Development of Amino-Oxazoline and Amino-Thiazoline Organic Catalysts for the Ring-Opening Polymerisation of Lactide

Article abstract of DOI:10.1002/chem.200902518

The ring-opening polymerisation of lactide by a range of aminooxazoline and amino-thiazoline catalysts is reported. The more electronrich derivatives are demonstrated to be the most highly active and polymerisation is well controlled, as evidenced by the

Full text of DOI:10.1002/chem.200902518

FULL PAPER
DOI: 10.1002/chem.200902518
Development of Amino–Oxazoline and Amino–Thiazoline Organic Catalysts
for the Ring-Opening Polymerisation of Lactide
Jan M. Becker,[a] Sarah Tempelaar,[a] Matthew J. Stanford,[a] Ryan J. Pounder,[a]
James A. Covington,[b] and Andrew P. Dove*[a]
Abstract: The ring-opening polymeri-
sation of lactide by a range of amino–
oxazoline and amino–thiazoline cata-
lysts is reported. The more electron-
rich derivatives are demonstrated to be
the most highly active and polymeri-
sation is well controlled, as evidenced
by the linear relationship between the
molecular weight and both the mono-
mer conversion and the monomer-to-
initiator ratio. Mechanistic studies
reveal significant interactions between
the monomer, initiator and catalyst and
that the polymerisation is first order
with respect to each of these compo-
nents. These observations indicate that
the polymerisation operates by a gener-
al base/pseudo-anionic mechanism.
Keywords: lactides · organocataly-
sis · polyesters · ring-opening poly-
merization
Introduction
molecule organics. Undoubtedly the most widely explored
field in this area has been the development and application
of discrete metal complexes from a wide portion of the peri-
odic table.[3–5] While these studies have led to the discovery
of a range of catalysts with high activities and/or high selec-
tivities (including stereocontrolled ROP), the polymers pro-
duced contain the catalytic metal residues used in their syn-
thesis. For applications in biomedicine and microelectronics
and to overcome concerns regarding leaching of these resi-
dues into the environment after disposal of the resultant
PLAs, the costly removal of the metal residues must be car-
ried out. The application of both enzymatic and organocata-
lytic methodologies enable the synthesis of PLAs without
the need for removal of metallic residues.
Enzymatic processes are highly efficient for the ROP of e-
caprolactone or larger less strained cyclic esters and, to
date, have shown relatively low activities towards lactide
ROP.[4,13–15] Recently, the development of small-molecule or-
ganic catalysts for ROP has led to the discovery of a range
of species that are proposed to operate by monomer-activat-
ed and supramolecular mechanisms.[2,4,6,16] Following the
report by Hedrick et al. in 2001 on the controlled ROP of
LA by DMAP,[17] several further reports have disclosed or-
ganocatalytic ROP by other nucleophilic catalysts, such as
NHCs,[18–22] supramolecular monomer/chain end activation
catalysts including cyclodextrins[23,24] and thiourea-
amines[25,26] and general base catalysis by guanidine and
phosphazene bases.[27–30] These reports have led to the dis-
covery of some of the most highly active catalysts reported
to date, which display high selectivities for ROP over trans-
The ring-opening polymerisation of lactide (LA) provides a
convenient route to the synthesis of polyACTHNUTRGNEUNG
(lactide)s, PLAs.[1–6]
When performed under optimal conditions in the presence
of a suitable catalyst, this methodology displays many of the
characteristics of a living polymerisation, including predicta-
ble molecular weights (based on the monomer/initiator
ratio), narrow polydispersities and high levels of control
over the polymer end groups. Additionally, ROP enables
the synthesis of high-molecular-weight polymers, which in
combination with their biodegradability and derivation from
renewable resources, is encouraging their investigation as
environmentally friendly packaging materials in addition to
their biomedical applications.[1,7–12]
The ROP process can be mediated by a wide range of cat-
alysts, including metal-based complexes, enzymes and small-
[a] Dr. J. M. Becker, S. Tempelaar, M. J. Stanford, R. J. Pounder,
Dr. A. P. Dove
Department of Chemistry
University of Warwick
Coventry, CV4 7AL (UK)
Fax : (+44)24-7652 4112
E-mail: a.p.dove@warwick.ac.uk
[b] Dr. J. A. Covington
School of Engineering
University of Warwick
Coventry, CV4 7AL (UK)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902518.
