Diastereoselective liquid assisted grinding: 'Cracking' functional resins to advance chromatography-free synthesis

Article abstract of DOI:10.1039/c2gc35669d

As regulations that restrict the use of organic solvents become more stringent, ball milling remains an attractive substitute for traditional organic synthesis. However, the mechanochemistry community does not have a purification pathway to complement the solvent-free, ball milling process. Functional resins have proven to be powerful synthetic tools that simplify purification, but traditional handling of these resins restricts their utility, as hazardous organic solvents are needed to swell the resin. Ball milling the functional resin exposes the functional groups as a function of surface area. This report details the use of ball milling and functional resins to perform an environmentally attractive version of the Wittig reaction.

Full text of DOI:10.1039/c2gc35669d

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Diastereoselective liquid assisted grinding: ‘Cracking’ functional resins
to advance chromatography-free synthesis
William C. Shearouse and James Mack*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
As regulations that restrict the use of organic solvents become more stringent, ball milling remains an
attractive substitute for traditional organic synthesis. However, the mechanochemistry community does
not have a purification pathway to complement the solvent-free, ball milling process. Functional resins
have proven to be powerful synthetic tools that simplify purification, but traditional handling of these
resins restricts their utility, as hazardous organic solvents are needed to swell the resin. Ball milling the
functional resin exposes the functional groups as a function of surface area. This report details the use of
ball milling and functional resins to perform an environmentally attractive version of the Wittig reaction.
1
0
Introduction
the resin such that the functional groups can be accessed through
1
8
diffusion within the pores of the polymer. As a result, SPOS
reactions are limited by the rate of diffusion, leading to extended
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Ball milling is gaining popularity in organic synthesis for the
potential it has shown to make reactions more environmentally
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reactions times. Green solvents, such as ethyl acetate and ethanol,
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friendly through the reduction of solvents. In a ball-milled
reaction, reagents are pulverized into small particles such that a
chemical reaction can occur between them. The majority of ball-
milled reactions require column chromatography or some other
purification technique to isolate their products. While green
solvents can be used for chromatographic separations, hazardous,
19,20
do not swell functional resins
. Given the amount of hazardous
organic solvent waste produced, functional resins are rarely used
21
for large-scale synthetic reactions. We believed the ease of
purification that functional resins have shown in solution would
complement ball milling conditions well. We investigated a ball
milled Wittig reaction that utilized triphenylphosphine-
functionalized polystyrene.
6
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non-polar solvents are often required to achieve separation.
We recently developed a chromatography-free method to isolate
the products of a ball milled, Horner-Wadsworth-Emmons
The Wittig reaction is notorious for the difficulties it presents
when separating the desired olefin product from the primary by-
product of the reaction, triphenylphosphine oxide. The Wittig
reaction has been previously studied under ball milling conditions
1
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reaction. This process eliminated the use of undesired solvents
at the reaction and purification stages. Although we were
successful, the chemistry was specific to the reaction. In order to
maximize the benefits a ball milling reaction presents, the ball
milling community needs a solvent-free purification technique, or
at the very least, a method that allows the user to choose a green
organic solvent.
22
by Pecharsky and co-workers , who isolated their products using
column chromatography. Additionally, there have been several
reports on the Wittig reaction using functional resins in
23-27
solution.
Further it has been shown that the
triphenylphosphine oxide functional resin can be recycled and re-
Merrifield resins are well known for their ability to facilitate
solid phase peptide synthesis (SPPS).
27,28
used.
If functional resins are going to be viable purification
1
1-13
Through a series of
tools for ball-milled reactions, we thought the Wittig reaction
would be a good initial reaction to investigate. To the best of our
knowledge, this is the first reported use of functional resins and
ball milling together.
protection and deprotection steps, peptides with desired
sequences can be formed using chromatography-free, facile
purification techniques, e.g. filtration. Following this model, solid
phase organic synthesis (SPOS), has been gaining popularity and
expanding with the development of functional resins that possess
1
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Results and Discussion
similar reactivity as their non-supported counterparts. As a
result, functional resins have seen an increase in their commercial
availability over the last decade.
Our initial task was to examine the effect ball milling had on the
functional resin. We theorized that instead of swelling the resin,
One of the drawbacks of functional resins is that only a small 75 the functional portions could be accessed through increasing the
1
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portion of the resin’s functionality is accessible on the surface.
surface area of the resin; more specifically, grinding the resin into
smaller particle sizes. sample of triphenylphosphine-
1
7
Consequently, functional resins require the use of hazardous
A
solvents such as benzene, toluene, or dichloromethane to swell
functionalized polystyrene was ball milled for one hour and the
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do not swell the functional resin. Consequently, they are not used
resulting powder was analyzed using a high magnification digital
microscope (Figure 1).
when functional resins are employed in synthetic processes. For
this comparison we used 5 mL of ethanol as the solvent and
conducted the reaction over a two-hour period. Through using
Before being ball milled, the functional resin particle size
consistently measured between 75-125 microns (Figure 1, a).
