Byproducts formed During Thiol-Acrylate Reactions Promoted by Nucleophilic Aprotic Amines: Persistent or Reactive?

Article abstract of DOI:10.1002/cplu.202000590

The nucleophile-initiated mechanism of thiol-Michael reactions naturally leads to the formation of undesired nucleophile byproducts. Three aza-Michael compounds representing nucleophile byproducts of thiol-acrylate reactions initiated by 4-dimethylaminopyridine (DMAP), 1-methylimidazole (MIM), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) have been synthesized and their reactivity in the presence of thiolate has been investigated. Spectroscopic analysis shows that each nucleophile byproduct reacts with thiolate to produce a desired thiol-acrylate product along with liberated aprotic amines DMAP, MIM, or DBU, thus demonstrating that these byproducts are reactive rather than persistent. Density functional theoretical computations support experimental observations and predict that a β-elimination mechanism is favored for converting each nucleophile byproduct into a desired thiol-acrylate product, though an S_N2 process can be competitive (i. e. within <2.5 kcal/mol) in less polar solvents.

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Byproducts formed During Thiol-Acrylate Reactions
Promoted by Nucleophilic Aprotic Amines: Persistent or
Reactive?
Vasileios Drogkaris and Brian H. Northrop*[a]
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The nucleophile-initiated mechanism of thiol-Michael reactions
naturally leads to the formation of undesired nucleophile
byproducts. Three aza-Michael compounds representing nucle-
ophile byproducts of thiol-acrylate reactions initiated by 4-
dimethylaminopyridine (DMAP), 1-methylimidazole (MIM), and
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) have been synthesized
and their reactivity in the presence of thiolate has been
investigated. Spectroscopic analysis shows that each nucleo-
phile byproduct reacts with thiolate to produce a desired thiol-
acrylate product along with liberated aprotic amines DMAP,
MIM, or DBU, thus demonstrating that these byproducts are
reactive rather than persistent. Density functional theoretical
computations support experimental observations and predict
that a β-elimination mechanism is favored for converting each
nucleophile byproduct into a desired thiol-acrylate product,
though an SN2 process can be competitive (i.e. within
<2.5 kcal/mol) in less polar solvents.
Introduction
Thiol-Michael reactions have been of significant interest over
the past decade,[1] in large part because they exhibit the
characteristics of “click” chemistry:[2] e.g. high yields, broad
substrate scope and solvent tolerance, little to no byproduct
formation, rapid kinetics, tolerance of oxygen, and straightfor-
ward purification. The desirable characteristics of thiol-Michael
reactions have enabled these transformations to become an
indispensable tool for a wide variety of applications such as the
synthesis of polymers,[3] dendrimers,[4] cross-linked and shape
memory networks,[5] hydrogels,[6] and vesicles[7] as well as for
bioconjugation[8] and the functionalization of surfaces.[9] The
mechanism of thiol-Michael reactions has been thoroughly
investigated both experimentally[10] and computationally.[11] The
two most prominent means of carrying out thiol-Michael
reactions are by using either catalytic base or a nucleophile
initiator.[1,10a,b] The base-catalyzed mechanism includes the
deprotonation of the thiol by the base (Scheme 1, blue), which
generates a thiolate that can in turn add to an activated double
bond. The nucleophile-initiated mechanism proceeds via the
nucleophilic addition of the initiator to a double bond creating
a zwitterionic intermediate. This intermediate can deprotonate
the thiol (Scheme 1, yellow) and thus initiate the thiol-Michael
reaction. The selection of the initiator and the solvent dictates
the mechanism that will generate the thiolate needed for entry
into the catalytic anionic cycle of the addition mechanism
(Scheme 1, green). For example, phosphines, when used as
Scheme 1. Representation of the two most prominent means of forming
catalytic thiolate along both nucleophile (yellow) and base (blue) pathways,
each providing entry to the catalytic anionic cycle (green) that leads to thiol-
Michael product formation. The nucleophile initiated pathway also results in
the formation of nucleophile byproducts, some of which are persistent while
others can be reactive depending on the nucleophile used.
initiators, are known to proceed through the nucleophilic
mechanism.[10a–b,d,11c–e] On the other hand, many amines can
initiate the reaction through a base-catalyzed mechanism, a
nucleophile-based mechanism or
a combination of both
mechanisms.[10a,c,11d] When amines are used, the nucleophilic
pathway produces aza-Michael adducts which can negatively
impact the reaction yields and complicate the purification of
the products. There is evidence that suggests that even strongly
basic amines, such as DBU,[10a] do not rely solely on the base-
catalyzed mechanism. It is therefore important to investigate
the degree to which the aza-Michael intermediates might
impact the product formation.