Chem. Eur. J. 2010, 16, 6099 – 6105
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esterification and the ability to control the tacticity of the
polymer chains at low temperatures.[29,31,32]
of tosyl chloride, whereas ring-closure under acidic condi-
tions led to the realisation of the corresponding amino–thi-
However, many of these catalyst systems do not offer a
great deal of flexibility within their design to enable struc-
ture–property relationships to be obtained and thus further
enable understanding and optimisation of their behaviour.
Herein, we report a modular synthesis for amino–oxazoline
and amino–thiazoline species and detail their application as
catalysts in a mechanistic study of the organocatalytic ROP
of lactide.
azoline compounds (Scheme 1).[33,36–38] Ring closure incorpo-
ACHTUNGTRENNUNG
rating O or S (or mixtures thereof) can be readily identified
by 1H NMR spectroscopic analysis of the products. The
chemical shift of the endocyclic methylene proton resonan-
ces are highly dependant on the adjacent heteroatom, such
that the oxazoline derivatives display much lower-field reso-
nances (typically dꢁ4 ppm) than the thiazoline analogues
(typically dꢁ3 ppm). In this manner, amino–oxazoline and
amino–thiazoline compounds were prepared to investigate
the influence of electronic structure on their behaviour as
catalysts for the ROP of lactide. Notably, ring closure of 1c
under basic conditions to provide the corresponding amino–
oxazoline resulted in the isolation of a mixture of O- and S-
heterocyclic compounds, comparable to that reported by
Heinelt et al.,[38] thus only further investigation with the
thiazoline derivative was pursued.
Results and Discussion
Oxazoline-based compounds provide a synthetically versa-
tile unit that have been widely applied as ligands for metal-
based catalysts in a wide range of processes.[33–36] The struc-
tural similarities between 2-amino derivatives and the highly
active 1,5,7-triazabicyclo
G
Amino–oxazoline compounds 2a and 2b and amino–thi-
applied in ring-opening polymerisation studies by Hedrick
ACHTUNGTRENaNUGN zoline compounds 3a–c were evaluated as catalysts for the
and Waymouth,[28] are clear (Figure 1). Both possess a three-
ROP of lactide. At ambient temperature in CH2Cl2 and
7 mol% catalyst loading (relative to monomer), the ROP of
rac-LA initiated from neo-pentanol (target degree of poly-
merisation, DP=100) was investigated. This initial screening
of the catalyst activity (Table 1) revealed that thiazoline de-
Table 1. Data for the polymerisation of rac-lactide by using amino–oxa-
Figure 1. a) 1,5,7-TriazabicycloACHTUNTRGNEU[GN 4.4.0]dec-5-ene (TBD). b) Amino–oxazo-
line (X=O) and amino–thiazoline (X=S) compounds.
zoline and amino–thiazoline catalysts.[a]
[d]
Entry
Catalyst
Target
DP[b]
t
Conv.[c]
[%]
DP[c]
Mn
PDI[d]
[h]
[gmolꢀ1
ACHTUNGTERNNUNG ]
ꢀ
centred N=C NH unit, but access to analogues of TBD is
1
2
3
4
5
6
7
8
2a
2b
3a
3b
3c
3c
3c
3c
3c
3c
100
100
100
100
100
50
25
10
100
100
48
48
48
48
36
28
16
8
0
9
0
11
95
94
95
94
94
98
–
8
–
10
100
45
20
9
–
500
–
1000
15400
7000
3900
2800
17900
20400
–
1.33
–
1.39
1.04
1.07
1.10
1.10
1.08
1.09
synthetically challenging whereas the modular synthesis of
amino–oxazoline and amino–thiazoline compounds makes
them an attractive option to explore the effect of structure
on ROP behaviour and further understand the polymeri-
sation mechanism.
Both oxazoline (2a,b) and thiazoline catalysts (3a–c)
were synthesised via common thiourea intermediates (1a–c)
that were prepared by the addition of equimolar amounts of
isothiocyanate and amine/aniline in THF at ambient temper-
ature (Scheme 1). Amino–oxazoline compounds were ac-
cessed by ring-closure under basic conditions in the presence
9[e]
10[f]
34
32
100
100
[a] Conditions: 7 mol% catalyst, [LA]=4.6m in CDCl3, 228C. [b] Deter-
mined from the monomer/initiator ratio. [c] Determined by 1H NMR
spectroscopy. [d] Determined by GPC. [e] At 408C. [f] At 608C.
rivatives with electron-withdrawing aryl groups resulted in
lower ROP activities. In all cases, atactic polymers of pre-
dictable DPs with narrow polydispersities (1.04–1.10) were
obtained.
