Understanding the effects of the polymer support on reaction rates and kinetics: knowledge toward...

Understanding the effects of the polymer support on reactionrates and kinetics: knowledge toward efficient synthetic designDaniel Walsh, Daqian Wu and Young-Tae Chang�

Solid-phase organic synthesis (SPOS) has an ever-expanding

role in the field of organic synthesis. Partially out of difficulty, and

partially from the rapid speed of progress, few basic studies on

the role of the physical structure of the resin have been

undertaken, and the dissemination of the existing knowledge has

been slow. Major advances have been made in the

understanding of the many factors that govern a SPOS reaction’s

performance as a function of the choice of solid support.

AddressesDepartment of Chemistry, New York University, 29 Washington Place,

Brown Building, Room 564, New York, NY 10003, USA�e-mail: [email protected]

Current Opinion in Chemical Biology 2003, 7:353–361

This review comes from a themed issue on

Combinatorial chemistry

Edited by Samuel Gerritz and Andrew T Merritt

1367-5931/03/$ – see front matter

� 2003 Elsevier Science Ltd. All rights reserved.

DOI 10.1016/S1367-5931(03)00054-1

AbbreviationsDCM dichloromethane

DMF N,N-dimethylformamide

FT-IR Fourier transform infrared

NMO N-methylmorpholine N-oxide

PEG polyethylene glycol

pfp pentafluorophenyl

PS polystyrene

PS-DVB polystyrene-divinyl benzeneSPOS solid-phase organic synthesis

TG TentaGel

TPAP tetra-n-propylammonium perruthenate

IntroductionSolid-phase organic synthesis (SPOS) is an important

technique in library synthesis, with a growing signifi-

cance in the field of organic chemistry [1–4]. Yet, while

its advantages over solution-phase synthesis (including

ease of product isolation, high product purity and the

ability to drive reactions to completion through the use

of excess reagents) are vastly exploited in the field,

knowledge of the very basic interactions and mechan-

isms controlling these reactions is often, at the very

least, overlooked or, more commonly, not understood.

This lack of understanding often comes at a price in the

form of undesirable side reactions (lower yields), wasted

time and increased expense through extreme reagent

excesses [5–7].

The solid polymer support plays the most pivotal role in

SPOS and understanding its effect on reactions is crucial.

Because of the inherent and unavoidable complexities

brought on by the use of solid polymer beads, as a result of

their very physical construct, the kinetics of SPOS is not

always similar to the relative solution-phase reactions.

Therefore, considerable work has gone into the transla-

tion of solution-phase reactions to SPOS.

Garnering a fundamental understanding of SPOS reaction

kinetics and mechanisms has been difficult due to the

lack of rapid and sensitive analytic tools available for

obtaining real-time information. This lack of information

seriously impedes the efficient application of SPOS [7,8].

Herein, we focus on the effect of polymeric solid supports

on reaction performance, as a function of its structure on

SPOS reaction kinetics.

Overview of solid-phase supportsThe development and improvement of polymeric sup-

ports for solid-phase synthesis is a never-ending focus of

work for many in the field. The most commonly used,

and one of the earliest developed, solid supports is

polystyrene (PS) cross-linked with divinylbenzene

(DVB) [9��]. The amount of cross-linking varies, altering

solubility and swelling characteristics, but the standard

PS-DVB is 1% cross-linked. Because about 96–98% of

the PS-DVB resin is constituted of PS and DVB (the

remainder being short linkers and reacting groups),

PS-DVB is very hydrophobic [8].

It was a common assumption that PS-DVB hindered

reaction kinetics because it did not provide an environ-

ment that was sufficiently ‘solution-like’, and through

steric hindrance effects [8]. Therefore, it became desir-

able to develop resins that gave the advantages of PS-

DVB-supported SPOS (product isolation, compound pur-

ity, etc.) combined with those of solution-phase synthesis,

namely fast reaction rates through rapid diffusion and

reagent mobility.

A major addition to SPOS came with the introduction of

PS resins cross-linked with poly ethylene glycol (PEG),

called TentaGel (TG) [10,11]. TG resins increased

hydrophilicity from its long, ethereal linkages gives it

properties that are sometimes desirable over PS-DVB

alone. The grafted PEG chains can be as long as 50–60

ethylene oxide units, and the PEG content can be as high

as 70%. These spacer PEGs mainly determine the prop-

erties of the resin as a solid support. PS-PEG resins

increased hydrophilicity, and more extended, free

353

www.current-opinion.com Current Opinion in Chemical Biology 2003, 7:353–361

flowing ‘solvent-like’ properties conferred mechanical

and physicochemical properties that are often desirable

over PS-DVB — although not always as is commonly

believed.