[a] V. Drogkaris, Prof. B. H. Northrop
Department of Chemistry
Wesleyan University
52 Lawn Avenue, Middletown, CT 06459, USA
E-mail: bnorthrop@wesleyan.edu
Early reports[1b,10a–b,e,11d–e] cautioned against the use of high
loading of nucleophile initiators in order to limit the formation
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cplu.202000590
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of undesired nucleophile byproducts (Scheme 1). To evaluate
the likelihood of forming undesired nucleophile byproducts we
have previously investigated[12] the thiol-methyl acrylate reac-
tion initiated by dimethylphenylphosphine (DMPP), hexylamine
(HA), and diethylamine (DEA). These three initiators are known
to promote the reaction predominantly via the nucleophilic
pathway, therefore model systems of the thiol-methyl acrylate
reaction were studied and the formation of initiator nucleophile
byproduct was monitored. Minimal byproduct was detected by
1H NMR spectroscopy, with byproduct formation accounting for
a maximum of 4% of the crude mixture even when using up to
a tenfold molar equivalent of the initiator. Nitrogen-centered
compounds DEA and HA were observed to form undesired aza-
Michael byproducts, however only in trace amounts (<4%) and
only when present in large excess (e.g. 10 equiv) relative to
thiol and methyl acrylate reactants. The choice of solvent also
played a role in aza-Michael byproduct formation, with greater
amounts of byproduct observed in less polar solvents. It is
important to note, however, that no quantifiable amounts of
aza-Michael byproducts could be observed when the amine-
promoted thiol-methyl acrylate reactions were carried out using
more commonly employed amounts of amine initiator, e.g. 1–
10 mol%. Interestingly, no phosphonium ester byproducts
could be detected by NMR spectroscopy when reactions were
initiated by DMPP, regardless of initiator loading or solvent
polarity. Experimental and computational studies[12] involving a
model phosphonium ester byproduct revealed that the lack of
any observable amount byproduct can be attributed to an
elimination-addition pathway that takes place in the presence
of thiolate, resulting in the formation of the desired thiol-
Michael product. Aza-Michael byproducts resulting from nitro-
gen-centered nucleophiles DEA and HA are not able to follow a
similar pathway and, therefore, can persist as undesired by-
products.
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Figure 1. Chemical structures of (a) the nitrogen-centered nucleophiles
DMAP, MIM, and DBU investigated in this study and (b) undesired
nucleophile byproducts 1–3 that can form when thiol-methyl acrylate
reactions are initiated by DMAP, MIM, and DBU, respectively. DABCO has
also been investigated, however no nucleophile byproduct containing
DABCO could be synthesized.
byproducts can be converted into desired thiol-methyl acrylate
adducts in the presence of thiolate. Computational modeling in
both polar (DMSO) and nonpolar (CHCl3) solvents is used to
explore the reaction pathways available for model compounds
1–3 to react with methane thiolate in an effort to determine
which pathway is the most favorable for each nucleophile in
each solvent type. Combined experimental and computational
results provide a thorough picture of how these charged aza-
Michael nucleophile byproducts are converted to desired thiol-
Michael adducts in the presence of thiolate. The results provide
a more complete understanding of the different roles that
different nitrogen-centered bases/nucleophiles can play when
promoting thiol-Michael reactions.
Herein we expand on previous work to include three aprotic Results and Discussion
amines – 4-dimethylaminopyridine (DMAP), 1-methylimidazole
(MIM), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
–
that are
Synthesis and spectroscopy
commonly used in thiol-Michael reactions and whose initiation
mechanism may include the nucleophilic pathway to some
degree (see Schemes S1–S4 of the Supporting Information for
the mechanism and calculated energetics of thiol-acrylate
additions initiated by DMAP, MIM, and DBU acting as
nucleophiles). Models of the aza-Michael adducts that can form
during nucleophilie initiation of thiol-acrylate reactions involv-
ing these aprotic amines have been synthesized (1–3, Figure 1).
It should be noted that attempts were made to include 1,4-
diazabicyclo[2.2.2]octane (DABCO) as a fourth aprotic amine in
this study. Despite extensive synthetic efforts, however, no
nucleophile byproduct of DABCO or related bicyclic amine
quinuclidine could be obtained.
Nucleophile byproducts 1–3 are charged quaternary spe-
cies, similar to the phosphonium ester DMPP byproduct. As
such it may be possible for quaternary aza-Michael byproducts
to be converted into desired thiol-Michael products in the
presence of thiolate along pathways similar to those inves-
tigated previously for phosphonium esters. Indeed experimental
investigations do show that each of these model nucleophile
The synthesis of model aza-Michael adducts 1–3 was carried
out along one of two similar pathways (Scheme 2). Model
byproduct 1 was prepared upon a reaction of DMAP with 3-
°
°
Scheme 2. Conditions: i) CH3CN, 80 C, ii) CH3OH, HBr, reflux, iii) THF, 0 C, iv)
acetone.
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bromopropionic acid followed by esterification under acidic
conditions, as shown in Scheme 2a. Byproducts 2 and 3 could
be prepared directly upon reaction of MIM or DBU with methyl
3-bromopropionate (Scheme 2b). The resulting ammonium salts
1–3 have exactly the same chemical structure as the nucleo-
phile byproducts that may be formed when the same nitrogen-
centered species are used to promote thiol-Michael reactions
involving methyl acrylate. The only difference between model
compounds 1–3 and those obtained during thiol-methyl
acrylate reactions is the counterion: model compounds 1–3 are
obtained as bromide salts whereas nucleophile byproducts
formed during thiol-methyl acrylate reactions exist as thiolate
salts as indicated in Scheme 1.
The model reaction summarized in Scheme 3 was designed
to test whether model byproducts 1–3 can be converted into
the desired thiol-Michael products. As noted above, for every
equivalent of adduct formed during the nucleophile-initiated
thiol-Michael reaction, one equivalent of thiolate is generated.