Compound 3c with a 2-cyclohexylamino substitution on
the thiazoline ring was noted to be the most active catalyst,
therefore, further investigations were focused on elucidating
the behaviour of this catalyst in the ROP of lactide. The
polymerisation mediated by 3c resulted in polyACTHNURTGNEU(GN lactide) that
exhibited a number average molecular weight, Mn, of
15400 gmolꢀ1 and a narrow polydispersity (1.04), which indi-
cates that the polymerisation was well controlled. Further
evidence of this control was obtained by demonstration of a
linear dependence of Mn on monomer conversion, with low
Scheme 1. Synthesis of thiourea, amino-oazoline and amino–thiazoline
compounds. i) THF; ii) NaOH, TsCl, THF, H2O; iii) HCl.
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Amino–Oxazoline and Amino–Thiazoline Organic Catalysts
FULL PAPER
Figure 2. Graph of average molecular weight (Mn [gmolꢀ1]) against mo-
nomer conversion [%] and PDI for the polymerisation of rac-lactide
mediated by 3c (DP100).
Figure 3. Graph of average molecular weight (Mn [gmolꢀ1]) against [M]/
[I] and PDI for the polymerisation of rac-lactide mediated by 3c.
polydispersity values being maintained throughout the poly-
merisation (Figure 2). Variation of the monomer-to-initiator
ratio revealed a linear dependence with a polymer molecu-
lar weight of between 20 and 150 equivalents of LA; again
the polydispersities remained low (Figure 3).
The initiator efficiency was
creased time periods transesterification side reactions occur
to a low extent. Investigation of the ROP of l-lactide results
in the observation of low levels of monomer epimerisation
as evidenced by the appearance of methyl signals corre-
sponding to meso-lactide (d=1.68 ppm) throughout the
investigated by analysis of the
DP10 PLA by 1H NMR and
MALDI-TOF MS (Figure 4).
1
The H NMR spectrum reveals
a singlet at d=0.93 ppm that
corresponds to the tert-butyl
methyl groups and a multiplet
at d=3.84 ppm that corre-
sponds to the methylene reso-
nance from the initiator in a
9:2:16 ratio (Me/CH2/polymer
CH), which indicates that a
DP8 polymer was isolated. Ac-
cordingly, the MALDI-TOF
MS (Figure 4, bottom) reveals
a
single distribution corre-
sponding to the sodium-
charged PLA with single
a
neo-pentyl end group. Addi-
tionally, an exclusive spacing
of 144 Da (at 94% monomer
conversion) is observed, with
the absence of a distribution
spaced at 72 Da that strongly
suggests that the catalysts are
highly selective towards ROP
over transesterification. Exten-
sion of the reaction time to
12 d for the DP100 PLA (Mn =
15400 gmolꢀ1
;
PDI=1.04),
however, revealed a reduction
in molecular weight (Mn =
12500 gmolꢀ1) and
a slight
broadening of PDI (1.32) that
suggests that at significantly in-
Figure 4. 1H NMR spectrum (top) and MALDI-TOF MS (bottom) of PLA (DP10) initiated from neo-pentanol.
Chem. Eur. J. 2010, 16, 6099 – 6105
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A. P. Dove et al.
polymerisation and the presence of a sss tetrad resonance
(d=69.4 ppm) in the 13C NMR spectrum (see the Support-
ing Information). Homonuclear decoupled H NMR analysis
of this polymer revealed that the iii tetrad represented
around 75% of the tetrad sequences.
nol], these experiments revealed a linear relationship be-
tween ln[LA]0/[[LA]t and time with a zero intercept. A plot
of lnkapp against ln[neo-pentanol] for each experiment re-
vealed a linear relationship with a gradient of 1.05ꢄ0.12
(see the Supporting Information), which approximates to
the polymerisation being first order with respect to initiator,
within experimental error. Repeat of this process at constant
[LA] and [neo-pentanol] ([LA]0 =2.7m; [neo-pentanol]0 =
0.11m) enabled the order with respect to the catalyst (3c) to
be determined (Figures 5 and 6) as 0.91ꢄ0.11. Again, this
1
Given the preference of the system towards ROP over
transesterification, we also decided to investigate the poly-
merisation at elevated temperature with a view to increasing
the activity of the polymerisation system. Interestingly, in-
vestigation of the ROP of rac-LA ([M]/[I]=100, [M]=
0.69m) in CDCl3 at 40 and 608C revealed very little rate en-
hancement over that observed at 228C, such that 94 and
98% monomer conversions were observed within 34 and
32 h at 40 and 608C, respectively (cf. 95% monomer conver-
sion within 32 h at 228C; see Table 1). We postulate that this
observation results from the decreased strength of the
supramolecular interactions postulated to occur in the tran-
sition state of the rate-determining step of the polymeri-
sation.[39,40]
These observations led us to further investigate the poly-
merisation kinetics and the interactions between the cata-
lyst, monomer and initiator. Notably, the observable time-
scale of the polymerisations enables direct study of the poly-
merisation mechanism of lactide with this class of catalyst
for the first time.
