Cover Page

Eco-compatibility of Organic Synthesis Set

coordinated by Max Malacria

Volume 3

Biphasic Chemistry and The Solvent Case

Edited by

Jean-Philippe Goddard

Max Malacria

Cyril Ollivier

Wiley Logo

1
Solid-phase Supported Chemistry

1.1. Introduction

Since Merrifield’s pioneering work in solid-phase peptide synthesis, which won him the Nobel Prize in 1963, supported organic synthesis has enjoyed constant popularity and development. The solid phase was first applied to the oligomeric synthesis of natural products such as polypeptides, polysaccharides and oligonucleotides. It was the work of Fréchet and Leznoff in the late 1970s that initiated its use in the synthesis of small molecules by performing organic reactions in which a substrate, reagent or catalyst was grafted onto an insoluble solid polymer. Another application is the purification of reaction mixtures by trapping agents attached to solid supports: scavengers. A significant number and diversity of organic reactions have been successfully transferred to the solid phase and were the beginning of the development of combinatorial synthesis in the 1990s and then parallel synthesis.

Solid-phase chemistry limits the use of toxic, flammable solvents, thus reducing their production and elimination, since it simplifies the purification steps to simple solid/liquid filtration. The polymer is recyclable, which reduces waste. Chemical syntheses are less dangerous and harmful due to the high chemical and physical stability of the substrates. Microwave, ultrasound and high pressure activations and the positive influence of green solvents, such as ionic liquids, have been demonstrated. Finally, the toxicity or volatility of the grafted compounds is minimal, which helps to prevent accidents, diseases, explosions and fires. For all these reasons, solid-phase chemistry has found its place in the concept of green chemistry.

1.2. Principle of solid-phase chemistry

When a reagent is attached to a polymer, the process is usually a single step. Reagents in solution A and B react with the supported entity, which may be, for example, a catalyst (Figure 1.1 and section 1.12). The resulting AB compound is isolated in the filtrate by simply filtering the regenerated polymer.

images

Figure 1.1. Use of a supported reagent

When a supported trapping agent (section 1.12.3) is used, excess reagents or unwanted by-products (denoted C) present in the reaction medium are fixed to the solid phase and then removed by simple filtration (Figure 1.2).

images

Figure 1.2. Using a scavenger

The use of a supported substrate requires prior functionalization and a succession of filtration (Figure 1.3). The first step involves grafting of a functionalized spacer arm (called linkers, section 1.10.2) of variable length onto the polymer, then incorporating a substrate (denoted A) at its end. As this grafted polymer is generally solid and insoluble in all solvents, the residual compound A is removed by simple filtration and washing. In order to obtain quantitative conversions, reactions can be repeated. This is usually necessary for processing large quantities. This grafted polymer is then used in conventional chemical reactions. Thus, a substrate (denoted B) reacts on the supported active site A to form the compound AB. The reaction by-products and residual reagent present in the filtrate (liquid phase) are removed by simple filtration. The polymer (AB) is thus purified and then the bond between the spacer arm (linker) and the AB molecule is broken (cleavage) by the action of a reagent C (often an acid). This cleavage step can, in some cases, also be a chemical transformation step (e.g. cyclization). The AB molecule is thus obtained with high purity and the initial polymer is regenerated.

images

Figure 1.3. General diagram of solid phase synthesis

1.3. Advantages

Many advantages have contributed to the use of polymers in organic synthesis and justify the green chemistry name:

1.4. Safety and environment

The use of solid phase in a synthesis strategy reduces the risk of intoxication and contamination since direct contact with the compounds by air and skin is avoided. The remarkable stability of these supports avoids drastic storage conditions that are costly in terms of energy (low temperature) and the use of inert gas. Finally, the purification steps are reduced to simple filtration and washing, thus avoiding long chromatographies that consume flammable toxic solvents or costly distillations. Safety is therefore improved and environmental risks and costs are reduced.

1.5. Disadvantages and limitations

This technique, although very practical and effective, has some limitations:

1.6. Evolution

Solid-phase chemistry underwent significant development in the 1990s with the advent of automation and combinatorial chemistry. Fifteen years later, this synthesis strategy refocused on the development of parallel synthesis in order to produce smaller targeted libraries. A wide range of supported scavengers, or catalysts, as well as a wide range of synthesis, extraction and purification automatons are now commercially available. Finally, the transfer to the solid phase of new methodologies, reagents and concepts developed in solution is necessary for the development of pharmaceutical and agrochemical industries that use these synthetic tools for the production and screening of innovative chemical libraries.