Polymeric supports: a look insideCzarnik [12], in an insightful paper, warned of the danger

of viewing the resin as just a ‘little ball’ from which

reactive groups simply dangle. As Czarnik states, ‘‘The

nature of this ‘ball’ can enormously affect the rate at

which reactions will occur, just as does the choice of

solvent’’ [12].

Any discussion or study on the effects of the polymer

support on resin kinetics must take into account the

functional groups attached to the resin that actively take

part in the reaction. It is now understood that the func-

tional groups on and in the resin beads are uniformly

distributed throughout the entirety of the bead (not just

the external surface as it is often graphically illustrated by

the nondescript black ball). Early autoradiography studies

demonstrated functional site homogeneity throughout

the resin from the surface through the center [13,14].

However, later fluorescence microscopy studies cast

doubt on the results by showing stronger fluorescence

on the bead surface compared with at the bead interior

[15,16]. Still later, it was shown this high external fluor-

escence was due to self-quenching in the interior of the

bead [17,18�]. Physical slicing of the bead in conjunction

with fluorescence spectroscopy showed homogeneous

site distribution [18�]. Product homogeneity was also

demonstrated through a Fourier transform infrared

(FT-IR study) and again through confocal Raman spec-

troscopy [18�,19�].

Recently, Bradley and co-workers [20] combined fluor-

escence spectroscopy and confocal Raman spectroscopy

to determine functional site distribution and kinetics on

two solid supports, PS and TG. It was shown that

fluorescence microscopy is useful only for beads with

a very low loading level of fluorophores, due to the

problems of absorption/re-absorption of the fluores-

cence, dye–dye interaction, spectral shifts, and quench-

ing at high loading levels. At higher loading levels,

confocal Raman spectroscopy was used to study the

kinetics of site loading in the reaction of 4-cyanobenzoic

acid onto aminomethyl PS and TG resins with diisopro-

pylcarboiimide (DIC). For the reaction with PS, all sites

reacted simultaneously, suggesting the reaction was

coupling rate limited. For TG, however, the outer region

of the bead coupled more quickly, with the interior being

more thoroughly coupled with time. This suggests that

with TG the reaction rate was under diffusion control.

This study did not investigate the effect of solvent, resin

swelling or reagent structure, but nicely demonstrates

the effect of the polymer support composition on reac-

tion rate [20].

The importance of those studies is this: the majority of

the reactive sites are located within the interior of the

resin itself. Numerically, assuming a surface ‘depth’ of

0.1 mm, 99% of the reactive sites are located within the

bead [5]. Therefore, it is obvious that access to these sites,

and the reagents mobility within the bead, are of utmost

importance to a reaction’s success. That is not to say,

however, that sterics are the only factor, as will be shown.

The kinetic properties of the resin beads are greatly

affected by the bead’s structure and environment. The

overriding environmental factor is solvent and its effect

on swelling. Generally, the amount of swelling is the

result of favorable non-covalent/non-ionic polymer/sol-

vent interactions, and is limited by the anchoring effect of

cross-linking that prevents dissolution and confers struc-

tural rigidity [9��].

Typically, resin beads during synthesis are swollen, and

the polymer is partially solvated in an attempt to more

fully and quickly expose the functional groups of a resin

to the reagent, or more precisely, to increase the rate of

diffusion. Based on experience in peptide syntheses, it is

generally assumed that the greater the resin beads swell,

the faster the reaction will be.

Cross-linking and its effect on rateDelving deeper still into the resin, the amount of cross-

linking has a demonstrable effect on reaction rate. Early

studies on the effect of cross-linking both in intra-resin

reactions and tri-phasic catalysis reactions showed linear-

ity with increased cross-linking content corresponding

with decreased reaction rate [21,22].

In an inherent relationship, of course, are the rate of

diffusion and the reaction rate. In a focused, thorough

diffusion study on macrobeads using a staining technique,

Meldal and co-workers [23��] have shown that increasing

cross-linking content decreases the diffusion rate and,

therefore, lowers the reaction rate.

