Developing benign syntheses using ion pairsviasolvent-free mechanochemistry

Article abstract of DOI:10.1039/d0gc01116a

Solvent-free mechanochemical conditions have been developed to investigate the significance of ion pairing and the use of weak bases for driving forward nucleophilic substitution reactions. This approach takes advantage of the lack of solvent shells to in

Full text of DOI:10.1039/d0gc01116a

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DOI: 10.1039/D0GC01116A
Journal Name
ARTICLE
Developing benign syntheses using ion pairs via solvent-free
mechanochemistry
Lianna N. Ortiz-Trankina, Jazmine Crain, Carl Williams III, and James Mack*a
Received 00th January 20xx,
Accepted 00th January 20xx
Solvent-free mechanochemical conditions has been developed to investigate the significance of ion pairing and the use of
weak bases for driving forward nucleophilic substitution reactions. This approach takes advantage of the lack of a solvent
shells to incorporate weaker and safer bases to drive reactions to completion through specific ion pairing pathways. The
most efficient reactions contained larger and more polarizable cation and anion pairs.
DOI: 10.1039/x0xx00000x
www.rsc.org/
significantly reducing the impact the solvent has on the
environment. Second, due to the lack of solvent, there would
be no solvation energy that would need to be overcome,
allowing for a greater reactivity of the reagents than is observed
Introduction
Acid-base and nucleophilic substitution reactions are some of
the most fundamental reactions in organic chemistry. Although
these reactions are very reliable in the generation of new
bonds, they often employ reagents and conditions that are
hazardous and harmful to the environment and human health.
Alkyl lithium, amides and hydrides are some of the most widely
used bases in organic synthesis; however, these reagents are
extremely hazardous and have been the subject of numerous
in solution. This would in turn allow bases and nucleophiles to
be stronger under mechanochemical conditions than solution
2
6
allowing for the ability to generate safer reaction conditions.
This allows the mechanochemist to choose less hazardous
reagents while getting similar results in solution. To test this
thought, we compared the deprotonation and subsequent
nucleophilic addition of phenols and alcohols to various
electrophiles to determine whether mechanochemical
conditions would allow for the use of safer nucleophilic
substitution reactions than conducted solution.
1
-4
incidents with some resulting in death.
We envisioned the
use of solvent-free mechanochemistry as a way to suppress the
use of these dangerous chemicals and substitute them for more
benign reagents while achieving the desired products. Although
the use of mechanochemistry has been most recognized for the
ability to limit the use of harmful solvents and auxiliaries,
inherently safer conditions have been demonstrated through
Results and Discussion
5
-16
mechanochemical conditions as well.
One of our goals for this project was to determine how far
In addition to the environmental impact of a solvent, we can take benign bases for effective use in deprotonation of
solvation also suppresses the reactivity of a reagent by certain acids. Since various carbonates have been shown to be
stabilizing it. This solvation energy needs to be overcome if a suitable bases for phenol deprotonation in solution, the
1
7-26
reagent is going to react in a particular reaction.
Traditionally organic chemists try to navigate this by the select interactions were the first studied variables.
interaction between the phenoxide and the various alkali metal
2
7-30
Metal
use of one solvent over another (e.g. non-polar, polar protic, phenoxides were synthesized to perform as nucleophiles to
polar aprotic). There is a delicate balance that must be substitute various benzyl halides, as shown in Scheme 1. (M=
considered when choosing a solvent for this type of reaction, alkali metal, X=halogen)
however the environmental effects of the solvent or safety of
the reagents is often not one of them. Under solvent-free
mechanochemical conditions we envisioned two benefits in the
creation of more sustainable reactions of this type. First, the
reaction would be conducted under solvent free conditions,
R
OH
X
2 3
M CO
+
O
+
M
X
+
MHCO3
R
16 h
1
Scheme 1. Typical reaction scheme for the nucleophilic
substitution of phenol towards various benzyl halides.
a. Department of Chemistry
University of Cincinnati
4
04 Crosley Tower, Cincinnati, Ohio (USA)
E-mail: james.mack@uc.edu
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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We believe there are two crucial interactions that drive this Table 1. Percent conversion and yield of the phenol and
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DOI: 10.1039/D0GC01116A
solventless reaction, both of which focus on the metal cation of carbonate reaction.
the base (i.e. “M”). The first is the metal-oxygen interaction (i.e.
R
OH
“M—O” interaction) of the carbonate, where the weaker the
X
2
M CO3
+
O
+
M
X
+
MHCO3
ionic bond, the more likely it will want to coordinate with the
halogen. The second is the metal-halogen interaction (i.e. the
R
16 h
“
M—X” interaction), where the stronger the “M—X” ion pair,
R
X
M
Li
conversion (%)
Yield (%)a
Entry
the stronger the coordination to the alkyl halide. If “M—X” ion
pair is strong and the “M—O” ion pair is weak, the proposed
intermediate is expected to form, followed by a break down to
the subsequent bicarbonate base, a metal-halogen salt, and the
1
2
Cl
Cl
Cl
Cl
3
3
Na
28
10
3
4
5
Cl
Cl
Cl
Cl
Cl
Cl
K
47
62
75
44
54
72
1
Rb
Cs
desired product. The reactions were tracked by both H NMR
and GC-MS to confirm product formation. Percent conversion
and yield are shown in Table 1. We attempted to use
bicarbonates as a base source, but those reactions gave poor
yields. This suggests at least one equivalent of carbonate is
needed for the reaction to give appreciable yield of product.