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5
Following ball milling, the functional resin particles (FRPs) 35 ethanol, any enhancement seen between the FRPs and normal
measured approximately 1-5 microns (Figure 1, b). At smaller
particle sizes, we expected the resin to have greater functionality.
To test whether the FRPs had greater functionality than the
functionalized resin, we compared the reactivity of the FRPs
resin could only be attributed to ball milling, and not resin
swelling. Using the functionalized resin, we observed only a 13%
yield to the product stilbene (Table 1, entry 1). By comparison,
using the FRPs we observed a 56% yield to the product stilbene
1
against the functionalized resin using solution-based conditions, 40 (Table 1, entry 2). As a control, we were interested in how well
where ethanol was used as the solvent in the synthesis of stilbene
Table 1).
the FRPs performed compared to the reagent, triphenylphosphine.
As expected, the triphenylphosphine performed best, however
byproducts remained in the product mixture (Table 1, entry 3). If
swelling played a major role in the reaction, both the FRPs and
(
Figure 1 Digital microscope images of triphenylphosphine-
1
functionalized polystyrene before ball milling (a) and following 45 the functionalized resin would yield similar, poor results due to
one hour of ball milling with a 5 mm milling ball at 18 Hz (b).
Images were taken using a Keyance VHX-S50 digital microscope
with a VH-220R lens.
the fact that ethanol is a non-swelling solvent. Since the FRPs
significantly outperformed the functionalized resin in ethanol,
further credence is given to the theory that swelling is less
important when using ball milled FRPs. Through using ball
milling, we have essentially created ‘filterable reagents’.
Ultimately, we wanted to use functional resins in a solvent-
free, ball milled reaction, whereby FRPs would be created in situ.
When we used triphenylphosphine-functionalized polystyrene in
the solvent-free, ball milled synthesis of stilbene, only 17% of the
aldehyde was converted to olefin in a sixteen-hour period (Table
5
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0
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2
, entry 1).
Table 2 Solvent-assisted ball milling synthesis of stilbene using
potassium carbonate (2.00 equiv.), triphenylphosphine-
functionalized polystyrene (1.75 equiv.), benzyl bromide (1.50
equiv.), benzaldehyde (1.00 equiv.) and 1 mL of the indicated
[a]
1
solvent. Percent yields and E:Z ratios were analyzed using H-
NMR spectroscopy integration.
2
0
Table 1 Comparative study of functional resins versus FRPs in
[a]
the solution-based synthesis of stilbene. Percent yields and E:Z
1
ratios were analyzed using H-NMR spectroscopy integration.
Traditionally, non-polar, organic solvents such as benzene or
dichloromethane were utilized to swell functional resins, allowing
reagents to diffuse through the cross-linked, functional portions
of the resin. Although these solvents are a good choice for
swelling the resin, they are not environmentally desirable. Polar
solvents, such as ethyl acetate and ethanol are much more
desirable from an environmental perspective, but these solvents
2
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Considering that the majority of the material used in the reaction
consisted of inert polystyrene from the FRPs, the low yield
observed in the solvent-free ball milled reaction can be attributed
to the lack of interaction between the benzyl bromide and the
triphenylphosphine on the FRPs. Liquid assisted grinding (LAG)
has shown to significantly increase the reaction rates of sluggish,
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mechanically driven processes.
We investigated a series of
This presentation allows for greater interaction between the
FRPs, base, and aldehyde, resulting in greater reactivity.
solvents for our LAG experiments in an attempt to improve the
interaction between the FRPs and the other reagents. At the
conclusion of these reactions, we were able to filter off the FRPs,
Conversely, in
a non-polar environment, the polystyrene
backbone is exposed, shielding the polar triphenylphosphonium
5
which separated the covalently attached triphenylphosphine 40 bromide functions (Figure 2). In this conformation, the base and
oxide. These reactions showed that even at much smaller particle
sizes, the FRPs could still be separated using filtration, allowing
the olefin product to be isolated without the need for column
chromatography. To our surprise ethyl acetate and ethanol (Table
aldehyde
have
decreased
interaction
with
the
triphenylphosphonium bromide, resulting in longer reaction times
and reduced yields.