In an interesting paper employing magic angle spinning

NMR, Lippens et al. [24,25] followed a Wittig–Horner

condensation of terephthaldehyde with a phosponodi-

ester (Figure 1). The reaction was conducted on Syn-

phase lanterns (SP-PS-D-RAM Rink linker, available

from Mimotopes, http://www.mimotopes.com) and was

shown to proceed more rapidly than the equivalent reac-

tion on standard PS resin. The authors hypothesized that

this was due to the lantern structure lacking any cross-

linking that increased the rate of diffusion and conse-

quently the rate [24].

Bradley, White and Rana [26��] have conducted the most

thorough study of the effect of cross-linking on resin

kinetics. Synthesizing their own PS-DVB resins of vary-

ing cross-linker content, a variety of reactions were

354 Combinatorial chemistry

Current Opinion in Chemical Biology 2003, 7:353–361 www.current-opinion.com

http://www.mimotopes.com

studied including methyl red cleavage from a resin with

trifluoroacetic acid (monitored by UV-VIS); the solid-

phase synthesis of Kawaguchipeptin B; and solid phase

Suzuki reactions. As expected, their work showed that

diffusion could be rate limiting with highly cross-linked

resins. In addition, it showed that even small changes in

cross-linker content, 0.9%–2.1%, can have a large effect

on kinetics — an important consideration because most

PS-DVB used ranges from 1–2% DVB. For example, a

fivefold decrease in rate was seen when resin cross-linking

was increased from 0.3% to 6%.

Lastly, as an aside, their work showed that for the synth-

esis of Kawaguchipeptin B, increased cross-linker content

gave purer product (the 28% purity of 3% DVB increased

to 50% for the higher cross-linked 3% and 6% resins).

This was quite possibly due to more side reactions in the

lower cross-linked resins as a result of greater reactivity

and accessibility of sites, or through site–site interactions

induced through greater mobility. This adds yet another

consideration to effective SPOS reaction design, where a

greater rate may not always be desirable.

Resin sizeAs would be expected, the effect on the reaction rate from

varied resins sizes can be significant. In the early days of

resin supports, it was understood that the bead size could

affect the reaction rate [27]. Other studies have shown

size effects and reactions under both diffusion and reac-

tion rate control; however, Meldal’s thorough diffusion

study best covered the topic [18�,20,23��,28]. Meldal

showed that the diffusion rate is not independent of

the resin radius. As expected, it was demonstrated that

the diffusion rate increased with decreasing bead size.

Also, diffusion rates are increased by the ratio between

the bead surface and the migration pathway, as well as on

increasing concentration gradient. In addition, diffusion

and rate can be increased through increasing temperature,

good swelling, small reagents and high concentrations

[20,29]. It was shown that sonication and mechanical

agitation did increase the rate of diffusion. On the basis

of observed rapid diffusion rates for small beads, Meldal

proposes that for small beads the reaction may be the

overall rate-limiting factor.

Kinetic studies of PS- and TG-based resinsSince 1995, Bing Yan has been monitoring solid-phase

reactions on-bead using FT-IR for kinetic studies and

reaction optimization, with more brief uses of fluores-

cence spectroscopy in determining loading levels, to great

benefit [30–32].

In 1996, Yan, Fell and Kumaravel [6] used single-bead

FT-IR to monitor a simple Sn2 reaction (Figure 2a). The

reactions were performed on both Merrifield resin (or

chloromethyl PS resin) and TG resin. The observed rates

dispelled a common assumption: for the reaction in

solution, t1/2 was measured to be 170–1700 min, whereas

on the solid support it was shown to be 23 min. This

acceleration of reaction rate demonstrated that not all

solid-phase reactions are necessarily slower than their

solution-phase counterparts.

A qualitative demonstration of the effect of resin structure

was also shown. The rates of two esterification reactions

were compared, one employing Wang resin (a hydroxy-

methyl functionalized PS resin) and the other a TG resin

(Figure 2b) [6,31]. The Wang resin, contrary to expecta-

tion, performed better than TG (Wang t1=2 ¼ 3 min ver-

sus TG t1=2 ¼ 20 min). Though this was not a rigid

comparison, as it was not strictly the same reaction, it

showed at the very least that TG yielded no obvious rate

improvements over the Wang resin. This led the way for

further studies.

Lastly, an important observation was made involving the

rate throughout the polymer matrix. Comparing the

results from attenuated total reflectance IR and from

transmission IR, the rate at the surface versus the rate

in the bead interior were shown to be roughly the same.

