Reactive side-chains

For a number of different substituted benzenes, the substituents are involved themselves in the redox chemistry. Among these substituent-active compounds, we find phenolic substances, aromatic amines, chalcogenide substituted benzenes, benzyUc substances, benzoic adds, thiobenzoic adds and benzyl alcohols. As has already been discussed, phenol radical cations, aniline radical cations and toluene radical cations are more or less acidic and can deprotonate to form the corresponding neutral radical. Chedcogenide substituted benzenes (S, Se and Te) are usually characterized by the fact that their redox properties are determined by the chalcogenides rather than by the substituent pattern. 

One-electron oxidation of benzoic and thiobenzoic acids usually results in the formation of neutral radicals rather than COj or COS substituted benzene radical cations.[69-72] For benzoic acids with strongly electron-donating substituents, the character of the radical becomes more zwitterionic.[69,73] 

These neutral radicals rapidly expel COj and COS. The expulsion of CO2 is faster than the expulsion of COS and for this reason, the one-electron reduction potentials of oxidized benzoic acids are practically impossible to measure while the potentials of a few oxidized thiobenzoic acids have been measured by pul radiolysis. These values are given in table 6. 

As for other substituted benzenes containing chalcogenides, the one-electron reduction potentials change very little with the substituent. One-electron oxidized benzyl alcohols, which are of vital importance for the understanding of lignin chemistry, display some very interesting properties since they can deprotonate to form two different types of radicals.[74] 

Acknowledgment. The author thanks the Swedish Natural Science Research Council for financial support. 

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Unfortunately, the modification of the side chain is not a generally applicable approach. Among the major, naturally occurring amino acids, only L-lysine has a chemically reactive side chain that would be as readily available for chemical modification as the side chain of glutamic or aspartic acid. Since, however, poly (L-lysine) is known to be toxic (10), its derivatives cannot be candidates for generally applicable biomaterials. Thus, most of the poly(amino acids) that have so far been suggested as biomaterials are derivatives of gluteunic or aspartic acid or copolymers of such derivatives with leucine, methionine, or a limited number of additional amino acids (11). 

To design amphiphilic and/or reactive copolymers containing aliphatic polyesters, one of the most promising approaches is copolymerization with functional monomers having protected reactive side-chain groups. Some kinds of monomers having reactive (hydrophilic) side-chain groups have been reported (Fig. 3). Recently, the synthesis of various types of functional polyesters has been reviewed [15-19],... 

Fig. 3 Examples of monomer units having reactive side-chain groups, which can be copolymerized with polyesters (a) a-malic acid, (b) [S-malic acid, (c) a-carboxyl- -caprolactone, (d) carboxy lactic acid, (e) trimethylene carbonate derivative, and (1) depsipeptide...

Fig. 4 Synthesis of polydepsipeptides and poly(depsipeptide-co-lactide)s having reactive side-chain groups...

The selective modification of reactive side chains within proteins with compounds containing NMR-sensitive isotopes offers an alternative route to the labeling of proteins. The chemical modification of side chains with reagents labeled with NMR-sensitive isotopes may permit detailed structural and dynamic questions to be addressed, although perturbations of the system caused by the labeling may be of concern in cases where the chemical identity... 

Wenkert and Khatuya (51) examined the competition between direct insertion of a carbene into furan (via cyclopropanation) and ylide formation with reactive side-chain functionality such as esters, aldehydes, and acetals. They demonstrated the ease of formation of aldehyde derived carbonyl ylides (Scheme 4.30) as opposed to reaction with the electron-rich olefin of the furan. Treatment of 3-furfural (136) with ethyl diazoacetate (EDA) and rhodium acetate led to formation of ylide 137, followed by trapping with a second molecule of furfural to give the acetal 138 as an equal mixture of isomers at the acetal hydrogen position. 

Jet fuel specifications are written to limit the amount of aromatic compounds as well as naphthalenes. However, it is possible that JFTOT failure can still occur if the aromatics present contain reactive side chains. Cycloparaffinic side groups or... 