1.7. Supports: linear skeletons

Linear skeleton polymers are soluble in certain organic solvents, thus allowing reactions to be carried out in a homogeneous medium without diffusion problems, with equal accessibility of all supported reaction sites and kinetics similar to the same reaction under conventional conditions. In addition, immobilized substrates can be characterized by standard analytical techniques. Finally, precipitation by adding a non-solvent to the polymer makes it possible to filter it. However, it is not always complete and selective, sometimes causing separation and purification issues.

The most commonly used linear polymers in organic synthesis are polyethylene glycol (PEG) 1, monomethyl ether polyethylene glycol (MPEG) 2 and linear polystyrene (PSl) 3 (Figure 1.4).

images

Figure 1.4. Soluble polymer structures

The molecular weight of PEGs is generally 20,000, so the number of grafting sites is very low (around 0.1 meq./g). PEGs precipitate in diethyl ether or tert-butylmethyl ether, but since these solvents are not very polar, impurities that are too polar sometimes precipitate with the polymer. The use of isopropanol helps to overcome this disadvantage. On the other hand, due to their insolubility at low temperatures in THF and their chelating potential for metal cations, PEGs are excluded from organometallic chemistry. In this case, the PSls are chosen. In addition, the latter can be functionalized at a rate higher than PEGs (up to 6 or 7 meq./g). However, too much functionalization can lead to intrapolymeric secondary reactions resulting in undesirable and irreversible cross-linking that modifies the structure and therefore the reactivity of the resin (section 1.9.10).

1.8. Three-dimensional resins

Three-dimensional skeleton polymers are in the form of small beads and are insoluble in almost all solvents. These are cross-linked polymers generally derived from polystyrene. Their cross-linking rate is an important characteristic leading to very different physical properties depending on its degree (section 1.9.4). Two subgroups can be distinguished, macroporous resins and gel resins.

1.8.1. Macroporous resins

These are characterized by a high rate of cross-linking (≥20%). As this cross-linking is not homogeneous, polymers have permanent pores of different sizes. The largest cavities (about 0.1 μm) are accessible by the molecules in solution without diffusion issues. This high cross-linking considerably limits the mobility and accessibility of reaction sites; therefore, high grafting rates can be achieved without fear of possible interpolymeric interactions between supported sites (section 1.9.10). The reaction sites are distributed over the surface of the pores and are therefore accessible. The reactivity of these polymers does not depend on their swelling in solvents because it is a surface reactivity inside the pores (>500 m2/g). They are therefore interesting supports for reactions developing very polar, even ionic intermediates. However, these resins are physically very fragile and prolonged agitation in a reactor or high temperatures can cause irreversible damage. Therefore, they are often used for solid–liquid extraction (SPE: solid-phase extraction) due to the presence of supported trapping agents (section 1.12.3) or as ion exchange resins. Some examples of functionalized macroporous polystyrenes (MPs) are illustrated in Figure 1.5.

images

Figure 1.5. Functionalized macroporous polystyrenes

MP-carbonate resin is chosen to trap amine hydrochlorides, carboxylic acids or phenols. The MP-NH2 polymer is a trapping agent for electrophiles such as acids and sulfonyl chlorides or isocyanates. Para-toluenesulfonic acid grafted onto MP, MP-TsOH, marketed as Amberlyst A-15, is generally used as a trapping agent for basic species and particularly amines. The supported hydrazines, MP-TsNHNH2, trap ketones and aldehydes.

1.8.2. Gel resins

These are weakly cross-linked polymers (0.5–2%). The cross-linking rate is an important characteristic that leads to polymers with different physical properties depending on their degrees (section 1.9.4).

Styrene and its functionalized derivatives are monovinyl compounds generally used to form the skeleton of gel resins. Para-divinylbenzene (DVB) is the most common bifunctional monomer used to create low cross-linking within the matrix. For example, Merrifield (chloromethylated) resin is obtained either by copolymerization of styrene, DVB and para-chloromethylstyrene, or by functionalization of polystyrene by a Friedel–Craft reaction (Figure 1.6).

images

Figure 1.6. Two ways of synthesizing Merrifield polymer

The control and reproductibility of polymerization reactions require specific know-how. These reactions allow the preparation of highly functionalized polymers (rate higher than 50%); however, all the sites created are not accessible because they are enclosed in the polymeric mesh. Organic chemists generally directly functionalize the previously formed polystyrene skeleton.