Figure 6. Graph of ln[3c] vs. lnACHTUNRGTNE[UNG kapp] for the polymerisation of rac-lactide
by neo-pentanol/3c at 228C in CDCl3. [LA]=2.7m; [neo-pentanol]=
0.11m.
Kinetic studies of the polymerisation of rac-lactide medi-
ated by 3c by using neo-pentanol as an initiator in CDCl3 at
228C were performed by monitoring monomer conversion
(determined by the integration of methine resonances of the
result approximates to the polymerisation being first order
with respect to the catalyst, confirmed by the direct linear
relationship between kapp and [3c] (see the Supporting Infor-
mation). In this case, the deviation from a rate order of one
with respect to the catalyst is more significant, however,
these observations suggest that the rate law follows Equa-
tion (2), which identifies that a molecule of monomer, initia-
tor and catalyst are involved equally in the rate-determining
step.
1
monomer vs. the polymer) by H NMR spectroscopy. Given
the three components the rate law can be assumed to follow
Equation (1).
x
y
z
ꢀd½LAꢂ=dt ¼ kp½LAꢂ ꢃ ½neo-pentanolꢂ ꢃ ½3cꢂ
ð1Þ
Analysis of the semilogarithmic plots (Figure 5) reveals
that the polymerisation is first order with respect to the mo-
nomer. Experiments in which the [neo-pentanol] was varied
and the [LA] and [3c] were kept constant ([LA]0 =4.6m;
[3c]0 =0.31m) were conducted to identify the order with re-
spect to the initiator (neo-pentanol). For each [neo-penta-
ꢀd½LAꢂ=dt ¼ kp½LAꢂ ꢃ ½neo-pentanolꢂ ꢃ ½3cꢂ
ð2Þ
To further elucidate mechanistic information relating to
the polymerisation, we undertook a series of experiments to
probe the interactions between the components of the reac-
tion mixture. Examination of the 1H NMR spectrum of a
mixture of 3c and lactide in CDCl3 in a 1:38 ratio at 228C
led to only small shifts of the NH and cyclohexyl CH reso-
nances (NH: from d=4.14 (free) to 4.15 ppm; CH: from d=
3.39 (free) to 3.36 ppm). As such, further work focused on
the application of d-valerolactone as a benzene-soluble
cyclic ester model compound to facilitate observation of
supramolecular interactions between the species. The
1H NMR spectrum of a mixture of 3c and d-valerolactone in
a 1:18 ratio in C6D6 at 228C ([3c]=0.035m; [dVL]=0.52m)
revealed a notable shift in the highly sensitive NH reso-
nance from d=3.55 to 4.17 ppm and a smaller shift in the
cyclohexyl CH resonance from d=3.68 to 3.70 ppm, which
indicates a significant interaction between the species. Com-
Figure 5. Semilogarithmic plot of time vs. monomer conversion for the
polymerisation of rac-lactide by neo-pentanol/3c at 228C in CDCl3.
*
[LA]=2.7m; [neo-pentanol]=0.11m +: [3c]=0.41m; : [3c]=0.34m;
:
*
~
&
^
[3c]=0.27m; : [3c]=0.14m; : [3c]=0.095m; : [3c]=0.068m.