Under mechanochemical conditions, there is a distinct trend
with the alkali metals and halogens that have a large effect on
the efficiency of the reaction. The trend for both the percent
conversion and percent yield tend to increase as the alkali metal
and halogen became larger and more polarizable in size. We
observed similar results in the solventless Wittig reaction. As
can be seen in Table 1, the most effective reaction was with
caesium carbonate and 4-bromobenzyl iodide showing that the
larger ion interaction of caesium-iodide is the most favourable
for the substitution with phenoxides. When caesium carbonate
is used as the base, we observed 75-94% conversion to the
ether product, suggesting caesium carbonate is a much stronger
base and/or caesium phenoxide is a much stronger nucleophile
under mechanochemical conditions. The trend declines to
having little to no ether product with lithium carbonate as the
base. Given the strength of the lithium-oxygen bond and the
weak bond strength of lithium and bromine, the proposed
intermediate should not be stable and thus no ether product is
produced. Instead we noticed a small amount of electrophilic
aromatic substitution products which have been shown to occur
when phenol is reacted directly with benzyl bromide in
solution.32
6
7
Br
Br
Br
Br
Li
<2
43
<2
38
Na
8
9
Br
Br
Br
Br
K
69
79
45
60
Rb
1
0
1
Br
Br
Br
I
Cs
Li
87
<2
74
<2
1
12
13
14
Br
Br
Br
I
I
I
Na
K
55
77
83
49
68
78
3
1
Rb
15
Br
I
Cs
94
89
a
Isolated yields
Upon further investigation, the ortho and para substituted
electrophilic aromatic products were observed in most of the
reactions as seen in Table 2. The ratio of products always
favoured ortho, which also increased in percent conversion as
the metal ion sized decreased. This demonstrates that the
smaller the metal ion, the stronger it pairs with the oxygen of
the carbonate and the less it will participate in the nucleophilic
substitution reaction. Lithium carbonate was observed to be a
weak base, producing only electrophilic aromatic substitution
products, where potassium, rubidium and caesium carbonate
produced smaller amounts of the aromatic substitution and
more of the nucleophilic substitution. Using Pearson’s Hard
3
3
34
Soft Acid Base and Jones-Dole theories, it is suggestable that
there should be strong overlap between lithium and oxygen
making for a more stable pair, and little overlap between
caesium and oxygen making this a less stable pair. This would
suggest that the more stable lithium carbonate would be less
reactive and give lower product yields than caesium carbonate,
which is consistent with our data. In solution all reagents gave
similar conversions and yields, suggesting this enhancement is
unique to solvent-free conditions.
Furthermore, it
demonstrates the fact that the solvation negates the ability to
create destabilized ion pairs due to the solvation of the
nucleophiles.
Table 2. Electrophilic aromatic substitution ortho:para product
4
| J. Name., 2012, 00, 1-3
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ratios and percent conversions with 4-bromobenzyl bromide Table 3. Pearson hardness rating and Jones-Dole Viscosity B
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coefficient
DOI: 10.1039/D0GC01116A
and different metal carbonates.
OH
OH
Br
2
M CO
ion
Li
HSAB Theory
Hard
Jones-Dole Viscosity B
Ionic radius (Å)
0.68
3
+
+
Br
16 h
Br
HO
Br
0.150
0.086
2
2a
Na
Hard
0.98
Entry
M
conversion (2)
conversion (2a)
K
Hard
-0.007
-0.030
1.33
1.48
1
2
Li
22
14
3
7
Na
Rb
Borderline
3
4
5
K
8
6
2
3
3
0
Cs
Cl
Soft
-0.045
-0.007
1.67
1.81
Rb
Cs
Hard
Br
I
Borderline
Soft
-0.032
-0.068
1.96
2.19
These results can be both qualitatively and quantitatively be
justified using Hard Soft Acid Base Theoryand/or the Jones-Dole In order to further demonstrate the ability to increase the
Viscosity B coefficients (Table 3). For both theories, ions that reactivity of bases and nucleophiles under mechanochemical
have similar B coefficients (Jones-Dole) and have similar conditions, we reacted carbonates with a benzyl alcohol instead
hardness or softness (Pearson) tend to be better paired of phenol (Scheme 2). In solution carbonates are strong enough
together. This trend is illustrated with the favourability of the bases to deprotonate phenols, however they are not as
ion pairing of the larger ions of caesium, iodide and bromide. effective at deprotonating alcohols. Typically, much stronger,
We can also use the ionic radius as a reference to understand harsher reagents such as sodium hydride are used for that
3
8, 39
the crystal structures of the MX salts in solid state and the purpose.
potential overlap of certain ion pairs.
