Acids, esterification using carbodiimide

The carboxylic functionalities inserted onto the tubes can be used as platforms to obtain further transformations (Fig. 3.5). A commonly utilized route is the reaction of carboxylic groups with thionyl chloride or oxalyl chloride to prepare the corresponding acyl chlorides, which are useful intermediates for amidation or esterification reactions. Amides can also be prepared directly from the acids by means of standard solution chemistry conditions, using carbodiimide derivatives in the presence of the selected amine. 

Support-bound phenols [173-176] or other compounds with an acidic OH group (oximes [177-179], hydroxamic acids, /V-hydroxy benzotriazoles, etc.) undergo rapid esterification with carbodiimides as coupling agents (Entries 13 and 14, Table 13.12). The resulting products are susceptible to nucleophilic attack, and can be used as insoluble acylating agents. 

A.7.1 Esterification of Acids using Carbodiimides. The formation of anhydrides from carboxylic acids, thiocarboxylic acids, sulfonic acids and phosphorous acids are discussed in Section 2.4.S.2. In this section only special cases of anhydride formation are described. Mixed anhydrides of amino acids and adenylic acid are produced from the corresponding acids using DCC as the condensation agent. ° Mixed anhydrides not containing amino acids, such as butyryl adenate, adenosine 5 -phosphosulfate and p-nitrophenyl-thymidine-5-phosphate are also obtained. 

Phenolic esters are obtained similarly. The presence of a nitro group in the aromatic nucleus and the use of pyridine as solvent facilitates the reaction. This reaction is recommended for the characterization of phenols. 2,4,5-Trichlorophenyl-, pentachlorophenyl-, 4-nitrophenyl- and thiophenyl esters of N-acylamino acids are prepared in this manner. These aromatic esters are used in the stepwise lengthening of peptides, du Vigneaud and coworkers synthesized lysine vasopressin from a nonapeptide which they prepared stepwise using the nitrophenyl ester method. Room temperature esterification of dicarboxylic acids and diphenols are also carbodiimide mediated using the 1 1 complex derived from DMAP and p-toluenesulfonic acid as catalyst Methacrylic acid is also esterified with phenols using carbodiimides and DMPA to mediate the reaction. ... 

In view of the rapid reaction of carbodiimides with water they are often used in dehydration reactions. Major examples are the intra- and intermolecular esterification reactions of carboxylic acids, and the formation of peptides from carboxylic acids and protected amino acids. Especially, dicyclohexylcarbodiimide (DCC) or diisopropylcar-bodiimide (DIPCD) are often used in carbodiimide mediated reactions because the corresponding urea byproducts are insoluble in most organic solvents and water, and therefore are readily removed by filtration. Also, water soluble carbodiimides, such as N-ethyl-N -(3-dimethylamino)propylcarbodiimide (EDC) or its hydrochloride (EDCCl, sometimes referred to as EDAC) are often used in these reactions. EDC reacts with carboxyl groups at pH of 4.0-6.0, but loses its reactivity at lower pH. Sometimes solid phase reactions are conducted using carbodiimide terminated linear or crosslinked polymers. 

Compounds such as 4-nitrophenyl and 2,4,5-trichlorophenyl esters of N-protected amino acids were originally prepared also by reaction of the N-protected acids with di- or trisub-stituted esters of carbonic,sulfinic,f l or phosphinic acids l in, or with addition of, pyridine. This was followed by the use of mixed carbonates 54 that served both for acylation of amino acid 53 to N-protected acid 55 and subsequent esterification to 56 using carbodiimide (Scheme 13).A variant of this was the preparation of the unusual l,l,4-trioxo-2,5-di-phenyl-4,5-dihydro-3-thienyl 57 esters of Boc amino acids 56c, which avoided the use of carbodiimide since esterification proceeds in the presence of tetramethylguanidine.P l... 

In summary, among the carbodiimide-based methods only the carbodiimide/dialkyl-aminopyridine technique has been widely used in the synthesis of depsipeptides. It usually affords the desired products in moderate or high yield and has good potential for routine use in the esterification of urethane-protected amino acids or peptide fragments even in the case... 