However, this method has drawbacks. Firstly, because of the accessibility of the reaction sites being lower than in the homogeneous phase, due to the size of the matrix, the reactivity is reduced. It is therefore important to use solvents that allow the resin to swell optimally (section 1.9.2). Secondly, at the end of the reaction, it is impossible to purify the polymer. Therefore, the functionalization reactions of the substrate must be quantitative and chemoselective in order to avoid the presence of undesirable sites. Finally, this method allows access to maximum functionalization rates of 30%; however, in this case, all the sites created are actually active. As this second approach has been widely used, many reactions meet these criteria and this method is therefore the most commonly used. Since the early 1980s, Fréchet et al. have been developing various functionalizations of polystyrene (Figure 1.7).

images

Figure 1.7. Functionalization of polystyrene

1.9. Characteristics of gel supports

1.9.1. Functionalization rate

The functionalization or loading rate is an important parameter. It determines the number of functionalized benzene rings in relation to the total number of aromatic rings of the polymer. For example, in the case of Merrifield resin (Figure 1.6), this parameter is expressed as the percentage by weight of chlorine (%Cl) or as the number of milliequivalents of chlorine per gram of resin (nCl). The correspondence between these different units is shown in Table 1.1.

Table 1.1. Variation in the functionalization rate of Merrifield polymer

nCl (mmol/g)0.82.14.3
%Cl2.84%7.46%15.27%
Functionalization rate9%32%56%

1.9.2. Swelling properties

The resins can, in suitable solvents, swell up to 10 times their dry volume. This property limits the diffusion issues of the reagents present in solution and increases the accessibility of the supported reaction sites. If the reaction solvent does not allow the polymeric mesh to expand, the mobility of the chains and the accessibility of the reaction sites are greatly reduced. As a result, the reactivity of the resin is limited and the conversion rate and reaction rate may be lower. The swelling of a polymer in a given solvent is very strongly dependent on its cross-linking, loading and functionalization. The lower the cross-linking, the better the polymer’s swelling properties.

In general, polar solvents do not promote mesh expansion and the addition of a suitable co-solvent improves the swelling of the polymer (Table 1.2).

Table 1.2. Swelling volumes for Merrifield resin 1% DVB

Solvents-WaterMeOHMeCNDMSOTHF/WaterEt2OTHF
Vpolymer (mL.g–1)1.51.51.81.81.83.13.37.7

In the absence of a solvent, the volume of the polymer is minimal because the chains are entangled and the pores are not expanded, while in the presence of a suitable solvent, the solvation of the chains causes the mesh to expand and the pores to be reconstituted (Figure 1.8).

images

Figure 1.8. Evolution of polymeric meshes in a solvent. For a color version of this figure, see www.iste.co.uk/malacria/biphasic.zip

The chains then become mobile, varying the volume and site of the pores. Consequently, when the diffusion issues of non-grafted reagents are overcome by a good swelling of the resin, the reactivity of polymer gels tends to approach the homogeneous phase conditions.

1.9.3. Size of the beads

During their formation by suspension polymerization, polymers form beads of sizes ranging from 50 µm to 1 mm in diameter. To ensure a homogeneous reactivity of the resins, the beads are sieved and grouped according to their size. The analysis of these homogeneous batches makes it possible to determine the number of active sites carried by a single bead (Table 1.3).

Table 1.3. Influence of bead size

Size of the beads(µm)Functionalization rate (meq./g)Beads (mg)Loading a bead (nmol)
35–75 (200–400 mesh)1.08,000–16,0000.06–0.12
75–150 (100–200 mesh)1.01,000–2,0000.5–1.0
75–150 (100–200 mesh)2.01,000–2,0001.0–2.0
150–300 (50–100 mesh)2.0125–2508–16
150–300 (50–100 mesh)4.0125–25016–32

The number of meshes corresponds to the mesh size of the sieve. As the size of the beads decreases, the finer the sieve is and the higher the number of meshes. On the one hand, the size of the beads increases as loading increases. On the other hand, for the same loading, the more the size of the beads decreases, the more the number of active sites per bead decreases.

1.9.4. Influence of cross-linking on swelling

The swelling (measured in mL/g) of Merrifield resin, cross-linked at 1% or 2% DVB, was compared in four solvents (Table 1.4).

