Developments in Dynamic Covalent Chemistries from the Reaction of Thiols with Hexahydrotriazines

Article abstract of DOI:10.1021/jacs.5b08815

Dynamic covalent chemistries have garnered significant attention for their potential to revolutionize technologies in the material fields (engineering, biomedical, and sensors) and synthetic design strategies as they provide access to stimuli responsiveness and adaptive behaviors. However, only a limited number of molecular motifs have been known to display this dynamic behavior under mild conditions. Here, we identified a dynamic covalent motif - thioaminals - that is produced from the reaction of hexahydrotriazines (HTs) with thiols. Furthermore, we report on the synthesis of a new family of step-growth polymers based on this motif. The condensation efficiently proceeds to quantitative yields within a short time frame and offers versatility in functional group tolerance; thus, it can be exploited to synthesize both small molecule thioaminals as well as high molecular weight polymers from the step-growth polymerization of HTs with dithiols. Careful evaluation of substituted HTs and organic thiols supported by DFT calculations led to a chemically diverse library of polymers based on this motif. Finally, dynamic substitution reactions were employed toward the facile preparation of functional oligomers and macromolecules. This dynamic covalent motif is particularly attractive for a range of applications that include material design and drug delivery due to the economic feasibility of synthesis.

Full text of DOI:10.1021/jacs.5b08815

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Communication
Developments in dynamic covalent chemistries
from the reaction of thiols with hexahydrotriazines
Rudy J. Wojtecki, Gavin O Jones, Alexander Y. Yuen, Willy Chin, Dylan J. Boday,
Alshakim Nelson, Jeannette M Garcia, Yi Yan Yang, and James L Hedrick
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 27 Oct 2015
Downloaded from http://pubs.acs.org on October 27, 2015
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Developments in dynamic covalent chemistries from the reaction of
thiols with hexahydrotriazines
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Rudy J. Wojtecki,†* Gavin O. Jones,† Alexander Y. Yuen,† Willy Chin,‡ Dylan J. Boday,§ Alshakim
Nelson,† Jeannette M. García,† Yi Yan Yang‡ and James L. Hedrick†
†
IBM Almaden Research Center, 650 Harry Road, San Jose, CA 95120
‡ Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, #04-01, Singapore 138669
§ IBM Power Systems Hardware Development, Office 1A07 Building 045, Austin, TX 78758
Supporting Information
tion2k. Dynamic covalent chemistries are revolutionizing
ABSTRACT: Dynamic covalent chemistries have garnered
synthetic design strategies and the field of adaptive materi-
als.
significant attention for their potential to revolutionize tech-
nologies in the material fields (engineering, biomedical &
sensors) and synthetic design strategies as they provide ac-
cess to stimuli responsiveness and adaptive behaviors. How-
ever, only a limited number of molecular motifs have been
known to display this dynamic behavior under mild condi-
tions. Here, we identified a dynamic covalent motif – thio-
aminals – that is produced from the reaction of hexahy-
drotriazines (HTs) with thiols. Furthermore, we report on
the synthesis of a new family of step-growth polymers based
on this motif. The condensation efficiently proceeds to
quantitative yields within a short time frame and offers ver-
satility in functional group tolerance; thus, it can be exploit-
ed to synthesize both small molecule thioaminals as well as
high molecular weight polymers from the step-growth
polymerization of HTs with dithiols. Careful evaluation of
substituted HTs and organic thiols supported by DFT calcu-
lations led to a chemically diverse library of polymers based
on this motif. Finally, dynamic substitution reactions were
employed towards the facile preparation of functional oligo-
mers and macromolecules. This dynamic covalent motif is
particularly attractive for a range of applications that include
material design and drug delivery due to the economic feasi-
bility of synthesis.
There are, however, only a limited number of molecular
motifs known to undergo dynamic behavior under mild con-
ditions. For instance, literature reports have extensively de-
a
tailed the dynamic behaviors of acetals,3 alkoxyamines,3b
borate esters,3c-e Diels-Alder cycloadditions,3g disulfides,3h
hydrazones,3i imines,3j oximes,3k and olefins3l (metathesis).