Figure 1

HNO

O

NHO

P

OEt

EtO

O

MeO

OMeOHC CHO

HNO

O

NHO

OH

MeO

OMe

LiBr, Et3NCurrent Opinion in Chemical Biology

Wittig–Horner condensation of terephthaldehyde with a phosponodiester.

Effects of polymer supports on reaction rates and kinetics Walsh, Wu and Chang 355


This showed that the reaction was not rate limited by

diffusion, as was often assumed [6].

In an attempt to better quantify the effects of resin

composition, Yan and Li [5] presented a comparison of

the kinetics of four types of general organic reactions

performed on PS- and TG-based resin beads — arguably

the two most commonly used solid supports.

The reactions include: the catalytic oxidation of an alco-

hol to an aldehyde with tetra-n-propylammonium per-

ruthenate (TPAP) and N-methylmorpholine N-oxide

(NMO) (Figure 3a), ester formations (Figure 3b), the

synthesis of dansyl hydrazones (Figure 3c), and C-term-

inal modification of aspartic acid through a ring-opening

reaction (Figure 3d).

In summary of the data, it was shown that the assumption

that a reaction will proceed faster in the more ‘solution-

like’ TG resins than in the ‘immobile’ PS resins is not

always true, and other factors contribute [5].

As can be seen in Table 1, the reactions in Figure 3a

proceed faster, as expected, with TG. This may be

explained by the fact that TPAP is a salt that would be

more compatible with a more polar polymer matrix. The

results for the reaction in Figure 3b show no real advan-

tage for either resin. Interestingly, the reactions shown in

Figure 3c and Figure 3d proceed faster on the PS resin.

Figure 3d step 2 was 18 times faster on PS than TG.

This suggests that a resin behaves much as the solvent

phase in a solution reaction and, as a micro-reactor, it is

very solvent like [14]. Therefore, it has an effect similar to

Figure 2

Cl

O

DMF

O

OO

− +K

(a)

NH

O O

OMeOH

FmocGly

HOBTDICDMAPDMF

NH

O O

OMeO

O

NHFmoc

O

OH

HO

O

F

NO2 O

O

O

F

NO2

DIC/DMAP

(b)

Current Opinion in Chemical Biology

Reactions used in single-bead FTIR studies of reaction progress on the solid phase. (a) Basic Sn2 reaction conducted on Merrifield and TG resins.

(b) The rates of two esterification reactions comparing Wang resin with TG resin. DIC, diisopropylcarbodiimide; DMAP, dimethylaminopyridine; Fmoc,

9-fluorenylmethoxycarbonyl; HOBT, 1-hydroxybenzotriazole.

Table 1

Rates of reactions in Figure 3 conducted on PS and TG resinswith their ratio.

Reaction Scheme kPS (1/s) kTG (1/s) kTG/kPS

3a 4.6 � 10�4 1.8 � 10�3 3.9

3b (R ¼ 3) 2.2 � 10�4 2.3 � 10�4 1

3b (R ¼ 4) 4.8 � 10�4 4.2 � 10�4 0.9

3b (R ¼ 5) 2.0 � 10�4 2.2 � 10�4 1.1

3c (R ¼ H) 3.1 � 10�3 1.8 � 10�3 1.1

3c (R ¼ 3) 4.1 � 10�4 1.9 � 10�4 0.6

3d (step 2) 1.13 � 10�4 6.26 � 10�6 0.55



the solvent on the reaction rate — a well-understood

effect. This area requires greater exploration, but the data

are persuasive. They suggest that resin/reagent compat-

ibility in terms of resin selection greatly influences the

rate, and the myth that ‘solution-like’ resins always per-

form better than less mobile, hydrophobic resins is false.

Figure 3

OOH

DMFO

H

O

NMO/TPAP

OOH

DMFO

OO

R

RCOOHDIC/DMAP

Reagent 3 R = (CH2)3COCH3 4 CH3Ph 5 CH2CH3

OH(R)

O

N(CH3)2

SO2NHNH2

OH(R)

NNHSO2

N(CH3)2

DMF/HAc

NH2 + cbz-N

O

O

HO

O

cbz-N

O

O

NH

ONH2

NH

NH

O

cbz

O

HN

(a)

(b)

(c)

(d)


Reactions used in comparing the effects of the polymer support on solid-phase reaction kinetics using polystyrene- and TentaGel-based resins.

(a) Catalytic oxidation of an alcohol to an aldehyde with TPAP and NMO. (b) Ester formations with various acids. (c) Dansyl hydrazone synthesis.