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Amino–Oxazoline and Amino–Thiazoline Organic Catalysts
FULL PAPER
parable studies with mixtures
of 3c and neo-pentanol in a
ratio of 16:1 ([3c]=0.035m;
[neo-pentanol]=0.002m)
re-
vealed no significant shift in
the NH or cyclohexyl CH reso-
nance of 3c and a minor shift
in the neo-pentanol CH2 and
CH3 resonance from d=2.99
and 0.79 ppm to d=3.03 and
0.81 ppm, respectively, which
Scheme 2. Key interactions between the catalyst, monomer and alcohol in the ROP of lactide mediated by 3c.
indicates a weak interaction between the two species under
these conditions. In all cases the OH resonance could not be
observed, due either to an overlap with another resonance
or to broadening as a consequence of rapid exchange on the
NMR timescale. Notably, the NH resonance of 3c was also
observed to shift significantly during the course of this titra-
tion. Further investigation of the effect of concentration of
3c upon the chemical shift of the NH resonance revealed a
concentration-dependant shift from d=4.60 to 3.05 ppm and
the cyclohexyl CH resonance shifted from d=3.61 to
3.66 ppm upon dilution from a 1.5 to 0.035m C6D6 solution.
These observations suggest that a concentration-dependant
dimerisation of the catalytic species exists in solution, in ad-
dition to the hydrogen-bonding interactions between the
catalyst and lactone and the catalyst and alcohol. Notably,
this concentration-dependant monomer–dimer equilibrium
rationalises the apparent deviation in the catalyst order of
one. Under conditions at which [3c] is high, free 3c will pre-
dominate as a dimer that must be broken up to allow mono-
meric 3c to mediate the ring-opening process. In extreme
cases in which all catalyst exists in the dimeric form but is
required to be monomeric to mediate the rate-determining
step of the polymerisation, the rate order would equal 0.5.
The lowering of the rate order with respect to 3c, tending
towards 0.5 at higher catalyst concentrations, suggests that
the monomer–dimer equilibrium plays an important role in
the polymerisation process.
These observations are consistent with ROP being medi-
ated by a general base/pseudo-anionic mechanism that in-
volves stabilisation of transition states by hydrogen bonding.
To differentiate between a mechanism involving activation
of the initiator/chain end solely by the thiazoline nitrogen,
ROP was attempted by using the commercially available 2-
methylthiazoline as the catalyst. Under conditions identical
to those applied above, no polymerisation activity was ob-
served over 24 h. This is consistent with the increased activi-
ty of TBD-catalyzed ROP over basic catalysts that do not
possess an amine proton, such as 7-methyl-1,5,7-
concurrent hydrogen-bonding interactions between the cata-
lyst, monomer and propagating chain end/initiator. Addi-
tionally, these studies reveal that the catalyst is in a rapid,
concentration-dependant equilibrium between its monomer-
ic and dimeric forms (Scheme 2).
To investigate if a relationship exists between these supra-
molecular interactions between the catalyst, monomer and
alcohol and the catalyst activity, the chemical shifts of key
1H NMR resonances for the interactions between 2b, 3a
and 3b and d-valerolactone and neo-pentanol were investi-
gated. After saturation of a solution of the respective
amino–oxazoline or amino–thiazoline compound in C6D6
with d-valerolactone (ꢁ13 equiv) under conditions compa-
rable to those described above ([catalyst]=0.035m), the
chemical shifts of the NH and the ortho-phenyl proton were
recorded. These spectra with aminothiazoline compounds
3a and 3b did not reveal the presence of an NH proton,
which is presumably a result of broadening of the resonance,
yet the same resonance for the amino–oxazoline compound
2b was observed to shift downfield by d=0.94 ppm. Howev-
er, the ortho-phenyl protons could all be observed to under-
go a downfield shift, with the magnitude of the shift corre-
lating to the electronic environment of the catalyst such that
the difference in chemical shift was in the order 3a>2b>
3b (>cyclohexyl CH shift in 3c; see the Supporting Infor-
mation). Further investigation of the interaction of the cata-
lyst species with neo-pentanol ([catalyst]=0.035m; [cata-
lyst]/[neo-pentanol]ꢁ20) revealed that the most electron
rich species resulted in the largest change of chemical shift
for both the neo-pentyl CH2 and CH3 resonances (i.e., 3c>
3b>2b>3a). These data show that, as may be expected,
the more electron-deficient compounds result in a stronger
interaction with cyclic esters but a weaker interaction with
added alcohol.
Clearly, subtle changes to the electronic nature of the cat-
alyst structure affect the ability to mediate the ROP reac-
tions of these compounds. These studies also demonstrate
that ROP activity is clearly not dominated by either compo-
nent and that both hydrogen-bonding sites are required to
be available to obtain efficient catalysis, further supporting
the proposed mechanism. Additional experimental and the-
oretical studies are planned to provide greater understand-
ing of these complex interactions.
triazabicyclo
[5.4.0]undec-7-ene (DBU).