While these have provided a very wide range of structural
variations, the number of these motifs has not grown signifi-
cantly with the surge in interest of this field, though addi-
tional motifs have been reported.4 In addition, dynamic cova-
lent chemistries generally require a catalyst to trigger dy-
namic behaviors. For instance, hydrozones require an acid
catalyst,5 disulfides will respond to redox conditions as well
as light and olefins a metathesis catalyst. There are few ex-
amples of catalyst free dynamic covalent motifs (Diels-Alder
cycloadditions and alkoxyamines but these have very specific
structural requirements). The discovery of dynamic covalent
motifs that offer catalyst free responses have significant ad-
vantages in applications where the addition of a catalyst may
not be tolerated such as the biomedical realm.
Described herein is a new family of step-growth polymers
from the facile transformation of hexahydrotriazines with
N
a.)
2
3
N
N
N
Dynamic covalent chemistries, where covalent bonds have
the ability to be reversibly broken and reformed under equi-
librium control, have attracted significant recent attention.1
Through the manipulation of this equilibrium one can en-
courage formation of a desired product, reform starting ma-
terials or exchange with additives to form new products.
These reversible motifs have been incorporated into macro-
molecules enabling them, in response to a stimuli, to reor-
ganize at the molecular-level which can translate to the mac-
roscopic scale in remarkable material properties that include
enhanced mechanical performance,2a-b self-healing,2c-g shape-
memory,2h-i modulated fluorescence2j and reversible gela-
H2S
N
N
N
+
+
H2N
H2N
1
S
S
N
N
N
N
SH
N
S
S
b.)
Scheme 1: (a) Reaction of hexahydrotriazine with hy-
drogen sulfide (top) and butane thiol (bottom). (b) Ex-
change reaction between thioaminals.
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dithiols under mild conditions to yield poly(thioaminal)s.
Evidently, the partial positive charge is better stabilized by
1
2
3
4
5
6
7
8
Interestingly, the thioaminal repeat unit of these polymers
was found to be a dynamic covalent motif that undergoes
exchange reactions through a chemical trigger, thiol addi-
tives, confirmed by both experiment and computation.
the neighbouring nitrogen atom than by sulfur leading to the
lower barrier for insertion of H2S into the C-N bond adjacent
to nitrogen atom. Since insertion of a third molecule of H2S
will always lead to neighbouring sulfur atoms interacting
with partial positive charge in the transition state, it is un-
surprising that the free energy barrier for trithiane formation
is large and that the reaction exclusively favours formation of
the disubstituted product under mild conditions. Reactions
of HTs with alkanethiols will also lead exclusively to the for-
mation of bis-substituted products. However, in contrast to
reactions of HTs with H2S, those involving alkanethiols are
more likely to proceed via a different mechanism involving
protonation and insertion by a single molecule of the al-
kanethiol because of steric effects (Fig. S5). Despite the dif-
ferent mechanisms, the exclusive formation of a disubstitut-
ed product in quantitative yields lends support to the utiliza-
tion of this transformation as a polymer forming process.
Initial attempts at the polymerization of 1 and 11 (1,6-
hexanedithiol) at 25°C in N-methyl-2-pyrrolidone (NMP)
only resulted in oligomer formation – no high molecular
weight polymer was formed. The reaction mechanism sug-
gests that small molecule amine byproducts are generated
during the thioaminal formation which could in turn affect
the reaction equilibrium and thereby prevent the formation
of high molecular weight polymer. In the case of 1 the amine
generated (3) is a high boiling point material (BP = 262°C)
that would be difficult to remove from the reaction by con-
ventional means, such as vacuum. Therefore a methyl-HT
(10) was selected for it’s ability to form a low boiling point
amine (BP= 22 °C) that could be removed by vacuum. The
change in substituents also affected the reactivity of this
monomer towards thiols. Model studies of 10 showed little
conversion with 1-butanethiol at room temperature, higher
temperatures (85°C) were found necessary to facilitate a reac-
tion with thiols. For the polymerization reaction the com-
ponents 10 and 11 were miscible liquids with boiling points
higher than these reaction conditions (162°C and 242°C, re-
spectively). Therefore, subsequent reactions were simply
carried out in bulk without the need for solvent. However, it
was found that application of vacuum to the reactions involv-
ing 10 can lead to changes in the ratio of monomers. There-
1,3,5-hexahydro-1,3,5-triazines (HTs) have found recent
materials applications in healable gels, thermosetting high-
modulus materials as well as use in the detection of heavy
metals.6 One particularly unique reaction of HTs involves the
formation of dithioazines from hydrogen sulfide (Scheme 1).7
From our investigations this transformation was found to be
quantitative under mild conditions (25°C) and inspired us to
expand on the range of sulfur containing substrates that
would undergo similar reactions (Fig. S1, S2)31. We extended
the scope of this transformation by investigating the reaction
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1
between 1-butane thiol and 1 following the reaction with H-
NMR (Fig. S3). Gratifyingly, this reaction proceeds to the
dithioaminal also in quantitative yields, though the reaction
requires longer time for full conversion (reaction is com-
plete after ca. 80 mins. vs. 30 mins. for dithiazine)(Scheme 1).