Stoichiometrically equal amounts of nucleophile byproduct and
thiolate are therefore expected to be present under normal
thiol-Michael conditions. In order to model these conditions
accurately, each of the aza-Michael adducts was reacted with an
equimolar amount of the sodium salt of methyl 3-mercaptopro-
pionate (M3MP-), under a nitrogen atmosphere in anhydrous
CDCl3. The thiolate was chosen with the aim that desired
product 4 is symmetric, resulting in a less convoluted NMR
spectrum of the crude reaction mixture. CDCl3 was chosen as
the solvent for this test reaction based on prior research12
showing a greater likelihood of nucleophile byproduct forma-
tion in less polar solvents.
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The DMAP byproduct 1 and its 1H NMR spectrum are shown
in Figure 2a. In the figure the proton signals for the DMAP and
the methyl propionate moiety are highlighted in red and blue,
respectively. Upon reacting byproduct 1 with the thiolate
M3MP-, large upfield shifts corresponding to the methylene
triplets can be observed, from 4.71 and 3.12 ppm in the
byproduct to 2.80 and 2.61 ppm in the crude spectrum of the
resulting product. A smaller but observable downfield shift is
also observed for the methyl ester singlet, from 3.65 ppm in
byproduct 1 to 3.68 ppm in the product. Residual DMAP can
also be seen in the crude mixture, however no detectable
amounts of DMAP byproduct 1 is observed spectroscopically.
The two triplets and the singlet at 3.68 ppm in the crude
spectrum match the signals of thiol-Michael product 4.[12] This
result indicates that residual thiolate present in DMAP-initiated
Figure 2. Partial 1H NMR spectra showing the conversion of nucleophile
byproducts 1, 2, and 3 into desired thiol-acrylate product 4 in the presence
of M3MP-. Signals corresponding to DMAP in 1 are highlighted in red in (a),
proton signals corresponding to MIM are highlighted in green in (b), and
those corresponding to DBU are highlighted in purple in (c). Dashed lines
indicate shifts of signals upon reaction with M3MP-.
thiol-acrylate reactions can indeed convert any undesired
nucleophile byproduct into desired thiol-acrylate products.
Similar spectroscopic results were obtained for reactions
involving MIM byproduct 2 and DBU byproduct 3 with thiolate
M3MP-. The spectrum of the MIM adduct is shown at the top of
Figure 2b, with the signals corresponding to the MIM moiety of
byproduct 2 highlighted green and the proton signals corre-
sponding to the methyl propionate moiety highlighted in blue.
The methylene signals of 2 appear as triplets at 4.69 and
3.10 ppm which, after reacting with M3MP-, shift upfield to 2.82
Scheme 3. Model reaction for investigating the potential consumption of
nucleophile byproducts by thiolate to give symmetric thiol-acrylate product
4. Thiolate M3MP- was prepared by treating methyl 3-mercapropropionate
with sodium hydride and then transferring the freshly prepared salt to
byproducts 1–3.
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and 2.63 ppm. The corresponding methyl ester singlet shifts
from 4.07 ppm in the byproduct to 3.70 ppm in the spectrum of
the crude mixture. As with DMAP, the undesired byproduct is
converted cleanly into thiol-acrylate product 4 while no trace of
residual 2 is observed. Spectroscopic support for the conversion
of DBU byproduct 3 into thiol-acrylate product 4 in the
presence of M3MP- is shown in Figure 2c. Diagnostic methylene
triplets of byproduct 3 are observed to shift from 3.99 and
2.85 ppm to 2.82 and 2.63 ppm upon reaction with the thiolate.
The methyl ester singlet in DBU byproduct 3 is not cleanly
resolved as it overlaps with other methylene signals of the DBU
moiety. Nonetheless, upon reaction with M3MP- the consump-
tion of byproduct 3 results in the observation of a well-resolved
methyl ester singlet of desired product 4 at 3.69 ppm.
Collectively, these experimental results constitute strong
evidence that charged aza-Michael byproducts 1–3 formed
during the initiation of thiol-acrylate reactions with DMAP, MIM,
and DBU can react with the available thiolate that exists in the
reaction mixture and yield desired thiol-acrylate products. In
order to gain further insights into the mechanistic details of
these reactions, the same model reactions were investigated
computationally.
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Scheme 4. Possible mechanisms for the conversion of nucleophile by-
products into desired thiol-Michael products include (a) direct SN2 displace-
ment by nucleophilic thiolate, (b) deprotonation by thiolate followed by
elimination of nitrogen-centered species and subsequent thiol-Michael
reaction, and (c) deprotonation by amine followed by elimination of the
nitrogen-centered species and subsequent thiol-Michael reaction.
Computational modeling
the initial nitrogen-centered nucleophile, (b) deprotonation of
the nucleophile byproduct by available thiolate followed by
elimination and thiol-Michael addition, and (c) deprotonation of
the byproduct by available base with subsequent elimination
and thiol-Michael addition. Given that the pKa values of the
four bases investigated range from approximately 7–12 it is
possible that the most favored mechanistic pathway might not
be the same for each of the byproducts 1–3, and it’s possible
that the most favored pathway in each case could be solvent-
dependent.