These observations support the theoretical results inde-
ACHTUNGTRENNUNG[4.4.0]dec-5-ene (MTBD) or 1,8-diazabicyclo-
ACHTUNGTRENNUNG
pendently reported by Rice and co-workers[39] and Simon
and Goodman[40] for the analogous TBD-catalyzed polymer-
isation, and indicate that the catalyst species serves to stabi-
lise the transition state of the rate-determining step of the
polymerisation involving lactide, alcohol and catalyst by
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A. P. Dove et al.
film. The samples were measured in reflectron ion mode and calibrated
Conclusion
by comparison to 2ꢁ103 and 5ꢁ103 gmolꢀ1 poly
ACTHNUTRGNE(UNG ethylene glycol) stand-
ards. Elemental analyses were performed by Warwick Analytical Serv-
ices.
We have reported the synthesis of a versatile and modular
catalyst system and its application to the ROP of LA,
namely, amino–oxazoline and amino–thiazoline compounds.
The electronic structure of the compounds has been demon-
strated to have a large effect on their activity, such that the
most active catalysts are those with electron-rich alkyl
groups and endocyclic sulfur heteroatoms. The optimum cat-
alyst structure, 3c, produces polymers with good control
over molecular parameters and displays a resistance to
transesterification. Mechanistic and kinetic studies have sug-
gested that this catalyst operates by a general base (quasi-
anionic) mechanism that is comparable to the other “super-
base” ROP catalysts with the involvement of hydrogen
bonding between catalyst, monomer and alcohol. Such ex-
perimental observations provide an excellent base for the
foundation of further rational catalyst design around this
template to provide a new family of tuneable organic cata-
lysts.
Synthesis of 1-(2-hydroxy-1,1-dimethylethyl)-3-[3,5-bis(trifluoromethyl)-
phenyl]thiourea (1a): 2-Amino-2-methylpropanol (1.9 mL, 19.5 mmol)
was added to a solution of (3,5-bis(trifluoromethyl)phenyl)isothiocyanate
(5.3 g, 19.5 mmol) in THF (150 mL). The solution was stirred for 18 h
before the solution was reduced under vacuum. The resultant oil was di-
luted in a small volume of dichloromethane, precipitated into stirred pe-
troleum ether (40/60), collected by filtration and dried in vacuo to give a
white solid (yield 6.2 g, 17.2 mmol, 88%). 1H NMR (CDCl3, 400 MHz):
d=10.60 (brs, 1H; NH), 8.06 (s, 2H; o-Ar), 7.63 (s, 1H; p-Ar), 6.37 (s,1
H; NH), 3.66 (s, 2H; CH2OH), 1.39 ppm (s, 6H; CH3); 13C NMR
(CDCl3, 100 MHz): d=180.8 (NC(S)N), 140.8 (Ar-ipso), 131.9 (2J
ACHTUNGTRENNUNG
33 Hz, CCF3), 123.1 (1J
ACHTUNGTRENNUNG
71.2 (CMe2), 58.2 (CH2OH), 24.5 ppm (CH3); MS (ESI+): m/z: 361.0
[MH]+; elemental analysis calcd (%) for C13H14N2SOF6: C 43.3, H 3.9, N
7.8; found: C 43.2, H 3.9, N 7.8.