Table 1.4. Influence of cross-linking on swelling

SolventMeOHEtherDCMTHF
V1%DVB (mL/g)1.83.37.47.7
V2% DVB (mL/g)1.62.55.25.9

The lower the percentage of DVB, the better the swelling properties of the polymer. Pore size is therefore inversely proportional to the rate of cross-linking.

1.9.5. Diffusion effect

Reactions on solid supports are often compared to those performed in solution. However, this analogy is not always obvious to establish because a heterogeneous system brings additional parameters that do not have an equivalence in the homogeneous phase. First of all, the kinetics of reactions are difficult to set in equation. Indeed, electronic or steric interactions between the polystyrene backbone and the substrate in solution can significantly affect the concentration of the reagent in solution in the vicinity of the supported active site. In addition, depending on the nature of the solvent that regulates the swelling of the polymer, the cross-linking of the solid support and the mode of agitation of the reaction medium, diffusion issues of the substrate through the mesh can greatly alter the contact between the two reagents and thus affect the reaction kinetics.

1.9.6. Influence of cross-linking on diffusion

Diffusion is dependent on the cross-linking of the three-dimensional skeleton. Two supported triphenyl phosphines with 0.5% and 2% cross-linking were tested in a Wittig reaction to convert aldehydes to olefins (Heitz and Michels 1972). It appears that the more cross-linked the polymer (2%), the more restricted the mobility of the sites and the more limited the interactions between sites; the reaction, in this case, is more difficult.

1.9.7. Influence of steric bulk

For the same polymer, diffusion is affected by the size of the substrate in solution and by the reaction solvent used. For example, the hydrogenation of alkenes in ethanol catalyzed by a supported Wilkinson catalyst analogue showed that the hydrogenation rate of a cyclic alkene decreased if the size of the ring increased, while this effect is not linear in solution (Grubbs and Kroll 1971). The reaction rate with the supported catalyst can be seven times slower for a cyclic alkene than for a linear disubstituted alkene with the same carbon number. In addition, a series of reactions was carried out in a benzene/ethanol mixture, allowing the mesh to expand. In this condition, the lower the proportion of ethanol (a solvent not very favorable to swelling), the faster the hydrogenation.

1.9.8. Influence of agitation

Different agitation techniques were tested in order to obtain, first, a correct diffusion of the substrates in solution and, second, a good homogeneity of reaction on the different polymer beads by an infrared spectroscopy study (section 1.11.4) conducted on each polymer bead and by fluorescence spectroscopy of the filtrate during a condensation reaction (Li and Yan 1997). Thus, it has been demonstrated that orbital or rotational agitation (180°) homogenizes the reactivity of the reaction sites but is not sufficient for good diffusion. Vigorous agitation is therefore necessary (magnetic, 360°, nitrogen bubbling) both for the homogeneity of the reaction and for obtaining good yields.

1.9.9. Proximity and pseudodilution effects

The nature of microenvironmental effects is difficult to assess because it depends on many factors. Depending on the characteristics of the polymer backbone (cross-linking rate and grafting rate), the distribution, mobility and nature of the substrates, but also on the solvent used (by playing on the swelling properties), it is possible to observe either a proximity effect of the grafted substrates or a pseudodilution effect (Figure 1.9) (Scott et al. 1977; Crowley and Rapoport 2007; Shi et al. 2007).

images

Figure 1.9. Microenvironmental effects

1.9.10. Proximity effect

Supported substrates have reduced mobility involving forced proximity that can lead to electronic interactions and influence reaction kinetics. As a result, high loading polymers will be highly subject to this type of interaction. Intrapolymeric reactions are often side reactions that need to be avoided but could be promoted by the forced proximity of the supported reaction sites. A common example of this type of reaction involves benzyl chlorines in Merrifield resin (Figure 1.10). In contact with a reducing agent, such as zinc, or in the presence of a Lewis acid, such as aluminum trichloride, intrapolymeric reactions are observed, favored by proximity effects. An additional cross-linking is then created, modifying the structure of the resin and thus its reactivity (Figure 1.10).

images

Figure 1.10. Proximity effect: cross-linking

1.9.11. Pseudodilution effect

The pseudodilution effect is the opposite of the proximity effect (Scott et al. 1977; Crowley and Rapoport 2007; Shi et al. 2007). It depends on the distance of the reaction sites from each other. The more a polymer is cross-linked, the more restricted the mobility of sites is and the more difficult the interactions between supported sites are. Similarly, the lower the loading, the further away the sites are from each other and therefore intrapolymeric reactions are limited. This effect can be illustrated by the formation of supported titanocene complexes (Figure 1.11).

images

Figure 1.11. Proximity and pseudodilution effects

In the presence of a 2% cross-linked polymer, the cyclopentadienyl titanium trichloride complex leads to titanocene with bispolymeric ligands. On the other hand, with the highly cross-linked resin, the complex obtained has only one polymeric ligand.