Computational investigations were also performed using
DABCO as the aprotic amine. Interestingly, a transition state
corresponding to nucleophilic attack of the acrylate π-bond by
DABCO could not be located despite extensive exploration of
the potential energy surface. This observation is noteworthy
given the fact that all experimental attempts to synthesize a
model nucleophile byproduct based on DABCO or related
analogue quinuclidine were unsuccessful. Given these exper-
imental and computational results it is reasonable to conclude
that DABCO does not follow a nucleophilic pathway in thiol-
acrylate reactions and is only capable of promoting such
additions by acting as a base.
The most straightforward mechanism to investigate, given
that it is a single step, is the direct SN2 displacement of the
nucleophile by thiolate attack at the β-carbon of the nucleo-
phile byproduct, as shown in Scheme 4a. Table 1 summarizes
the computational results for the nucleophilic attack of by-
products 1–3 resulting in the formation of thiol-Michael product
5 and nitrogen species DMAP, MIM, or DBU, respectively.
Results are provided in solvent models for CHCl3 and DMSO.
It is clear from the results in Table 1 that thiolate attack at
the β-carbon nucleophile byproducts 1–3 is thermodynamically
1H NMR results clearly demonstrate that model ammonium
nucleophile byproducts 1–3 react with the conjugate base of
methyl-3-mercaptopropionate to give thiol-Michael product 4.
Spectroscopic results do not, however, reveal the mechanism of
this transformation. Previous research[12] involving phospho-
rous-centered nucleophile DMPP explored two mechanistic
pathways that can convert undesired phosphonate ester by-
products into desired thiol-Michael products in the presence of
thiolate: (i) an SN2 displacement of DMPP from the
phosphonium ester byproduct, and (ii) an elimination followed
by addition pathway involving deprotonation of the
phosphonium ester by thiolate followed by elimination of
DMPP that also produces methyl acrylate, which can then
undergo a productive thiol-methyl acrylate reaction. Computa-
tional modeling in solvent models for CHCl3 and DMSO both
showed that the elimination followed by addition pathway is
favored over the SN2 pathway by 15.9–17.7 kcal/mol, depending
on the solvent.
A significant difference between prior investigations of
DMPP and the current work involving nitrogen-centered species
DMAP, MIM, and DBU is that each of the nitrogen-centered
species is able to act as both a nucleophile and as a base. The
basic nature of these species opens up an additional potential
mechanistic pathway that’s not available to DMPP, which is
non-basic. In particular, it is possible that ammonium nucleo-
phile byproducts 1–3 could be deprotonated by either thiolate
or by residual base (DMAP, MIM, and DBU) present in the
reaction mixture. The three reaction pathways that are capable
of converting byproducts 1–3 into thiol-Michael product 4 and
have been investigated computationally are summarized in
Scheme 4. These three pathways are: (a) SN2 displacement of
°
favored in both CHCl3 (À ΔG =28.1–38.2 kcal/mol) and DMSO
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Table 1. Relative free energies[a] calculated for the SN2 transition state and
fact, elimination of DBU following thiolate deprotonation of
nucleophile byproduct 3 is predicted to be endergonic by
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2
3
4
5
6
7
8
9
the resulting thiol-Michael and NR3 products.[b]
°
ΔG =0.4 kcal/mol in DMSO. By contrast, results in CHCl3 are all
Nucleophile
Byproduct
CHCl3
SN2 T.S.
DMSO
SN2 T.S.
Products
Products
exergonic by 19.0–29.0 kcal/mol. The difference in overall
reaction free energies can again be attributed to each solvent’s
ability to stabilize charged species versus neutral products. It is
interesting to note that the difference in overall reaction free
1
2
3
18.0
16.4
20.7
À 32.3
À 36.1
À 28.1
34.5
33.8
37.7
À 13.1
À 15.8
À 8.5
[a] Relative energies (ΔG , ΔG ) are given in kcal molÀ 1. [b] See Scheme 4a.
�
°
°
°
energies in CHCl3 versus DMSO (ΔG DMSO–ΔG CHCl3) is approx-
imately 20 kcal/mol for both the SN2 pathway (Scheme 4a) and
the thiolate deprotonation followed by elimination pathway
(Scheme 4b).
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°
(À ΔG =8.5–16.0 kcal/mol). Computational results therefore
While computations predict that overall reaction energetics
are quite different in the two solvents investigated, the rate-
determining step along the Scheme 4b pathway is predicted to
be the same for both solvents. Specifically, results in both CHCl3
and DMSO predict that the rate-determining step along the
Scheme 4b pathway is the initial deprotonation of nucleophile
byproducts 1–3 by thiolate. The one possible exception is
deprotonation of DBU byproduct 3 in DMSO, where the
deprotonation and elimination transition states are within
computational error of each other (ΔG� =22.5 vs 22.1 kcal/mol,
respectively). It is also worth noting that rate-determining steps
along the Scheme 4b pathway are lower in CHCl3 than DMSO
by approximately 6.0–8.6 kcal/mol. Computational results sug-
gest that, in CHCl3, deprotonation of nucleophile byproducts 1–
3 is rather facile (ΔG� �16.4 kcal/mol) and leads to rapid
elimination to give products thiol, methyl acrylate, and
eliminated nucleophile.