To obtain a more comprehensive understanding of these
transformations, computational studies with the dispersion-
corrected B3LYP-D3 method were employed to investigate
mechanisms involved in dithioazine formation in the reac-
tion of Me-HT with H2S (Fig. 1). It is intriguing that the reac-
tion of between HT and H2S does not result in the formation
of trithioazine, in which all of the amino groups were re-
placed by sulphur, but instead stops after formation of dithi-
oazine. The mechanism for the reaction between H2S and
Me-HT involve the opening of the HT ring concurrent with
the insertion of thiol into the ring-opened heterocycle (see
SI).8 Calculations indicate that dithioazine formation is fa-
5
6
4
8
7
9
1a
11
12
10
Figure 1: Computed mechanism for insertion of H2S into
the heterocyclic ring of 3,5-dimethyl-1,3,5-thiodiazine (a)
adjacent to sulfur (top) adjacent to nitrogen (bottom).
Relative free energies are shown below each structure.
20000
18000
16000
14000
12000
10000
8000
6000
4000
2000
0
1.3:1
2:1
voured over trithiane formation due to the fact that the free
energy barrier for dithiazine formation is 19 kcal/mol, almost
27 kcal/mol lower than that for formation of trithiane (see SI
for details). This preference for dithioazine formation may be
simply understood considering the relative free energy barri-
er for insertion of H2S into the C-N bond adjacent to the sul-
fur atom in 5 is 39 kcal/mol, which is 29 kcal/mol larger than
the barrier for formation of the regioisomeric product by the
insertion of H2S into the C-N bond adjacent to the other ni-
trogen atom in 8. This large difference can be simply under-
stood by considering that a partial positive charge develops
on the breaking carbon atoms next to the sulfur or nitrogen
atoms in the transition states for these reactions (Fig. S4).
1:1
Triazine : Dithiol
Vacuum
Applied
0
5
10
15
20
25
30
35
40
45
Time (hrs)
Figure 2: scheme of polymerization method and graph of
molecular weight as a function of time for varying ratios
of hexahydrotriazines to 1,6-hexane dithiol. Data points
are connected for clarity.
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fore, the polymerization was carried out in two steps to re-
jority of weight loss (95-20 wt. %) occurred between 220°C
1
2
3
4
5
6
7
8
duce the degree to which the stoichiometry changes during
this reaction. The first involved the reaction of 10 and 11 in a
sealed vessel over the course of 18 hrs at 85°C, this was in-
tended as a means to oligomerize components and was fol-
lowed by the application of a continuous vacuum to remove
the volatile side-product. After the first step of this proce-
dure (18 hrs) as anticipated, low molecular weight oligomers
were observed by GPC (Fig. 2). When a vacuum was then
applied the molecular weight dramatically increased from
oligomers (Mn < 1000 g mol-1) to 9,000 g mol-1 (Fig. 2). The
molecular weight was observed to continually increase and
plateau after ca. 7 hrs at a Mn of 17,600 g mol-1 and further
increased to 19,800 g mol-1 with an additional 23 hrs of ap-
plied vacuum at 85°C. Beyond 28 hrs; however, the molecu-
lar weight was observed to decrease after 46 hrs. Even with
an oligomerization step changes in stoichiometry were still
observed. Cold trapping of the species removed by vacuum
confirmed the removal of monomer as well as the presence
of a small molecule amine (Fig. S9)
The chemical diversity of this polymerization was explored
using a variety of HT monomers prepared and purified ac-
cording to previously reported literature procedures.9 10 The
size of the HT substituent X was systematically varied and its
effect on the generation of polymer explored (Fig. 3a). From
the variety of HT monomers employed it was observed that
the size of the HT substituent influenced the maximum mo-
lecular weight of the resulting polymer, where larger substit-
uents resulted in lower molecular weights (Fig. 3b). The
smallest methyl substituted HT produced a polymer with Mw
of 19.8 kDa while the cyclohexyl substituted HT only pro-
duced a polymer with an Mw of 5.2 kDa. And the use of 1 did
not result in polymer formation. This effect is related to the
volatility of the byproduct amine generated during reaction.