1.9.12. Availability and costs

A very wide choice of variously functionalized resins is commercially available and generally classified according to their specific uses. However, for regular and consistent use, it is preferable to functionalize your own supports from more affordable basic supports (Rink (amino), Merrifield (chlorinated), Wang (alcohol), etc.).

Finally, most syntheses allow the solid phase to be recycled, either directly after filtration and washing or after a simple acidobasic treatment. Saving time, energy and solvents with this synthesis strategy is also a financial parameter to be taken into account.

1.10. Functionalization of the solid support

Before grafting the desired substrate onto a solid support, it is often advisable to introduce a spacer arm and/or linker (Figure 1.12).

images

Figure 1.12. General diagram of a supported substrate

Indeed, if the active site is grafted directly onto the polymer skeleton, its accessibility, and therefore its reactivity, can be reduced by the sterically hindered matrix.

1.10.1. Spacer arms

The introduction of a spacer arm moves the supported reaction site away from the polymeric mesh. It is usually a functionalized linear chain that must be compatible with solvents, allowing the polymer mesh to expand, and chemically inert to the desired reactions (Figure 1.13).

images

Figure 1.13. Influence of a spacer arm

The spacer arm can also be introduced to modify the physicochemical properties of the resin. Polymers with polystyrene structures swell only in aprotic solvents, which is sometimes a limiting factor for the chemistry considered. The introduction of polyethylene glycol arms on the polystyrene skeleton (Figure 1.14) makes the resin compatible with polar solvents. These polystyrene/DVB/polyethylene glycol (PS-DVB-PEG) copolymers are resins known as “TentaGel”. They allow NMR spectra of 1H and 13C of grafted substrates with good resolutions.

images

Figure 1.14. Structure of TentaGel polymers

1.10.2. Linkers

A linker is a bisfunctional group. One of the two functions allows grafting on the polymer by a chemically stable covalent bond (carbon-carbon, ether, thioether, etc.). The second is used to immobilize the substrate to the resin and allows the modified substrate to be cleaved, while resisting chemical transformations (Figure 1.15). Thus, the linker is considered, in part, as a supported protective group.

images

Figure 1.15. Use of a linker in supported chemistry

It can also modify the reactivity of the substrate by acting as an activating group, or by inducing stereoselectivity of the reaction in asymmetric synthesis. There is a wide variety of linkers adapted to the type of chemistry being considered. Initially developed for peptide synthesis, Wang, Trityl and Rink linkers are the most widely used in organic synthesis (Figure 1.16).

images

Figure 1.16. Structures of Wang, Trityl and Rink resins

1.10.3. Influence of functionalization

The swelling of the mesh varies according to the nature of the groups grafted onto the polystyrene skeleton. Table 1.5 illustrates these variations (measured in mL/g) between cross-linked polystyrene (PS-1% DVB) and cross-linked polystyrenes functionalized by polyethylene glycol arms (PS-DVB-PEG) at different rates (nPEG) (Santini et al. 1998). Polystyrene with a non-polar structure has good swelling properties in aprotic solvents, while protic polar solvents cause almost no mesh expansion. TentaGel PS-DVB-PEG resins consist of an apolar skeleton and protic polar grafts. Water, methanol and ethanol allow, for these resins, a correct expansion of the chains.

Table 1.5. Influence of functionalization on swelling

Solvents Water MeOH EtOH DCM Toluene DMF MeCN THF Ether
V PS-1%DVB (mL/g) 1.6 1.7 8.3 8.5 5.6 3.2 8.8 4.0
V PS-DVB-PEG (mL/g) nPEG = 0.3 mmol/g 4.2 4.2 2.1 5.1 5.3 5.4 5.1 5.8 1.9
V PS-DVB-PEG (mL/g) nPEG = 0.6 mmol/g 3.1 3.6 3.5 5.7 4.1 4.6 3.9 4.2 2.4

Therefore, during multistage functionalization on solid substrates, the choice of solvent is variable and influenced, on the one hand, by the structure of the polymer backbone itself and, on the other hand, by the nature of the grafted groups.