to the desired single unit insertion product
before any significant oligomerization or polymerization occurs. Scheme 37. “Away From” Process for “Grafting From” with
Zard and co-workers pioneered the use of this chemistry to a Z-Connected RAFT Agent
carry out a wide range of organic transformations which involve
insertion of single units of unactivated alkenes (LAMs) into
xanthate RAFT agents (Z = OR).204,205 Chen et al.206
demonstrated that with appropriate choice of reaction conditions
a similar methodology could be applied to perform single unit
monomer insertion of MAMs to form macro-RAFT agents. One
of the first examples reported was insertion of the St derivative
86 into 2-cyano-2-propyl dithiobenzoate to provide 87.
the thiocarbonylthio groups (e.g., hydrolysis, thermolysis) also
Scheme 35. Preparation of a RAFT Agent by Single-Unit results in the loss of the graft. With the “attached to” strategy
Monomer Insertion of Coumarin-Functionalized Styrene206 (Scheme 36) most propagating species remain attached to the
surface, and the thiocarbonylthio functionality is maintained at the
chain ends. Termination can result in cross-linking.
Methods used for preparing RAFT agent-functionalized
surfaces have been reviewed.212 The methods used include
those used for the synthesis of other macro-RAFT agents such
as esterification or amidation (method I) in the case of graphene
oxide,213 cellulose,214 or nylon surfaces;215 active ester-amine
reaction (method J) for silica176 and proteins;216 azide−alkyne
1,3-dipolar cycloaddition (method K) for silica179,217,218 and
gold nanoparticles;136,219 thio Michael reaction for proteins
(method L);182,197 single unit monomer insertion (method M)
for St−divinylbenzene microspheres.220 Other methods have
also been used for specific substrates such as electrodeposition
for conductive ITO or gold surfaces.221−223
Other recent examples of single unit monomer insertion While many processes for surface-initiated RAFT polymerization
include vinylphosphonic acid,207 St derivatives,208−210 NIPAM,210 involve attaching the RAFT agent functionality to the substrate
and 2-vinylthiophene derivatives (including a poly(3-hexylthio- directly, another commonly used approach involves forming
phene) macromonomer).165 While successful single unit radicals on the surface (e.g., by irradiation or from attached initiator
monomer insertion into an initial low molecular weight RAFT functionality) to initiate polymerization in the presence of a “free”
agent can be successfully performed to provide high yields of new RAFT agent which becomes attached to the surface during RAFT
macro-RAFT agents, there remain some challenges in using the polymerization in a process analogous to radical-induced R group
methodology to performing successive single unit insertions.210 exchange (method H above). The mechanism is then the same as
In particular, initiator-derived byproducts become an issue when that shown in Scheme 36. The approach has been used to modify
silica224 and polypropylene225 surfaces.

■
R is different from the initiator-derived radical.
Agents for RAFT Surface Modification. A variety of
chemistries have been exploited for attaching RAFT agent (or CONCLUSIONS AND OUTLOOK
initiator) functionality to surfaces for use in “grafting from” or This Perspective has reviewed the design and synthesis of
surface-initiated polymerization. RAFT agents. Many factors need to be considered when
So-called “away from” processes, where Z is bound to the choosing a RAFT agent. The RAFT agent should be selected to
substrate (Scheme 37), have an advantage over “attached to” achieve the anticipated molar mass, block purity, and low
processes, where R is bound to the substrate (Scheme 36), in that dispersity which requires that the reagent possess a high Ctr. At
during RAFT polymerization the propagating radicals are never the same time, the RAFT agent should not retard polymer-
directly attached to the surface. Termination involves the reaction ization or undergo any side reactions. It must be borne in mind
of “free” propagating radicals in solution to produce a byproduct that the reagents that have the highest Ctr are often those that
that can be washed away. The thiocarbonylthio func- are most prone to side reactions. The RAFT agent must also
tionality remains directly attached to the surface. It has been sug- have appropriate solubility in the reaction medium and possess
gested that steric factors associated with attack of the propagating the requisite end-group functionality for the intended
radical on the surface-bound RAFT functionality could become an application. The dependence of these parameters on RAFT
issue, particularly at high conversions.211 A potential disadvantage agent structure and the Z and R substituents is now largely
of the “away from” strategy is that any reaction which cleaves understood such that a rational choice can be made.
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Macromolecules Perspective