(d) C-terminal modification of aspartic acid through a ring-opening reaction. Cbz, benzyloxycarbonyl.



This study did not discuss the effect of solvent and

swelling ability [5].

Kinetic comparison of amide formation onvarious cross-linked PS resinsCzarnik and co-workers [28] studied the reaction kinetics

of an amide formation employing a Knorr linker reaction

on various PS and PEG-type resins (Figure 4). The

reaction was performed with 100–200 mesh PS resin in

N,N-dimethylformamide (DMF) and dichloromethane

(DCM). The reaction in DCM showed a half-life of

t1=2 ¼ 33 s with a conversion of 93%, whereas in DMF

showed a half-life of t1=2 ¼ 88 s with a conversion of 71%.

The greater performance in DCM was proposed as stem-

ming from the greater swelling ability of the resin in

DCM versus DMF, although no swelling data were

reported. No comment was made as to the compatibility

of the reagent, polymer and solvent.

The reaction was also carried out with DCM under the

same conditions but with varying sized (mesh) PS beads.

It was found that the reaction proceeded faster on smaller

beads (Table 2). No comment was made to explain this

effect, although it is presumed that this results from a

diffusion effect. It would seem that the rate of diffusion is

slightly slower than the rapid reaction rate. However,

while diffusion is often a factor, for small beads and in

reactions with fast diffusion rates in comparison to the

reaction rate, one would not expect to see an appreciable

diffusion effect.

Finally, the reaction was studied using PS beads with

different levels of the PEG moiety. It was shown that

the PEG moiety had a positive effect on the reaction rate,

which increased with greater PEG content. Suggested

explanations for this improvement include PEG-induced

favorable modification in solvation, dielectric properties

and possible hydrogen bonding. A key point made within

the text is that these results are highly reaction-dependent

— this holds true for all SPOP kinetic studies to date.

Solid-support reactivity and HammettrelationshipsGerritz, Trump and Zuercher [33��] used Hammett rela-

tionships to determine the effect of the solid support on

reactivity. In a related review, Gerritz [34] also nicely

covered the topic of quantitative techniques for compar-

ing solid supports. For the Hammett study, the displace-

ment of a solid supported pentafluorophenyl ester (pfp)

with various para-substituted anilines on seven different

solid supports including methacrylic acid/dimethyl acry-

lamide copolymer crowns, low-loading PS, high-loading

PS, PS lanterns, poly(tetrafluoroethylene) tubes, PS resin

and PS-PEG resin.

The study determined Hammett equation r values by

performing competition experiments. The pfp ester

resins were subjected to treatment with a 0.5 M solution

of two anilines. (All binary combinations of five anilines

were used to give a total of 10 competition experiments.)

The study was significant not only for its ability to

determine the effect of the solid support on r, but also

because the study was high-throughput in that the solid

supports were present in the same reaction vessel for the

competition experiments. This generates many data

points simultaneously and is, in a sense, a ‘combinatorial’

method for Hammett plot generation [33��].

Figure 4

NH2

HNO

ONHFmoc

OMe

OMe

OHO

ONHFmoc

OMe

OMe

+

DIEA/PyBOP


Amide-forming Knorr linker formation on various solid supports.DIEA, N,N0-diisopropylethylamine; PyBop, (benzotriazol-1-yloxy)-

tripyrrolidinophosphonium hexafluorophosphate.

Table 2

The kinetics of the Knorr formation reaction on different resins of various sizes.

Resins (size) kobs (1/s) t1/2 (s) Conversion (%) Loading (mmol/g)

PS (100–200 mesh), DCM 2.1 � 10�2 33 93 1.38PS (100–200 mesh), DMF 7.9 � 10�3 88 71 1.38

PS (200–400 mesh) �8 � 10�2 �9 96 0.43

PS (70–90 mesh) 3.9 � 10�3 178 96 1.12

Champion-1 (100–200 mesh 60% PEG) �4 � 10�1 �2 98 0.4

ArgoGel-AM (164 mm) 70% PEG �7 � 10�2 �10 94 0.44

TentaGel-AM (130 mm) 70–80% PEG �6 � 10�2 �12 91 0.29



The results showed a dependence on the solid support for

the value of r. Generally, the r value was higher than that

of the comparable solution-phase reactions, except for

PS-PEG, which was similar — anecdotal evidence of PS-

PEG’s ‘solution-like’ nature [33��]. Additional data sug-

gested that for the crown resins, r correlated more

strongly with the graft density than the actual chemical

structure of the graft. Lastly, the effect of solvent was

tested, and it was shown that changing the solvent from

DMF to CH2Cl2 minimized the difference between rvalues in solution and on solid support. This was proposed

to be a function of swelling — greater swelling in CH2Cl2exposes a greater proportion of the solid support to

solvent. A key point made is of the ‘synergistic’ interac-

tion between the solvent and solid support, factors that

should no longer be considered independently [33��].