Another interesting result we observed in our LAG
1
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2
2
3
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0
5
0
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2, entries 2-5) significantly enhanced the reaction over 45 experiments was the change in diastereoselectivity of the reaction
traditionally used non-polar, ‘swelling’ solvents (Table 2, entries depending on the reaction ‘solvent’. In solution, semi-stabilized
-9). This suggested that under LAG conditions, the added
solvent’ was not swelling the FRPs, as non-swelling ‘solvents’
outperformed traditional swelling ‘solvents’.
4
1,42
8
ylides are Z-selective
while under ball milling conditions they
2
2
‘
are E-selective. Under our LAG experiments, ethyl acetate, n-
hexane, toluene, and solvent-free conditions were E-selective,
Instead of swelling the FRPs, we believe they undergo 50 while dichloromethane, ethanol and isopropanol were Z-selective.
conformational changes that depend on the polarity of the
surrounding ‘solvent’ environment. Polymer coatings and brushes
have shown to reptate and ‘present’ their polar regions depending
Initially, we believe diastereoselectivity is tunable depending on
the dielectric constant of the solvent; however, more
experimentation is needed to fully understand this unique
phenomenon.
3
8-40
on their solvent system.
We believe similar chemistry is
taking place in this instance, where the ability to ‘present’
functional groups comes as a result of being ball milled. The
cross-linked, spherical network of the non-milled functional resin
restricts its ability to change its conformation, where as the
disturbed network in the FRPs allows for greater degrees of
55
We investigated the scope of the reaction and determined our
optimized reaction conditions were applicable to a wide variety
of substrates (Scheme 1). Stabilized ylides provided E-
diastereoselectivity, while semi-stabilized ylides gave a (roughly)
50:50 mixture of E- and Z- diastereomers. Yamataka and co-
4
3
freedom. The first step in the Wittig reaction is the attack of the 60 workers demonstrated that electron-withdrawing substitutions
triphenylphosphine on the halide, resulting in the formation of the
phosphonium salt. The phosphonium salt needs to be accessible
to the base and aldehyde for the subsequent Wittig reaction to
on the aldehyde favor Z-selectivity whereas electron-donating
substitutions favor E-selectivity. Our LAG conditions showed no
electronic effect on diastereoselectivity as anisaldehyde and p-
nitrobenzaldehyde showed E:Z ratios of 50:50 and 51:49
take
place.
In
a
polar
environment,
the
polar
triphenylphosphonium bromide functions on the FRPs are 65 respectively. Further, when we used 2-napthaldehyde in the
exposed, whereby the non-polar polystyrene backbone is shielded reaction, we achieved the same diastereoselectivity as reported by
Figure 2).
2
2
(
Balema and Percharksy . Conversely, when we used p-
bromobenzaldehyde, a 47:53 E:Z ratio of products was observed,
comparable to previous semi-stabilized reactions, but not
70 Balema’s findings. These results suggest that diastereoselectivity
under our LAG conditions is not only dependent on the solvent
environment, but also the interaction the reagents participating in
the reaction have with the polystyrene backbone of the functional
resin. We are in the process of conducting more experiments to
Figure 2 FRPs are generated in the ball mill and depending on
the surrounding solvent, adopt different conformations, affecting
the accessibility of triphenylphosphonium bromide functions.
75
better understand these results.
Conclusions
When used together, ball milling and functional resins effectively
carry out organic reactions. Ball milling significantly reduces
organic solvent use while the use of functional resins allows for
the isolation of products in a chromatography-free manner. We
have shown that reactivity and reaction rate are strongly
dependent on the reaction environment under LAG conditions,
where ethanol provided optimal yields and faster reaction times
than traditional functional resin solvents. We observed a change
in diastereoselectivity as a function of the polarity of the milling
environment, and that electronic-effects have little influence on
the diastereoselectivity of the reaction. We are currently
investigating other ball milling opportunities that utilize
functional resins with the goal of finding new synthetic outcomes
that are not attainable under traditional, solution-based methods.
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Scheme 1 Substrate study of LAG ball milling synthesis of stilbene with various aldehydes. Ethyl bromoacetate derivatives were ball
milled for one hour. Benzyl bromide derivatives were ball milled for two hours. Yields reported are isolated yields. E:Z ratios given were
1
determined using H-NMR spectroscopy integration.
This research is supported by the National Science Foundation;
5
Experimental
25 grant number CHE-1058627, and the University of Cincinnati
Research Counsel (URC).
A customized 3.0 mL stainless steel vial was charged with 500
mg (2.24 mmol/g) of triphenylphosphine-functionalized
polystyrene (2% cross-linked with DVB, 100 µm diameter),
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