Support-bound primary or secondary aliphatic alcohols can be acylated under conditions similar to those used in solution, provided that these conditions are compatible with the chosen linker. For instance, acids can be activated with a carbodiimide either as symmetric anhydrides or as O-acylisoureas, which quickly react with alcohols in the presence of a catalyst, such as DMAP or another base, to yield esters (Table 13.12). Further acid derivatives suitable for esterification reactions on solid phase include acyl halides and imidazolides. HOBt esters react only slowly with alcohols, but enable the selective acylation of primary alcohols in the presence of secondary alcohols (Entry 5, Table 13.12). 

In a related study by the same authors, the effect of microwave irradiation on carbodiimide-mediated esterifications on solid support has been investigated employing benzoic acid28. Activation of the carboxylic acid was carried out using diisopropy-lcarbodiimide (DIC) via the O-acyl isourea or the symmetrical anhydride protocol, respectively (Scheme 7.8). 

The combination of carboxyl activation by a carbodiimide and catalysis by DMAP provides a useful method for in situ activation of carboxylic acids for reaction with alcohols.10 The reaction proceeds at room temperature. Carbodiimides are widely applied in the synthesis of polypeptides from amino acids. The proposed mechanism for this esterification reaction involves activation of the acid via isourea 28 followed by reaction with another acid molecule to form anhydride... 

Esterification with alcohols in the presence of pyridine was used by Felder et al. [36]. Water produced in the reaction mixture is bound by the addition of N,N -dicyclohexyl-carbodiimide (Scheme 4.8). The acid (ca. 10 mequiv.) is dissolved in 25 ml of alcohol and 4 ml of pyridine and an excess of dicyclohexylcarbodiimide (12 mequiv.) are added (even more if the sample is not dry). The amount of pyridine can also be larger and it then acts as a solvent, e.g., if the alcohol used is solid (menthol). The mixture is then stirred at room temperature only with some higher alcohols or acids must the mixture be heated at 40—80°C for 30—120 min. If a precipitate of N,N -dicyclohexylurea is produced in the reaction, it is allowed to sediment and, after adding an internal standard,... 

The formation of ketene intermediates facilitates the carbodiimide mediated esterification reaction with alcohols and phenols when carboxylic acids with an electron withdrawing group in the a-position are used as substrates. ... 

Linear soluble PEG (polyethylene glycol) is used as a liquid phase in the synthesis of polypeptides. In this case the esterification of the carboxylic acid group of the N-protected amino acids with the terminal - OH groups of PEG can be conducted using DCC or a water soluble carbodiimide to give 684. Reaction of 684 with a different N-protected amino acid produces 685. 

The soluble oligomeric carbodiimide is used as a coupling reagent for esterification, ami-dation and dehydration of carboxylic acids. 

Organothiols chemisorbed on gold surfaces are especially usefiil for electrochemical and chemical studies. For example, carboxylic acid terminated monolayers are often used. An example is the attachment of cytochrome C with its side chain lysine groups to acid terminated self assembled monolayer gold electrodes. Carbodiimide mediated esterification of ferrocene-l,l -dicarboxylic acid with phenols is used to construct thermotropic liquid crystals. ... 

Polymeric carbon nanocomposites are often functionalized with matrix polymers. An example is the functionalization of SWNTs and MWNTs with poly(vinyl alcohol) using a carbodiimide mediated esterification reaction. Also, poly(ethylene-co-vinyl alcohol) is used for this purpose to produce DMSO soluble functionalized SWNTs. In a similar manner poly(m-aminobenzene sulfonic acid) is covalently bonded to SWNTs to form water soluble graft copolymers. ... 

Monobifunctional crossUnkers, synthesized in the carbodiimide mediated esterification of dicarboxylic acids in the presence of sodium N-hydroxysuccinimide-3-sulfonate, are used in the mapping of protein structures. " ... 