Fluorescence resin kinetics: the effects ofsolvent and swellingChang, Walsh and co-workers [35��] compared the per-

formance of six representative aminomethyl resins in five

common solvents in an in situ fluorescence kinetics study

(Figure 5). The reaction involved the nucleophilic dis-

placement of a highly fluorescent dye from an activated

tetrafluorophenol resin [36,37]. The dye was then freed

into solution, and the change in fluorescent intensity with

time was measured. (Mechanical stirring with a stirbar

was used to ensure rapid diffusion and has been shown to

be one of the best stirring methods in SPOS [22].) The

resins and solvents used, along with the relevant swelling

and reaction rates, can be seen in Table 3.

From the data, it was shown that two factors determined

the resin performance: resin swelling and solvent polarity.

Generally, increased swelling and solvent polarity

increased the rate. More specifically, it appears that it

is actually a combination/balance of the two factors that

governs the resin’s performance (Figure 6). Specifically,

consider the case of PS in Table 3. The rate does not

increase linearly with swelling. The solvent polarity

effect is demonstrated by comparing the entries for

THF (excellent swelling, lower solvent polarity) to

DMF (good swelling, high solvent polarity).

An interesting application of this data, and an example of

the utility of these kinetic studies, occurs with Argopore

resin, a highly cross-linked macroporous polymer. Based

on the previous discussion, it would be expected that

Figure 5

HN

O

F

F

O

F

F

O

N OO

NHO

NH

N

O

NH O

OO

NH2


Release of fluorescent dye from the solid support upon addition of 10 mM benzylamine.

Table 3

Rates of different resins in various solvents shown with resin swelling and solvent polarity data.

Resin DMF, PI ¼ 6.4 Acetonitrile, PI ¼ 6.2 THF, PI ¼ 4.2 DCE, PI ¼ 3.7 Toluene, PI ¼ 2.3

k Swelling k Swelling k Swelling k Swelling k Swelling

PS 2 5.2 0.23 2 1.31 6 0.27 4.4 0.41 4

JandaJel 2.65 6 0.22 1.9 7.4 0.2 0.22

ArgoPore 1.31 5.6 1.43 5.3 1.17 5.4 0.28 0.16 5.7

TentaGel 2.95 5 2.2 4 1.92 6 0.53 5 0.68 3.6

NovaGel 2.57 7 1.51 5 1.62 7.5 0.72 0.29

PEGA 2.95 8 1.83 6 1.95 4 0.26 5 0.21 3



Argopore, as a highly cross-linked polymer with poor

swelling properties, would perform poorly. However, in

a solvent where other resins swell poorly (shrink), Argo-

pore actually had a greater rate — its high degree of cross-

linking preventing it from being adversely affected

through shrinkage (CH3CN data, Table 3). Again, it must

be reiterated that this data only refers to this reaction.

ConclusionThe community’s understanding of the effect of the

polymer support on reaction rates grows every year. No

longer are blind assumptions based on common sense, but

not grounded in fact, held as synthetic guidelines. For it

has been shown that the choice of the proper support will

increase everything from yield and purity to speed and

cost. In addition, it has been shown that each combination

of support, solvent and reagents deserves unique con-

sideration as to the performance of the reaction, and that

no general guide exists — at least not yet.

Most important of all for a researcher designing a SPOS

synthesis, it is incumbent upon them to understand, as

much as possible, the variables present in their support

selection (swelling, solvent polarity, size, polymer/

reagent compatibility, etc.), and to put serious effort into

monitoring the reaction progress. There remains a vast

amount of work to be done in this field, particularly in the

area of polymer/reagent interactions, especially given that

the polymer is now viewed as a de facto solvent.