Finally, Table 3 summarizes computational results for the
pathway summarized in Scheme 4c, which involves deprotona-
tion of nucleophile byproducts 1–3 by their respective nitrogen
species, followed by elimination similar to Scheme 4b (as
indicated by the pathways converging). Three key conclusions
can be drawn from the data summarized in Table 3. First and
foremost, computational investigations predict that none of the
deprotonation followed by elimination pathways shown in
Scheme 4c are thermodynamically favored in either solvent
indicate there is a strong thermodynamic driving force for the
conversion of a thiolate/nucleophile byproduct salt into desired
thiol-Michael product and starting nucleophile by the SN2
mechanism. Computations also indicate that the SN2 reaction is
significantly more exergonic in CHCl3 than in DMSO on account
of the fact that starting materials, i.e. thiolate and nucleophile
byproducts 1–3, are charged species while the products of the
reaction, i.e. 5 and nitrogen species, are neutral. Relative to
neutral products, the charged reactants are destabilized to a
greater extent in less polar solvents such as CHCl3 than in more
polar solvents such as DMSO.
Transition state Gibbs free energies (ΔG�) for the SN2
reaction are also found to be significantly lower in CHCl3 than in
DMSO. This result may also be expected on account of each
solvent’s ability to stabilize the separate charges of the
reactants versus the net-neutral SN2 transition state. The lower
transition state free energies in CHCl3 are also in line with the
Hammond postulate given the greater exergonicity of the
reaction in the less polar solvent and indicate an earlier, more
reactant-like transition state. Comparisons of reaction ener-
getics in different solvents are important given that it is
possible different solvents may favor different pathways for
converting nucleophile byproducts into desired thiol-Michael
products.
Table 2 provides a summary of the reaction energetics for
deprotonation of the nucleophile byproduct by available
thiolate followed by elimination and thiol-Michael addition
(Scheme 4b). Overall reaction energetics are again predicted to
be more favorable in CHCl3 than DMSO for the thiolate
deprotonation followed by nucleophile elimination pathway. In
°
model. Overall reaction free energies are endergonic by ΔG =
°
3.4–11.0 kcal/mol in CHCl3 and by ΔG =2.2–9.4 kcal/mol in
DMSO. Second, in each solvent, transition state free energies for
the deprotonation of nucleophile byproducts 1–3 by their
respective nitrogen-centered base trend with the pKa of that
Table 2. Relative free energies[a] calculated for the reaction pathway
summarized in Scheme 4b.
Table 3. Relative free energies[a] calculated for the reaction pathway that
begins with deprotonation of byproducts 1–4 by nitrogen-centered bases,
as summarized in Scheme 4c.
Nucleophile
Byproduct
Thiolate
Deprotonation
Zwitterion
Intermediate
Elimination
T.S.
Products
Nucleophile Base
Zwitterion
Intermediate T.S.
Elimination
Products
Byproduct
Deprotonation
T.S.
T.S.
1 (CHCl3)
2 (CHCl3)
3 (CHCl3)
1 (DMSO)
2 (DMSO)
3 (DMSO)
16.4
14.0
13.9
22.4
22.5
22.5
À 0.5
À 1.6
1.5
15.9
16.0
17.3
1.4
2.1
2.6
18.8
19.4
22.1
À 23.2
À 27.0
À 19.0
À 4.3
À 7.0
0.4
1 (CHCl3)
2 (CHCl3)
3 (CHCl3)
1 (DMSO)
2 (DMSO)
3 (DMSO)
24.9
27.7
17.9
25.7
29.0
19.3
23.1
27.3
17.7
25.6
28.8
19.1
33.3
38.6
26.5
30.3
35.8
23.9
9.2
11.0
3.4
7.2
9.4
2.2
[a] Energies (ΔG , ΔG ) are given in kcal molÀ 1 and are relative to reactants
for each pathway. A graphical plot of the reaction energetics in both
solvents is provided in the Supporting Information.
[a] Energies (ΔG , ΔG ) are given in kcal molÀ 1 and are relative to reactants
for each pathway. A graphical plot of the reaction energetics in both
solvents is provided in the Supporting Information.
�
�
°
°
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residual base. For example, deprotonation of byproduct 3 by
DBU is predicted to have the lowest transition state Gibbs free
energy (ΔG� =17.9 and 19.3 kcal/mol in CHCl3 and DMSO,
respectively) while deprotonation of byproduct 2 by MIM is
predicted to have the highest transition state Gibbs free energy
(ΔG� =27.7 and 29.0 kcal/mol in CHCl3 and DMSO, respectively).