Given our success using caesium carbonate, we
3
5
wanted to determine if it could be used to successful
In order to determine if our results are unique to para- deprotonate alcohols, our results are in Table 4. Due to
substituted benzyl halides, we replaced the para-substituted availability, ease of use, and relative small effect halogens had
bromobenzyl halides for ortho and meta-substituted on the reaction, 4-bromobenzyl bromide was the only alkyl
bromobenzyl halides. We noticed the same trend with these halide used for further studies.
experiments, whereby Li
Cs CO
producing 80-92% conversion to product. Because of Scheme 2. Typical reaction scheme for the nucleophilic
these results, we do not believe the halide on the aromatic ring substitution of 4-bromobenzyl alcohol towards various benzyl
2 3
CO producing little to no product and
2
3
has much effect on the overall reaction.
halides.
We propose the reaction to go through a Zimmerman-
Traxler type model, where a six-membered transition state can
OH
+
Br
+
Br
M CO3
2
3
6, 37
O
M
X
+
MHCO3
be formed(Figure 1).
These pathways are well known in
Br
16 h
organic synthesis and our results support at least a similar
pathway.
3
O
M
X
O
O
R
M
O
C
H
H
2
Figure 1. A proposed Zimmerman-Traxler reaction mechanism
of solventless nucleophilic reaction under mechanochemical
conditions.
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Table 4. Comparison of 1 mmol and 2 mmol of carbonate base which gave poor results for lithium carbonate, gave 52%
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DOI: 10.1039/D0GC01116A
used in substitution reaction
conversion to product when lithium hydroxide was used as the
base. However, when caesium hydroxide was used the reaction
gave quantitative conversion and produced the highest yield.
These results show that similar to solution, hydroxide acts as a
stronger base/nucleophile than carbonates, however unlike
solution, we can increase the reactivity of reagent through the
use of proper pairing under mechanochemical conditions.
OH
Br
+
Br
2
M CO3
+
O
M
X
+
MHCO3
Br
16 h
3
equivalents of base
Yield (%)a
Entry
M
1
2
Li
1
1
5
8
Na
Table 5. Percent conversion and yield of substitution of 4-
bromobenzyl bromide and 4-bromobenzyl alcohol
with different metal hydroxides.
3
4
5
K
1
1
1
13
34
54
Rb
Cs
6
7
Li
2
2
5
8
OH
Br
Br
MOH
16 h
Na
+
O
+
M X
Br
8
9
K
2
2
2
55
76
94
3
Rb
Cs
Entry
M
conversion (%)
Yield(%)
36
10
1
2
Li
52
84
a
Isolated yields
Na
64
3
4
K
91
99
80
88
The efficiency of the carbonate’s deprotonation was measured
based on conversion and yield of the 4-bromobenzyl ether
product. A similar trend to the phenol experiments was shown
with the percent conversion and yield increasing as the alkali
metal size increased. While this trend was similar, the success
of deprotonation had decreased by approximately 20 percent
with 1 equivalent of carbonate. Experiments with lithium
carbonate and sodium carbonate again revealed not as much
product, suggesting increased reactivity of caesium carbonate
over sodium and lithium carbonates.
Cs
Conclusions
In conclusion, we have determined the lack of solvent stabilization
affords the opportunity to use safer reagents than what could
typically be used in solution. This creates an overall safer reaction
pathway while still affording high yields of products. The most
reactive bases were observed when there was little overlap
between the ions according to either the Pearson or the Dole-Jones
scale. With respect to nucleophilic reactions, we observed in
addition to the nucleophile having little overlap between the ions,
the metal of the nucleophile needed to have strong overlap with
To see if we could increase the reactivity of carbonates with the
benzyl alcohol, we increased to 2 equivalents of carbonates. We
noticed a significant increase in both percent yield and
conversion for all the metal cations except for lithium and
sodium. Again, we believe this is due to the strong attraction the leaving group of the electrophile. Finally, we were able to
these metals have with the oxygen of the carbonate. We develop more environmentally benign conditions under
propose a similar 6-membered transition state to the phenol mechanochemical conditions than can be observed in solution.
reactions where the metal-oxygen and the metal-bromide
reactions are important to the production of product. We
believe increasing the equivalents of carbonate, increases the
Acknowledgements
number of interactions between the alcohol and halide, thus We are thankful for financial support for this research from the
increasing the amount of product.
National Science Foundation, CHE-1465110 and CHE- 1900097.
We also express gratitude for the support from the
Since we observed the efficiency of carbonates as bases, we Undergraduate Student Research Fellowship, University of
wanted to continue to explore the use of safer bases and Cincinnati University Research Council. Lastly, we are very
determine their effectiveness under mechanochemical appreciative of Ronald Hudepohl’s (University of Cincinnati
conditions. Although hydroxides are slightly more hazardous machine shop) assistance in making the vials used in this work.
than carbonates, they are widely used at various levels of
chemistry and are easily handled by undergraduate chemists.
We began these experiments with the benzyl alcohol as the Notes and references
acid, but used 1 mmol of hydroxides in place of carbonates.
Unlike the case with carbonates, all the hydroxides produced 1.
significant yields of the desired ether (Table 5). Even lithium,
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