Some guidance is available in the form of Figure 3, for selection broadly applicable, methods for end-group conversion post-RAFT
of the Z, and Figure 4, for the selection of R. polymerization,67 and the design of the initial RAFT agent can be
The aforementioned factors always need to be balanced extremely important in facilitating these transformationsboth in
against the availability, potential toxicity, and ease of synthesis of terms of the efficiency of the process and dealing with any
the RAFT agent. Many methods for RAFT agent synthesis have byproducts that might be formed. The recent discussion on polymer
been described. That most commonly used is the reaction of a chemistry and “click” reactions is extremely relevant in this context.226
carbodithioate salt with an alkylating agent. Other processes
with mostly niche applications include various thioacylation
reactions, the thiation of carbonyl compounds, the ketoform
■
Notes
AUTHOR INFORMATION

reaction, thiol exchange, and radical substitution of bis(thioacyl) The authors declare no competing financial interest.
disulfides and other thiocarbonylthio compounds. An attempt
has been made to summarize these methods in Scheme 38. Biographies
Scheme 38. Main Methods Used for RAFT Agent Synthesis
(RX = Alkylating Agent, LR = Lawesson’s Reagent or
Equivalent)

Dr. Daniel Keddie obtained his PhD in synthetic organic chemistry in

2008 from the School of Physical and Chemical Sciences, Queensland
University of Technology (QUT), where he worked on the synthesis of
profluorescent nitroxides. He then undertook a postdoctoral position
within the Institute of Health and Biomedical Innovation, QUT, involving
Challenges, however, remain in RAFT agent design and the synthesis and characterization of amphiphilic siloxane copolymers for
synthesis. One which has attracted the attention of several groups potential biological application. Since 2009, Dr. Keddie has held a OCE
is the development of a truly universal RAFT agentone able to postdoctoral fellowship at the Commonwealth Scientific and Industrial
control polymerization of all monomers polymerizable by radical Research Organization, Australia (CSIRO). He is currently working on
polymerization. The proposal that the fluorine might be the the development of “switchable” chain transfer agents for RAFT
universal Z group remains largely untested.42,43 However, a polymerization. His research interests include free radical chemistry and
positive outcome seems unlikely based on the experimental the synthesis and application of functional small molecules and polymers.
findings to date. Switchable RAFT agents do provide scope for
controlling a much wider range of monomers.44,45,47,107 However,
there are obvious issues with the current proton switch in
controlling the polymerization of monomers which possess acidic
or basic functionality or where there is particular sensitivity to
acid. Current work planned or underway in our laboratories seeks
to address these issues by examining alternative switching
mechanisms based on photochemical, redox, or other processes.
While we are some way toward a universal Z group, there is
also a need for a more widely applicable or switchable R group.
One possible solution lies with the single unit monomer insertion
process (method M). Also needed, perhaps as a stopgap, is a
convenient, high yielding, synthesis of RAFT agents with tertiary
R (or equivalent) suitable for controlling the polymerization of
methacrylic and other 1,1-disubstituted monomers.
However, most current activity in RAFT agent design and
synthesis is in the area of functional-, macro-, and surface attached- Graeme Moad was born in Orange, NSW, Australia. He obtained his BSc
RAFT agents with particular applications in such fields as (Hons, First Class) and PhD from the Adelaide University in the field of
biomedicine158 and optoelectronics.164 Common strategies for the organic free radical chemistry. After undertaking postdoctoral research at
preparation of macro- and surface attached-RAFT agents involve Pennsylvania State University in the field of biological organic chemistry,
esterification or amidation of a carboxy functional RAFT agent he joined CSIRO in 1979 where he is is currently a chief research scientist.
(method I) and reactions such as azide−alkyne 1,3-dipolar Dr. Moad is author or coauthor of over 150 journal papers, coinventor of
cycloaddition (method J) and the active ester−amine reaction 33 patent families (9 relate to the RAFT process), and coauthor of the
(method K). There is also continuing demand for convenient, book The Chemistry of Radical Polymerization. More than 12 000 papers

5337 dx.doi.org/10.1021/ma300410v | Macromolecules 2012, 45, 5321−5342

Macromolecules Perspective

cite his work, and his h-index is 52. His research interests lie in the fields of University and PhD also at Griffith University in 1987 with Prof. Ian
polymer design and synthesis (radical polymerization, reactive extrusion, Jenkins, Associate Prof. Ken Busfield, Dr. Ezio Rizzardo, and Dr. David
polymer nanocomposites) and polymerization kinetics and mechanism. Solomon as supervisors. He joined CSIRO in 1986 as a Research
Dr. Moad is a fellow of the Royal Australian Chemical Institute and the Fellow, and in late 1987, he moved to ICI Australia to undertake the
Australian Academy of Science. He was recently (February 2012) awarded challenge of industrial research in synthetic UV sunscreens and
the RACI Polymer Division’s Battaerd-Jordan Medal. agrochemicals. San rejoined CSIRO in late 1990 and currently is a
Senior Principal Research Scientist at CSIRO Materials Science and
Engineering where his research focuses on the interface between
biology and polymer chemistry. San has published over 100 papers in
refereed journals which to date have received over 10 000 citations. He
is responsible for several key inventions in the area of controlled/living
radical polymerization; significantly, he is a coinventor of the RAFT
process. San is a Fellow of the Australian Academy of Technological
Science and Engineering and Fellow of the Royal Australian Chemical
Institute. Currently, he also serves as Adjunct Professor of Monash
University.

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