As the mass of substituent X increases the volatility of the
small-molecule by-product of the reaction is reduced, there-
by making the polymerization increasingly difficult to drive
to high molecular weights. It was also observed that as the
size of the substituent X increased the glass transition tem-
perature of the resulting polymer to decreased from -59.1°C
in polymer 1a to -64.3°C in polymer 1b. No obvious trend in
thermal stability was observed with the variety of monomers
utilized, most of the polymers were experienced weight loss
at ca. 150°C and proceeded to 5 wt. % at ca. 220°C. The ma-
and 300°C (Fig. S10).
Polymers were also prepared using a range of dithiol mon-
omers. As this component does not generate a by-product
that is subsequently removed, the volatility of the monomer
is not a consideration. Therefore, monomers of varying
lengths (up to low molecular weight polymer dithiols) and
bearing different chemical functionalities were employed
(Fig. 3a). It was observed, through the dithiol monomers
utilized, that what appeared to limit the final polymer mo-
lecular weight was the glass transition temperature (Tg) of
the resulting polymer. As Tg increases the molecular weight
of the polymer generated decreased. As one may anticipate a
kinetically controlled process under these conditions.
DSC measurements of these polymers revealed no obvious
trend when varying the HT monomer, though a significant
difference in the thermal transitions of linear aliphatics (HT
R= a,b,c) compared with the cyclohexyl HT substituent ca. -
30°C vs. -47°C, respectively. The series of dithiol monomers
used lead to large variations in these thermal transitions (All
DSC data available, see SI).
The structural similarity between thioaminals and known
chemically responsive dynamic covalent moieties (e.g. hemi-
aminals & imines) motivated investigations as to whether
this motif is also dynamic covalent. It was surmised that if
the material is a chemically responsive structurally dynamic
polymer the presence of a monofunctional thiol should com-
pletely depolymerize the polymer and result only in oligo-
mer. Furthermore, because the equilibrium of a dynamic
process can be readily manipulated if the monofunctional-
ized thiol is sufficiently volatile the polymer should, in prin-
ciple, be able to be regenerated by its removal. The depoly-
merization was carried out with polymer 1a (Mw 17,985 g mol-
1) in the presence of a large excess of a monofunctional 1-
butanethiol. After heating this mixture for 1 hr at 40°C a
GPC trace revealed complete depolymerization. Only low
molecular weight oligomers were observed (Fig 4). A result
consistent with a polymer that becomes dynamic under the
appropriate chemical trigger. The mixture was then heated at
80°C under vacuum over a period of 18 hrs to remove the
small molecule 1-butanethiol. Gratifyingly, high molecular
weight polymer could be regenerated and GPC of this mate-
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120
a
c
(16.4k g mol-1)
Mw
Mn
PDI Tg(°C)
η
100
80
60
40
20
0
b
a
(g mol-1) (g mol-1)
(Pa · S)‡
c
1a 19,800
1b 17,100
8,100
9,000
4,900
2,900
<1,500
2,500
7,500
2.4 -59.1
1.9 -64.3
1.8 -64.5
1.8 -25.8
107.1
297.0
7.8
X=
R=
a
(18k g mol-1)
b
1c 8,700
1d 5,200
1e* <2,000
2a 3,800
3a 15,000
115.9
--
b
(~1k g mol-1)
--
--
1.5 50.8
2.0 -44.4
--
46.8
4a 35,600
20,700
1.7 -50.5† --
‡ measured at 20°C
† MDSC also indicatesTc at 46.4°C
* High retention times, approximation
15
20
25
30
35
Retention Time (minutes)
Figure 4: Polymer 1a (18k, GPC trace a) can be depoly-
merized with excess of 1-butanethiol (GPC trace b).