To avoid any possible a — 7 conversion promoted by the anhydrous conditions during esterification Franzblau (1962) and Franzblau el al. (1963) developed a method by which the hydroxamic acids could be formed directly from the unmodified proteins in an aqueous system. This was achieved using a water-soluble carbodiimide, 1-cyclohexyl-3[2-morpholinyl-(4)-ethyl]-carbodiimide metho-p-toluene sulfonate (Fig. 5). The reaction conditions (pH 4, 25°C, in aqueous medium) eliminated any possibility of a —> 8 conversion. These conditions also precduded the possibility of hydroxyaminolysis of the natural ester linkages of collagen which will be discussed in Section V. This method, in common with all the others used to study 7-glutamyl links, was not quantitative. After subsecpient dini-... 

RCO2H, R OH, DCC/DMAP, EtjO, 25°C, l-24h, 70-95% yield. This method is suitable for a large variety of hindered and unhindered acids and alcohols. The use of Sc(OTf)3 as a cocatalyst improves the esterification of 3° alcohols. Carboxylic acids that can form ketenes with DCC react preferentially with aliphatic alcohols in the presence of phenols whereas those that do not show the opposite selectivity. In some sterically congested situations the 0-acyl urea will migrate to an unreactive A-acyl urea in competition with esterification. Carbodi-imide I was developed to make the urea by-product water soluble and thus easily washed out. Isoureas are prepared from a carbodiimide and an alcohol which upon reaction with a carboxylic acid give esters in excellent yield. A polymer supported version of this process has been developed. This process has been reviewed. Note that DCC is a potent skin irritant in some individuals. 

The resin-supported carbodiimide 2 (R = Cy), related to the popular solution phase reagent dicyclohexylcarbodiimide (DCC), has been the most successfully employed polymeric carbodiimide of this series, especially in the presence of additives to accelerate the coupling reaction and avoid the acylisourea-unreactive acylurea rearrangement [2]. This carbodiimide has been used for esterification reactions, as exemplified in the reaction of dithiane-containing alcohol 3 with Fmoc-protected valine in the presence of a catalytic amount of N,N-dimethylami-nopyridine (DMAP) to give ester 4 [10] (Scheme 7.1). This polymer-supported reagent 2 (R = Cy) has also been used without any additive in the amidation reaction of 3,4-diaminocyclopentanol scaffolds with 2-(methylsulfanyl)acehc acid [11]. 

Carboxylic acids can be attached to these linkers using methods of ester bond formation such as carbodiimide/DMAP [23] and acid chloride/base. For the loading of N-protected-a-amino acids in particular, an array of different methods has been developed to minimize enantiomerizahon and dipeptide formation during the esterification reaction. These include the use of MSNT/N-methylimidazole [24], mixed anhydrides generated with 2,6-dichlorobenzoyl chloride [25], esters of 2,5-diphenyl-2,3-dihydro-3-oxo-4-hydroxythiophene [26] and acid fluorides [27]. Phenols and N-protected hydroxylamines have been immobilized using the Mitsunobu reaction [28, 29], The latter are particularly useful for the preparation of hydroxamates [29, 30],... 

Since esterification is essentially a condensation reaction between a carboxylic acid and an alcohol with the elimination of water, coupling reagents such as the carbodiimides [113-115] also work well for esterification. Figure 4 shows a typical reaction using dicyclohexyl-carbodiimide (DCCI) [116]. Dicyclohexylurea is formed as a by-product. 

The most relevant methodologies of reaction for the formation of esters, which are also used in the context of PVMRs for esterification, are hereafter proposed. For the purpose of this work, information about Lewis acid-activators, esterification base-activators, carbodiimide activators, the Mitsunobu reaction, induced activation of the condensation reaction using template compounds, and other reaction methodologies between carboxylic acids and alcohols used in ester synthesis will not be proposed. For this information, the reader is referred to the literature (Otera, 2003). 

Materials-. PVC pellets, extrusion medical-grade RB1/T3M of 1.25 g cm density, were obtained from ModerrPlast (Italy) and used as received. Pectin from apple, (BioChemika, with esterification of 70-75%), acrylic acid (AA) (99.0%, anhydrons), and V-(3-dimethyl aminopropyl)-V -ethyl carbodiimide hydrochloride (EDAC, 98.0%) were supplied by Fluka (USA). Chitosan from crab shells with meditun molecttlar weight and deacetylation degree of 75-85%. 

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