In conclusion, the IBTFA-mediated Hofmann rearrangement is the most convenient method for the synthesis of the N-acylated gem-diaminoalkyl derivatives and is certainly the most frequently used procedure for the generation of peptidyl gem-diaminoalkyl derivatives. However, as mentioned above, this method has limitations with regards to the choice of protecting groups and therefore requires careful consideration when applied to amino acids with reactive side chains. 

P" Knowledge about the structure-function interrela-i tionships in proteins and peptides has encouraged biochemists to develop techniques for synthesizing peptides and proteins with predetermined sequences. To synthesize a peptide in the laboratory, we must overcome several problems related to preventing undesired groups from reacting. The amino and carboxyl groups that are to remain unlinked must be blocked so must all reactive side chains. 

The proportion of reactions in the side chain, relative to those at the a-carbon atom, increases with the size of the side chain. In amino acids with a reactive side chain, such as the aromatic and sulfur-containing amino acids, this proportion is increased further. Similar trends are found in the data for amino acid destruction. Thus, Shimazu and Tappel (34) found that at pH 7 in 0.01M solution the most radiolabile among the amino acids studied were phenylalanine and methionine. They also showed an increase in radiolability with the size of the side chain for aliphatic amino acids. In comparing the radiolabilities of the amino acids, it should be borne in mind that pH and concentration effects vary from one amino acid to another. 

Zugates GT, Anderson DG, Little SR et al (2006) Synthesis of poly(beta-amino ester)s with thiol-reactive side chains for DNA delivery. J Am Chem Soc 128 12726-12734... 

In solid phase peptide synthesis, polypeptides are chemically synthesized by addition of free amino acids to a tethered peptide. To prevent unwanted reactions, the a-amino group and reactive side chain groups of the free amino acids are chemically protected or blocked, and then deprotected or deblocked once the amino acid is attached to the growing polypeptide chain. 

Protein chemical modification is a problem-solving technique in research and technology. Modifications also occur in natural deteriorations. Generally these modifications are with the most reactive side chains and are predominantly oxidations, reductions, and nucleophilic and electrophilic substitutions. Deteriorations include peptide bond scissions, racemizations, fi-eliminations, and formation of products by the reaction of proteins with added chemicals. Proteins are modified intentionally for structure-function relationship studies or for development of new and improved products. Although appearing quite varied, the techniques used in pharmacological, food and feed, or other industrial areas differ more operationally than from major differences in the levels of chemical sophistication that are used. 

Among the more important factors affecting reactions with proteins, pH is the most important since it controls the distribution of potentially reactive side chains between reactive and unreactive ionization states (see Table II). Iodoacetic acid is a commonly used reagent in protein modifications and serves as an example. At low pH values (such as 2-5)... 

The active sites of enzymes frequently contain residues whose side chains play an important role in catalysis particularly because their reactivity is exacerbated by the local environment. Affinity labeling by reagents designed to dock in the active site and that able to form a stable covalent bond with a reactive side chain has been used to extract active enzymes or abzymes from libraries. 

Guga, P.J., Bozzini, M., DeFranco, R.J., Large, G.B., and Boyd, V.L. (1993). C-terminal Sequence Analysis of the Amino Acid Residues with Reactive Side-Chains Ser, Thr, Cys, Glu, Asp, His, Lys. Presented at the Seventh Symposium of the Protein Society, San Diego, CA. 

Besides HF and TFA, the two extremes of acid treatment generally employed in the final deprotection step, alternative acids have been proposed, such as MsOH and TfOH, particularly in the context of arginine protection (Table 2). These acids, however, are known to generate serious side reactions such as aspartimide formationt and an N O shift at serine or threonine residues.Moreover, independent of the type of arylsulfonyl group employed, cations originating from the acid-mediated cleavage lead to alkylation and arylsulfonylation of reactive side chains, as present in tryptophan and tyrosine residues. Additionally, sulfation of hydroxy groups is even observed, as well as... 

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