This observation highlights the greater variability in the
behavior of nitrogen-centered compounds when used to
promote thiol-Michael reactions relative to phosphorus-cen-
tered nucleophiles, which are non-basic and do not follow a
pathway analogous to that shown in Scheme 4c.[10a–b,11c–e,12]
Third, in both CHCl3 and DMSO, the rate-determining step
along the Scheme 4c pathway is predicted to be nucleophile
elimination. This is in contrast to the Scheme 4b pathway,
where deprotonation of nucleophile byproducts by thiolate was
the rate-determining step. Similarly, relative to reactants in each
case, the formation of a protonated ammonium and zwitterion
intermediate along pathway Scheme 4c is predicted to be less
energetically favorable than the formation of the same
zwitterion and thiol along pathway Scheme 4b. This difference
in rate-determining step and the energetic difference of
zwitterion formation along the two pathways is not attributed
to the relative pKa values of the nitrogen-centered species
versus that of methyl mercaptan. After all, the pKa of methyl
mercaptan (~10.4) lies approximately in the middle of the
range spanned by DMAP, MIM, and DBU (7–12). Instead the
difference is likely a reflection of the greater separation of
charge that occurs along the pathway shown in Scheme 4c
versus that in Scheme 4b. Deprotonation of the nucleophile
byproduct by its neutral nitrogen-centered base incurs the
energetic penalty of forming a zwitterion and formally positive
ammonium species. By contrast, deprotonation of the by-
product by thiolate along pathway Scheme 4b involves a
consolidation of charge as the ammonium byproduct reacts
with a negatively charged thiolate to produce the same
zwitterion and a neutral thiol.
model is DMSO. Comparing the DMSO results in Tables 1 and 2
reveals that the rate-determining step of the thiolate deproto-
nation pathway is predicted to be more favorable than the SN2
pathway by 11.3–15.2 kcal/mol. In a less polar solvent such as
CHCl3, however, the Gibbs free energy differences between the
thiolate deprotonation and the SN2 pathways are notably
smaller. In the case of DMAP nucleophile byproduct 1, for
example, the rate-determining step along the thiolate deproto-
nation pathway has a Gibbs free energy barrier of 16.4 kcal/mol
while the Gibbs free energy barrier for SN2 displacement is
18.0 kcal/mol. This predicted difference of only 1.4 kcal/mol
suggests that in CHCl3 the thiolate deprotonation and SN2
displacement pathways are likely competitive, with the thiolate
deprotonation pathway being followed approximately 91% of
the time and the SN2 pathway accounting for the other 9% at
298 K.[13] For the MIM nucleophile byproduct 2 the difference
between the two pathways is 2.4 kcal/mol, again in favor of the
thiolate deprotonation pathway. This difference in calculated
Gibbs free energy barriers is slightly larger than in the case of
DMAP, however it may still be possible for the SN2 pathway to
compete with thiolate deprotonation (approximately 1.7%
versus 98.3% at 298 K) during the conversion of byproduct 2
into desired thiol-Michael product.[13] Considering DBU nucleo-
phile byproduct 3, however, the difference between the thiolate
deprotonation and SN2 pathways grows to a calculated 6.8 kcal/
mol. Computations therefore indicate that the conversion of
nucleophile byproduct 3 into desired thiol-Michael product is
predicted to follow the thiolate deprotonation pathway in less
polar solvents such as CHCl3 and the SN2 pathway will not be
competitive. Figure 3 provides a summary of these insights
provided from computational investigations along with the
calculated structures of rate-determining step transition state
geometries for each byproduct in both solvent models.
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Conclusion
Overall, computational results suggest that the deprotona-
tion followed by elimination pathway involving thiolate as a
base (Scheme 4b) is, in general, energetically preferred over the
pathway involving nitrogen species as bases (Scheme 4c). The
one possible exception to this observation centers on con-
version of DBU byproduct 3 into thiol-acrylate product 5 in
DMSO, where the rate-determining steps along the Scheme 4b
pathway (22.5 kcal/mol) is only 1.4 kcal/mol more favorable
than along the Scheme 4c pathway (23.9 kcal/mol). Computa-
tional results therefore predict that, in DMSO, deprotonation of
DBU byproduct 3 by residual DBU may be competitive with
deprotonation of 3 by thiolate. In all other cases investigated
deprotonation by residual thiolate is predicted to be more
favored by �7.9 kcal/mol.
Model systems representing nucleophile byproducts that can
be formed during thiol-acrylate reactions initiated by DMAP,
MIM, or DBU have been synthesized and their reactivity with
methyl 3-mercaptoproprionate has been investigated experi-
mentally as well as computationally. Spectroscopic studies
reveal that each unwanted nucleophile byproduct reacts
completely with the methyl 3-mercaptoproprionate to give a
desired thiol-acrylate product and a liberated aprotic amine
base (DMAP, MIM, or DBU). These model reactions indicate that
concerns regarding the accumulation of unwanted nucleophile
byproducts during thiol-Michael reactions promoted by aprotic
amines are unwarranted. The results also highlight key differ-
ences between using aprotic amines to promote thiol-Michael
reactions versus using protic amines, e.g. diethylamine, hexyl-
amine. Specifically, protic amines are able to undergo aza-
Michael reactions and result in unwanted nucleophile by-
products that are persistent, whereas aza-Michael byproducts
formed from aprotic amines are reactive species that are
converted into desired thiol-Michael products in the presence
of residual thiolate. Computational modeling supports exper-
While computational results predict that pathway Sche-
me 4b is generally more favorable than pathway Scheme 4c in
both solvents modeled, comparisons of the thiolate deprotona-
tion followed by nucleophile elimination pathway and the
direct SN2 pathway are found to have greater solvent depend-
ency. Computational modeling shows a clear preference for the
thiolate deprotonation pathway (Scheme 4b) when the solvent
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chased from Chem-Impex International. All chemicals were used as
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received. Deuterated solvents were purchased from Cambridge
Isotope Laboratories. Reagent-grade solvents were dried using an
Innovative Technologies SPS-400-5 solvent purification system.