References and recommended readingPapers of particular interest, published within the annual period ofreview, have been highlighted as:

� of special interest��of outstanding interest

1. Jung G: Combinatorial Chemistry: Synthesis, Analysis, Screening.Weinheim; New York: Wiley-VCH; 1999.

2. Dorwald FZ: Organic Synthesis on Solid Phase: Supports, Linkers,Reactions. Weinheim; Chichester: Wiley-VCH; 2000.

3. Seneci P: Solid-Phase Synthesis and Combinatorial Technologies.New York: Wiley-Interscience; 2000.

4. Miertus S, Fassina G: Combinatorial Chemistry and Technology:Principles, Methods and Applications. New York:Marcel Dekker; 1999.

5. Li WB, Yan B: Effects of polymer supports on the kineticsof solid-phase organic reactions: a comparison ofpolystyrene- and TentaGel-based resins. J Org Chem 1998,63:4092-4097.

6. Yan B, Fell JB, Kumaravel G: Progression of organic reactions onresin supports monitored by single bead FTIRmicrospectroscopy. J Org Chem 1996, 61:7467-7472.

7. Yan B, Yan H: Combination of single bead FTIR andchemometrics in combinatorial chemistry: application of themultivariate calibration method in monitoring solid-phaseorganic synthesis. J Comb Chem 2001, 3:78-84.

8. Bing Y: Monitoring the progress and the yield of solid phaseorganic reactions directly on resin supports. Acc Chem Res1998, 31:621-630.

9.��

Vaino AR, Janda KD: Solid-phase organic synthesis: a criticalunderstanding of the resin. J Comb Chem 2000, 2:579-596.

A complete guide to understanding the most basic nature of the resin.

10. Bayer E, Dengler M, Hemmasi B: Peptide-synthesis on the newpolyoxyethylene-polystyrene graft copolymer, synthesis ofinsulin-B21-30. Int J Pept Protein Res 1985, 25:178-186.

11. Bayer E: Towards the chemical synthesis of proteins.Angew Chem Int Ed 1991, 30:113-129.

12. Czarnik AW: Solid-phase synthesis supports are like solvents.Biotechnol Bioeng 1998, 61:77-79.

13. Merrifield B: The role of the support in solid-phasepeptide-synthesis. Br Polym J 1984, 16:173-178.

14. Yan B: Single-bead analysis in combinatorial chemistry.Curr Opin Chem Biol 2002, 6:328-332.

15. McAlpine SR, Lindsley CW, Hodges JC, Leonard DM, Filzen GF:Determination of functional group distribution within Rastaresins utilizing optical analysis. J Comb Chem 2001, 3:1-5.

16. McAlpine SR, Schreiber SL: Visualizing functional groupdistribution in solid-support beads by using optical analysis.Chem Eur J 1999, 5:3528-3532.

Figure 6

Polarity index x swelling (mmol/g)

0

0.5

1

1.5

2

2.5

3

3.5

0 5 10 15 20 25 30 35 40 45 50 55

Rat

e (1

/M s

ec)


Plot of polarity index � swelling versus the rate. A demonstration of the cofactor effect of swelling and solvent polarity on rate.



17. Yan B, Martin PC, Lee J: Single-bead fluorescencemicrospectroscopy: detection of self-quenching influorescence-labeled resin beads. J Comb Chem 1999,1:78-81.

18.�

Rademann J, Barth M, Brock R, Egelhaaf HJ, Jung G: Spatiallyresolved single bead analysis: homogeneity, diffusion, andadsorption in cross-linked polystyrene. Chem Eur J 2001,7:3884-3889.

A thorough study using fluorescence microscopy (confocal and non-confocal) as well as IR microscopy. Studied the effects of bead sizeand diffusion and particularly highlights adsorption’s effect on reactionprogress. Importantly, confirms functional site homogeneity throughoutthe resin.

19.�

Kress J, Rose A, Frey JG, Brocklesby WS, Ladlow M, Mellor GW,Bradley M: Site distribution in resin beads as determinedby confocal Raman spectroscopy. Chem Eur J 2001,7:3880-3883.

Study showing essentially uniform site distribution in dry and swollenaminomethylated polystyrene resin beads using scanning confocalRaman spectroscopy.

20. Kress J, Zanaletti R, Rose A, Frey JG, Brocklesby WS, Ladlow M,Bradley M: Which sites react first? Functional site distributionand kinetics on solid supports investigated using confocalRaman and fluorescence microscopy. J Comb Chem 2003,5:28-32.

21. Kim B, Kirszensztejn P, Bolikal D, Regen SL: Kinetic features of anintraresin reaction. J Am Chem Soc 1983, 105:1567-1571.