Removal of 1-butanethiol with vacuum repolymerizes the
small molecules to produce a molecular weight similar to
the starting polymer 1a (GPC trace c).
Figure 3: (a) Chemical compositions of poly(thioether)s
prepared. Mw of PEG dithiol (4) 3,400 g mol-1 (b) molecu-
lar weight values, thermal and physical properties of
associated poly(thioether)s.
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rial displays an Mw of 16,382 g mol-1. In comparison to the
range of chemically diverse polymers can be produced by this
1
2
3
4
5
6
7
8
original polymer regeneration recovered 91% of the original
molecular weight. This result indicates the thioaminal link-
age is a chemically responsive dynamic covalent bond; this is
a useful which provides access to the facile incorporation of
thiol-containing molecules such as therapeutics.
strategy that is limited primarily by the volatility of the
amine generated during polymer formation. Furthermore,
the thioaminal linkage is dynamic covalent triggered by thi-
ols. This provided access to polymers that can be depolymer-
ized, repolymerized and to the facile preparation of func-
tional oligomers. The ability to undergo exchange reactions
is particularly suited for applications in the facile preparation
of drug conjugates and as a loading strategy.
The dynamic covalent character of these poly(thioaminals)
was further explored in the preparation of functional oligo-
mers using thiol containing end-capping agents. This was
carried out using a mixture of polymer 1a (Mw=8,768 g mol-1)
in a CHCl3 solution together with 2 mol. % 4-mercapto-
phenol. The combination of these two followed by one hour
reaction time at 40°C resulted in a decrease in the total mo-
lecular weight of the polymer (Fig. 5). The end-capping reac-
tionwas further confirmed by 1H-NMR by the diagnostic peak
l, which corresponds with the formation of a thioaminal
bond between the aromatic thiophenol and polymer 1a (Fig.
5). GPC traces of polymer 1a before and after functionaliza-
tion are consistent with endgroup functionalization where
the molecular weight of the starting polymer (Mn=8.8k g
mol-1) is significantly reduced to Mn=1.9k g mol-1 after reac-
tion with thiophenol (Fig. S11). This method of preparing
9
ASSOCIATED CONTENT
Supporting Information
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The supporting information is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*rjwojtec@us.ibm.com
ACKNOWLEDGMENTS
functional oligomers was tolerant to
–NH2, -OH and –
This work was funded by IBM Almaden Research Center and
the Institute of Bioengineering and Nanotechnology (Bio-
medical Research Council, Agency for Science, Technology
and Research, Singapore).
COOH functional groups, which can be used as handles for
further chemical transformations (Fig. 13).
The dynamic behavior of the thioaminal bond was trig-
gered by a chemical stimulus, a thiol additive, and accelerat-
ed by increases in temperature. The stability of a water solu-
ble poly(thioaminal) was studied in water. Stirring polymer
4a at 25°C in water and found to degrade over the course of
90hrs (Fig. S38) indicating the thioaminal linkeage is suscep-
tible to hydrolysis.
One application for poly(thioamimnal) may include the
preparation of therapeutic polymer conjugates. In principle,
this would simply require mixture of a thiol-containing ther-
apeutic with the desired poly(thioaminal) and mild heating.
This was explored with water soluble PEG based 4a and a
doxorubicin (DOX) derivative bearing a thiol group that was
prepared by a literature procedure.11 After addition of the two
components in a water/acetonitrile mixture at elevated tem-
peratures (80°C) a sawtooth like pattern was observed by
GPC believed to relate to DOX attachement to integer num-
bers of the PEG repeat unit (Mn 3400 gmol-1) (See SI for full
characterization).
Notes
The authors declare no competing financial interests.
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We presented a new polymer forming reaction between
hexahydrotriazines and dithiols carried out in solvent free
reaction conditions to produce poly(thioaminals). A broad
HS R S
N
S
R
S H
n
Mn = 8768 g mol=1
CHCl3, 40oC
HO
SH
m
HO
S
S
R
N n
S
N
S R
S
OH
I
n
g
h
Mn = 1941 g mol=1
R=
n
I
g
h
CHCl3
Figure 5: (a) Polymer 1a can be readily functionalized
through the addition of thiophenol. Chemical shift l is
indicative of this functionalization. Scale in ppm.
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