Reactions were carried out under an inert atmosphere of N2(g)
unless otherwise noted. Thin layer chromatography (TLC) was
carried out on aluminum-backed sheets coated with silica gel 60
with fluorescent indicator F254. Visualization of TLC plates was
performed using a UV/vis lamp and/or by staining with I2(s) or p-
1
anisaldehyde solution. All H and 13C NMR spectra were recorded
on a Varian Mercury (300 and 75 MHz, respectively) or Varian Unity
(500 and 125 MHz, respectively) spectrometer using residual solvent
as the internal standard. All chemical shifts are reported using the δ
scale. All coupling constants are reported in Hertz (Hz). High-
resolution ESI mass spectrometric analysis was performed at the
University of Illinois, Urbana-Champaign Mass Spec Facility.
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Synthesis and Characterization
1: To a solution of 4-dimethylaminopyridine (0.88 g, 7.2 mmol) in
acetonitrile (20 mL), 3-bromopropionic acid (0.74 mL, 7.2 mmol)
was added under an inert atmosphere and the reaction was stirred
°
at 80 C overnight. The solution was then allowed to cool down to
Figure 3. Structures of rate-determining step transition state geometries for
the reaction of methane thiolate with DMAP nucleophile byproduct 1 (a),
MIM nucleophile byproduct 2 (b), and DBU nucleophile byproduct 3 (c) as
obtained from computational modeling. Dashed lines indicate bonds being
broken/formed, with bond distances provided in angstroms. Transition state
Gibbs free energies relative to starting reactants are provided in kcal/mol.
While thiolate deprotonation is the major pathway for the three nucleophile
byproducts in both solvents investigated, the SN2 pathway provides an
alternative, minor pathway for byproducts 1 and 2 in less polar solvents
such as CHCl3.
room temperature. A precipitate was formed and was washed with
acetonitrile and diethyl ether. The precipitate was then dissolved in
methanol (15 mL), a small amount of concentrated HBr was added,
and the solution was refluxed overnight. The solvent was then
removed under reduced pressure and the desired dimeth-
ylaminopyridinium byproduct was precipitated from a mixture of
DCM and EtOAc as a white solid (1.3 g, 62%). Melting point: 166–
+
°
168 C. TOF MS ES (m/z) [M] calculated for C11H17N2O2, 209.1290,
found 209.1293. 1H NMR (CDCl3, 300 MHz): δ ppm 8.70 (d, 2H), 6.89
(d, 2H), 4.71 (t, 2H), 3.65 (s, 3H), 3.25 (s, 6H), 3.12 (t, 2H); 13C NMR
(CDCl3, 125 MHz):δ ppm 171.49, 156.38, 143.40, 107.81, 53.38,
52.23, 40.43, 35.05.
imental observations in that the conversion of nucleophile
byproducts into thiol-acrylate products and recovered aprotic
amines is predicted to be exergonic in all cases. Mechanistic
analysis reveals that the most favored mechanism for the
conversion involves deprotonation of the nucleophile byprod-
uct by thiolate followed by elimination of the aprotic amine
and a subsequent thiol-acrylate reaction. There are, however,
subtle differences between the different aprotic amines and
their reactivity in polar (DMSO) versus less polar (CHCl3) solvents
that enable alternative pathways to be competitive in some
cases. In particular, while thiolate deprotonation is predicted to
be preferred, an alternative SN2 pathway may be competitive in
less polar solvents. Overall the cumulative results provide
further evidence that researchers who would like to take
advantage of the many valuable attributes of thiol-Michael
reactions can initiate these useful transformations with aprotic
amines without needing to worry about the accumulation of
undesired aza-Michael nucleophile byproducts.
2: A solution of 1-methylimidazole (148 mg, 1.8 mmol) in THF
°
(10 mL) was cooled down to 0 C under an inert atmosphere and
methyl 3-bromopropionate (0.196 mL, 1.8 mmol) was added. The
reaction mixture was allowed to warm up to room temperature
slowly and stir for 3 hours. The resulting precipitate formed was
removed by filtration and washed with diethyl ether. The solvent of
the filtrate was removed under reduced pressure and the product
was purified by column chromatography on silica gel using a
gradient starting with acetone and increasing to 9:1 acetone:
methanol. The desired methylimidazolium byproduct was isolated
as a colorless liquid (200 mg, 45%). TOF MS ES (m/z) [M]+
1
calculated for C8H13N2O2, 169.0977, found 169.0978. H NMR (CDCl3,
300 MHz):δ ppm 10.34 (s, 1H), 7.57 (m, 1H), 7.30 (s, 1H), 4.69 (t,
2H), 4.05 (s, 3H), 3.69 (s, 3H), 3.10 (t, 2H); 13C NMR (CDCl3,
125 MHz):δ ppm 171.00, 137.74, 123.22, 123.16, 52.35, 45.41, 36.86,
34.65.
3: To a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene ( 5.48 g,
36 mmol) in acetonitrile (50 mL), methyl 3-bromopropionate
(3.9 mL, 36 mmol) was added slowly and the mixture was heated to
reflux overnight. The solvent was removed under reduced pressure
and the product was purified by column chromatography on silica
gel using a gradient starting with 1% methanol in DCM and
increasing to 5% methanol in DCM. The desired diazabicyclounde-
cene byproduct was isolated as a colorless liquid (52 mg, <1%).