22. Li WB, Yan B: A direct comparison of the mixing efficiencyin solid-phase organic synthesis by single bead IR andfluorescence spectroscopy. Tetrahedron Lett 1997,38:6485-6488.

23.��

Groth T, Grotli M, Meldal M: Diffusion of reagents in macrobeads.J Comb Chem 2001, 3:461-468.

Measured diffusion rates in macro beads simply and effectively using anacylation reaction stopped at various time points. Beads were stained todetect the extent of diffusion and the stained versus unstained areas weremeasured to calculate the diffusion rate. Highlights many factors that aidin diffusion rates.

24. Rousselot-Pailley P, Ede NJ, Lippens G: Monitoring of solid-phase organic synthesis on macroscopic supports by high-resolution magic angle spinning NMR. J Comb Chem 2001,3:559-563.

25. Chin J, Fell B, Shapiro MJ, Tomesch J, Wareing JR, Bray AM:Magic angle spinning NMR for reaction monitoring andstructure determination of molecules attached to multipincrowns. J Org Chem 1997, 62:538-539.

26.��

Rana S, White P, Bradley M: Influence of resin cross-linking onsolid-phase chemistry. J Comb Chem 2001, 3:9-15.

Use d PS-DVB resins with a range of cross-linker content to determinethe effect of cross-linking on the reaction kinetics. Drastic rate enhance-ments were seen as a function of cross-linking content, as well as some

surprising results regarding increased cross-linker content giving increasedproduct purity.

27. Tomoi M, Ford WT: Mechanisms of polymer-supportedcatalysis. 1. reaction of 1-bromooctane with aqueous sodium-cyanide catalyzed by polystyrene-bound benzyltri-normal-butylphosphonium ion. J Am Chem Soc 1981, 103:3821-3828.

28. Li WB, Xiao XY, Czarnik AW: Kinetic comparison of amideformation on various cross-linked polystyrene resins.J Comb Chem 1999, 1:127-129.

29. Fang LL, Demee M, Sierra T, Kshirsagar T, Celebi AA, Yan B:Kinetics study of amine cleavage reactions of variousresin-bound thiophenol esters from Marshall linker.J Comb Chem 2002, 4:362-368.

30. Yan B, Li WB: Rapid fluorescence determination of the absoluteamount of aldehyde and ketone groups on resin supports.J Org Chem 1997, 62:9354-9357.

31. Yan B, Kumaravel G, Anjaria H, Wu AY, Petter RC, Jewell CF,Wareing JR: Infrared-spectrum of a single resin bead forreal-time monitoring of solid-phase reactions.J Org Chem 1995, 60:5736-5738.

32. Yan B, Sun Q, Wareing JR, Jewell CF: Real-time monitoring of thecatalytic oxidation of alcohols to aldehydes and ketones onresin support by single-bead Fourier transform infraredmicrospectroscopy. J Org Chem 1996, 61:8765-8770.

33.��

Gerritz SW, Trump RP, Zuercher WJ: Probing the reactivity ofsolid supports via Hammett relationships. J Am Chem Soc 2000,122:6357-6363.

A novel method is reported in the study of solid-support reagent inter-actions and the effect of solvent on solid-support reactivity for varioussolid supports. The method determined Hammett relationships for thedisplacement of a solid-supported pentafluorophenyl ester with fourpara-substituted anilines ( p-MeO, p-Me, p-F, p-Cl) and aniline.

34. Gerritz SW: Quantitative techniques for the comparison of solidsupports. Curr Opin Chem Biol 2001, 5:264-268.

35.��

Walsh DP, Pang C, Parikh PB, Kim YS, Chang YT: Comparativeresin kinetics using in situ fluorescence measurements.J Comb Chem 2002, 4:204-208.

Novelmethod that rapidlydeterminesthereactionkineticsof thereleaseofafluorescentdye fromaresin-boundactiveester intosolutionupontreatmentwith benzylamine using in situ fluorescence measurements. Studied abroad range of commercially available resins in various common solventsand showed the considerable effects of these factors on rate.

36. Chang YT, Schultz PG: Versatile fluorescence labeling methodusing activated esters on solid support. Bioorg Med Chem Lett1999, 9:2479-2482.

37. Salvino JM, Kumar NV, Orton E, Airey J, Kiesow T, Crawford K,Mathew R, Krolikowski P, Drew M, Engers D et al.: Polymer-supported tetrafluorophenol: a new activated resin forchemical library synthesis. J Comb Chem 2000, 2:691-697.



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