Synthesis of 2-[3,5-bis(trifluoromethyl)phenyl]amino-4,4-dimethyloxazo-
line (2a): The procedure was adapted from that previously reported by
Munslow et al.[36] Tosyl chloride (2.5 g, 13.1 mmol) in THF (5 mL) was
added dropwise to a stirred solution of 1a (3.0 g, 8.3 mmol) in THF and
10m aqueous sodium hydroxide (7.5 mL, 2:1 vol). After stirring for 18 h,
the THF was removed under vacuum and the residue was partitioned
with Et2O (150 mL) and H2O (100 mL). The aqueous layer was extracted
with Et2O (2ꢁ50 mL) before the combined organic fractions were dried
over MgSO4, filtered and reduced under vacuum to give 4 as a white
solid that was extracted and recrystallised from hexanes (yield 1.0 g,
3.1 mmol, 37%). 1H NMR (CDCl3, 400 MHz): d=7.52 (s, 2H; o-Ar),
7.45 (s, 1H; p-Ar), 4.18 (s, 2H; CH2), 1.37 ppm (s, 6H; CH3); 13C NMR
Experimental Section
Materials: rac-Lactide and l-lactide (Aldrich) were purified by recrystal-
lisation from dry dichloromethane and sublimed twice before use. Di-
chloromethane and CDCl3 for polymerisations was refluxed over CaH
and then distilled, degassed and stored under a nitrogen atmosphere. All
alcohol initiators were dried over suitable drying agents, distilled and de-
gassed. 1-(2-Hydroxy-1,1-dimethylethyl)-3-phenylthiourea (1b),[36] 1-(2-
hydroxy-1,1-dimethylethyl)-3-cyclohexylthiourea (1c)[33] and 2-phenyl-
(CDCl3, 100 MHz): d=155.9 (NC(-O)=N), 130.8 (2J
ACTHNUGRTENUNG(C,F)=33 Hz,
CCF3), 122.5 (1J
ACHTNUGTRNEUNG(C,F)=273 Hz, CF3), 121.7 (Ar-o), 114.3 (Ar-p), 78.5
(CMe2), 56.4 (CH2), 26.3 ppm (CH3); MS (ESI+): m/z: 327.0931 [MH]+;
elemental analysis calcd (%) for C13H12N2OF6: C 47.9, H 3.7, N 8.6;
found: C 47.8, H 3.7, N 8.6.
ACHTUNGTRENNUNG
amino-4,4-dimethyloxazoline (2b)[36] were synthesised according to litera-
Sample procedure for synthesis of amino–thiazoline: The procedure was
adapted from that previously reported by Crust et al.[33] Concentrated
HCl (100 mL) was slowly added to 1a (3.0 g, 8.3 mmol). The solution was
heated under reflux at 958C for 4 h. After cooling, the solution was dilut-
ed with H2O (20 mL) and made basic by the addition of Na2CO3 in an
ice bath (CAUTION: addition should be made in small portions because
the reaction is exothermic and leads to vigorous effervescence). The solid
was collected by filtration and washed with H2O (20 mL) before being
dissolved in chloroform (50 mL), then dried over MgSO4. Removal of
drying agent by filtration and reduction of the solution under vacuum
gave in a white solid, 2-[3,5-bis(trifluoromethyl)phenyl]amino-4,4-dime-
thylthiazoline (3a), that was extracted and recrystallised from hexanes
(0.7 g, 2.0 mmol, 24%). 1H NMR (CDCl3, 400 MHz): d=7.52 (s, 1H; p-
Ar), 7.45 (s, 2H; o-Ar), 3.11 (s, 2H; CH2), 1.36 ppm (s, 6H; CH3);
13C NMR (CDCl3, 100 MHz): d=161.9 (NC(-S)=N), 150.6 (Ar-ipso),
ture procedures. Organic catalysts were dried by dissolution in dry THF
and subsequent stirring at 608C over CaH for 18 h before filtration and
drying under vacuum. All other chemicals and solvents were obtained
from Aldrich and used as received.
General considerations: All manipulations were performed under mois-
ture- and oxygen-free conditions either in a nitrogen-filled glovebox or
by standard Schlenk techniques. Gel-permeation chromatography (GPC)
was used to determine the molecular weights and polydispersities of the
synthesised polymers. The system comprised a Polymer Laboratories
Midas autosampler and LC1120 HPLC pump equipped with a guard
column (Polymer Laboratories PLGel 5 mm, 50ꢁ7.5 mm), two mixed D
columns (Polymer Laboratories PLGel 5 mm, 300ꢁ7.5 mm) and a Poly-
mer Laboratories ERC-7515A differential refractive index (DRI) detec-
tor. The mobile phase (eluent) was chloroform/triethyl amine (95:5) at a
flow rate of 1.0 mLminꢀ1 and samples were calibrated against linear poly-
131.1 (2J(C,F)=33 Hz, CCF3), 122.4 (1J
ACTHUNTRGENNGU ACHTUTGNERN(NUGN C,F)=272 Hz, CF3), 121.5 (Ar-
ACHTUNGTRENNUNG
(styrene) standards (540 to 2.9ꢁ104 gmolꢀ1) by using Cirrus 3.0 software;
o), 115.4 (Ar-p), 59.4 (CMe2), 41.5 (CH2), 26.5 ppm (CH3); MS (ESI+):
m/z: 343.0710 [MH]+; elemental analysis calcd (%) for C13H12N2SF6: C
45.6, H 3.5, N 8.2; found: C 45.65, H 3.5, N 8.2.