Note that the yield of nucleophile byproduct 3 was especially low
because the addition of DBU and methyl 3-bromopropionate
results in the predominant E2 elimination of bromine to give methyl
acrylate. The same E2 reaction occurs during the synthesis of 1 and
2, however it is especially pronounced in the presence of DBU.
Despite this complication, a sufficient quantity of the model DBU
Experimental Section
Materials and Reagents
4-Dimethylaminopyridine was purchased from Oakwood Chemical.
1-Methylimidazole was purchased from Sigma Aldrich. 1,8-Diazabi-
cyclo[5.4.0]undec-7-ene and methyl-3-mercapto-propionate were
purchased from Acros Organics. Methyl 3-bromopropionate was
purchased from Combi-Blocks. 3-Bromopropionic acid was pur-
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byproduct 3 was obtained to enable the current study. TOF MS ES
Acknowledgements
1
2
3
4
5
1
(m/z) [M]+ calculated for C13H23N2O2, 239.1760, found 239.1756. H
NMR (CDCl3, 300 MHz): δ ppm 3.99 (t, 2H), 3.76 (m, 7H), 3.70 (t, 2H),
3.06 (d, 2H), 2.85 (t, 2H), 2.20 (m, 2H), 1.84 (m, 6H); 13C NMR (CDCl3,
125 MHz):δ ppm 171.08, 167.63, 55.87, 52.25, 49.67, 49.64, 47.36,
33.09, 29.27, 28.52, 25.97, 23.02, 20.15.
The authors gratefully acknowledge financial support from the
National Science Foundation CAREER program (award CHE-
1352239) and from Wesleyan University.
6
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General procedure for byproduct reactions with thiolate. Sodium
hydride was added to a round-bottom flask under inert atmosphere
followed by the addition of anhydrous CDCl3. The solution was
Conflict of Interest
°
cooled down to 0 C using an ice bath and methyl 3-mercaptopro-
pionate was added to the NaH solution dropwise. The mixture was
The authors declare no conflict of interest.
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°
allowed to stir for 2 h at 0 C. An equimolar amount of the aza-
Michael nucleophile byproduct (1–3) was added to a separate
round-bottom flask under inert atmosphere. A minimal amount of
dry CDCl3 was added, and the resulting solution was taken up by
Keywords: click chemistry
· density functional theory ·
nucleophiles · reaction mechanisms · thiol-Michael reactions
°
syringe and transferred dropwise to the NaH mixture at 0 C. The
combined reaction was stirred and allowed to warm to room
temperature overnight. The reaction mixture was passed through a
short pad of Celite, concentrated under reduced pressure, and
dried further under high vacuum. The residue was diluted with
CDCl3 and analyzed by 1H NMR spectroscopy.
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The quantities used for thiolate reactions with nucleophile by-
products 1–3 were as follows: DMAP nucleophile byproduct 1
(28.9 mg, 0.1 mmol) was mixed with sodium hydride (60%
dispersion in oil) (4.0 mg, 0.1 mmol) and methyl 3-mercaptopropio-
nate (11 μL, 0.1 mmol). MIM nucleophile byproduct 2 (24.9 mg,
0.1 mmol) was mixed with sodium hydride (60% dispersion in oil)
(4.0 mg, 0.1 mmol) and methyl 3-mercaptopropionate (11 μL,
0.1 mmol). DBU nucleophile byproduct 3 (42.7 mg, 0.13 mmol) was
mixed with sodium hydride (60% dispersion in oil) (5.4 mg,
0.13 mmol) and methyl 3-mercaptopropionate (15 μL, 0.13 mmol).
Each reaction resulted in the formation of symmetric thiodipropio-
nate 4.
Computational Modeling
Computational investigations were performed using the Gaussian16
suite of programs.[14] Structures of stationary points along each
reaction mechanism were each subjected to a conformational
search by scanning all freely rotating torsional angles at the B3LYP/
6-31G(d)[15] level to locate approximate global energy minimum
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breakage/formation. Each approximate transition state geometry
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single imaginary vibrational frequency, whereas all minima had
only real vibrational frequencies. Prior computational modeling of
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shown that geometry optimization at the B3LYP/6-31+G(d) level
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functional[16] with a large basis set provides reaction energetics that
agree well with CBS-QB3 benchmarks. Reaction and transition state
enthalpies and free energies reported herein were therefore
calculated at the M06-2x/6-311+G(2d,p)//B3LYP/6-31+G(d) level.
Reaction energetics were obtained at 298.15 K, 1.0 atm pressure,
and in a PCM model[17] of CHCl3 and DMSO solvents.
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[13] The direct SN2 displacement by thiolate (Scheme 2) is a single step
process while deprotonation by thiolate followed by elimination
(Scheme 2; is a two-step mechanism where the first step (deprotona-
tion) is rate-determining. Transition state theory therefore predicts that
the difference in likelihood of following these two pathways will be
proportional to the difference in relative Gibbs free energy of the two
competitive transition states.
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Manuscript received: August 20, 2020
Revised manuscript received: October 28, 2020
ChemPlusChem 2020, 85, 2466–2474
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