elution time was standardised against that of toluene. 1H and 13C NMR
spectra were recorded by using a Bruker DPX-300, DPX-400, AC400 or
DRX-500 spectrometer at 293 K unless stated. Chemical shifts are report-
ed as d in parts per million (ppm) and referenced to the chemical shift of
the residual solvent resonances (CDCl3: 1H d=7.26 ppm; 13C d=
77.16 ppm). Mass spectra were acquired by using a Bruker Micro-TOF
(ESI+) or a Bruker Esquire200 ESI mass spectrometer. MALDI-TOF
mass spectrometry was performed by using a Bruker Daltonics Ultraflex
II MALDI-TOF mass spectrometer, equipped with a nitrogen laser deliv-
ering 2 ns laser pulses at l=337 nm with positive-ion TOF detection per-
formed by using an accelerating voltage of 25 kV. Solutions of trans-2-[3-
(4-tertbutylphenyl)-2-methyl-2-propylidene]malonitrile as the matrix
(0.3 mL of a 10 gLꢀ1 solution in acetone), sodium trifluoroacetate as the
cationisation agent (0.3 mL of a 10 gLꢀ1 solution in acetone) and analyte
(0.3 mL of a 1 gLꢀ1 CH2Cl2 solution) were applied sequentially to the
target followed by solvent evaporation to prepare a thin matrix/analyte
2-Phenylamino-4,4-dimethylthiazoline (3b): This compound was isolated
from 1b as a white solid (yield 1.1 g, 5.3 mmol, 39%); 1H NMR (CDCl3,
400 MHz): d=7.28 (t, 3J(H,H)=8.1 Hz, 2H; m-Ar), 7.07 (d, 3J
ACTHNUGTRENNUGN ACHTUNGTRENNUNG
8.7 Hz, 2H; o-Ar), 7.06 (t, 3J
ACHTUNGTRENNUNG
CH2), 1.36 ppm (s, 6H; CH3); 13C NMR (CDCl3, 100 MHz): d=160.3
(NC(-S)=N), 148.9 (Ar-ipso), 128.9 (Ar-m), 123.1 (Ar-o), 121.8 (Ar-p),
77.1 (CMe2), 43.0 (CH2), 27.7 ppm (CH3); MS (ESI+): m/z: 207.0950
[MH]+; elemental analysis calcd (%) for C11H15N2S: C 64.0, H 6.8, N
13.6; found: C 64.0, H 6.8, N 13.5.
2-Cyclohexylamino-4,4-dimethylthiazoline (3c): This compound was iso-
lated from 1c as a white solid (yield 1.03 g, 4.9 mmol, 54%); 1H NMR
(CDCl3, 400 MHz): d=4.17 (brs, 1H; NH), 3.39 (m, 1H; NCH), 3.08 (s,
2H; SCH2), 1.98 (m, 2H; Cy-H), 1.33 (s, 6H; CH3), 1.05–1.75 ppm (m,
6104
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 6099 – 6105

Amino–Oxazoline and Amino–Thiazoline Organic Catalysts
FULL PAPER
8H; Cy-H); 13C NMR (CDCl3, 100 MHz): d=157.6 (NC(-S)=N), 53.7
(Cy-CH), 46.0 (SCH2), 28.3 (CH3), 33.7, 25.6, 24.7 ppm (Cy-CH2); MS
(ESI+): m/z: 213.1417 [MH]+; elemental analysis calcd (%) for
C11H20N2S: C 62.2, H 9.5, N 13.2; found: C 62.1, H 9.5, N 13.1.
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Acknowledgements
The Research Councils UK (RCUK) are acknowledged for funding a fel-
lowship for A.P.D. We gratefully acknowledge the support provided by
the Warwick Innovative Manufacturing Research Centre (WIMRC) for
financial support and the EPSRC (EP/C007999/1) for the purchase of the
Bruker Ultraflex MALDI-TOF MS instrument in addition to the provi-
sion of funding, including a studentship for M.J.S. to support this work
(EP/D079136/1). The GPC equipment used in this research was obtained
through Birmingham Science City: Innovative Uses for Advanced Mate-
rials in the Modern World (West Midlands Centre for Advanced Materi-
als Project 2), with support from Advantage West Midlands (AWM) and
part-funded by the European Regional Development Fund (ERDF). Dr
David Fox (University of Warwick) is thanked for helpful discussions.
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Received: September 11, 2009
Revised: February 15, 2010
Published online: April 13, 2010
Chem. Eur. J. 2010, 16, 6099 – 6105
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6105