Nucleophilic acylation catalyst

In 1967, (3) it was discovered that DMAP catalyzes the benzoylation of m-chloroaniline 10 times faster than pyridine. This enormous increase in reaction rate is unmatched by any other nucleophilic acylation catalyst (3. It was shown that the catalytic action of DMAP and PPY is not primarily due to their larger pKa s with respect to pyridine, but is a result of enhanced nucleophilic catalysis. 

NUCLEOPHILIC ACYLATION CATALYSTS EFFECT ON LUMINOL CHEMILUMINESCENCE... 

This type of reaction is often accelerated by nucleophilic acylation catalysts,7 especially 4-aminopyridines. This study investigates the effect of these compounds on chemiluminescence light output when used in association with redox enhancers and their use in substrates for HRP chemiluminescent assays with the goal to achieve a higher detectability of HRP. 

Pyridines, and especially 4-dialkylaminopyrines, are well-known nucleophilic acylation catalysts and are widely used in organic synthesis.7 When they are added to the SPTZ substrate the reported7 overall reactivity is observed ... 

Nucleophilic Acylation Catalysts Effect on Luminol Chemiluminescence 133... 

Marzocchi E, Grilli S, Della Ciana L, Mirasoli M, Prodi L, Roda A. Chemiluminescent detection systems of horseradish peroxidase employing nucleophilic acylation catalysts. Anal Biochem, accepted for publication. 

This reaction was initially reported by Einhorn and Hollandt in 1898. It is the acylation of alcohols using anhydride or acyl haUde in a tertiary amine such as pyridine. Therefore, this reaction is known as the Einhorn acylation, Einhorn reaction, and Deninger-Einhorn method." The function of tertiary amines in this reaction have been identified as both nucleophilic acylation catalyst and acid scavenger. The solid evidence of nucleophilic catalyst is to record the UV spectrum of the intermediate acetylpyridinium salt in water. Subsequently, a number of highly nucleophilic tertiary amines have been employed for the acylation of alcohols. These tertiary amines include triethylamine, 4-(dimethylamino)pyridine (DMAP), l,4-diazabicyclo[2.2.2]octane and... 

Breslow and co-workers elucidated the currently accepted mechanism of the benzoin reaction in 1958 using thiamin 8. The mechanism is closely related to Lapworth s mechanism for cyanide anion catalyzed benzoin reaction (Scheme 2) [28, 29], The carbene, formed in situ by deprotonation of the corresponding thiazolium salt, undergoes nucleophilic addition to the aldehyde. A subsequent proton transfer generates a nucleophilic acyl anion equivalent known as the Breslow intermediate IX. Subsequent attack of the acyl anion equivalent into another molecule of aldehyde generates a new carbon - carbon bond XI. A proton transfer forms tetrahedral intermediate XII, allowing for collapse to produce the a-hydroxy ketone accompanied by liberation of the active catalyst. As with the cyanide catalyzed benzoin reaction, the thiazolylidene catalyzed benzoin reaction is reversible [30]. 

Esters are produced by acid-catalysed reaction of carboxylic acids with alcohols, known as Fischer esterification. They are also obtained from acid chlorides, acid anhydrides and other esters. The preparation of esters from other esters in the presence of an acid or a base catalyst is called transesterification. All these conversions involve nucleophilic acyl suhstitu-tions (see Section 5.5.5). 

If the nucleophile is a neutral molecule with a lone pair of electrons (H2O, ROH), it requires an acid catalyst for nucleophilic addition reaction to occur. Under acidic conditions, the carhonyl group becomes protonated, and thus is activated towards nucleophilic acyl substitution. Attack by a weak nucleophile generates the tetrahedral intermediate. A simultaneous deprotonation and loss of the leaving group reforms the carbonyl C=0 double bond. 

Preparation of esters Acid chlorides react with alcohols to give esters through a nucleophilic acyl substitution. Because acid chloride is reactive towards weak nucleophile, e.g. alcohol, no catalyst is required for this substitution reaction. The reaction is carried out in base, most commonly in pyridine or triethylamine (EtaN). 

Scheme 5.2 outlines our design of nucleophilic transacylation catalysts based on crown-complexed alkaline-earth metal ions. By virtue of the acidity-enhancing effect ofthe complexed metal ion, dissociation ofthe proton-ionizable function XH should take place under moderately basic conditions. The metal ion assists acyl transfer from a reactant ester to the catalyst and its subsequent transfer from the acylated catalyst to an external nucleophile (solvent), thus restoring the active form of the... 

In analogy with iron-catalyzed Barbier-type reactions with Sml2 (cf. Scheme 8.5), intramolecular nucleophilic acyl substitutions (SNt) can be used to prepare cyclic ketones from esters [50]. An illustrative example is shown in Scheme 8.13 [51], Again, tris(l,3-diphenyl-l,3-propanedionato)iron(III) [Fe(dbm)3] is used as the catalyst. Compound 40 is obtained as one racemic diastereoisomer. 

Direct nucleophilic acylation of nitroalkenes (164), promoted by a combination of (g) fluoride anion and thiourea catalyst (165), has been developed, using the thiazolium derivative (163) as the umpolung reagent (<20 1 dr, 74% ee).214 ... 

In addition to phosphines and pyridines, N-alkylated imidazoles are also known to act as a nucleophilic catalysts in acylation reactions [1], In the approach by Miller et al. short oligopeptides incorporating N-alkylhistidine derivatives were used as enantioselective acylation catalysts [27]. The design of, e.g., the tripeptide... 

Catalytic kinetic resolution of amines has been a typical domain of enzymatic transformations. Attempts to use low-molecular-weight catalysts have notoriously been frustrated by the rapid uncatalyzed background reaction of the amine substrate with the acyl donor [40]. The first solution to this problem was recently developed by Fu, who used the planar chiral catalyst 21d and O-acyl azlactone 40 as the acyl donor (Scheme 12.19) [41]. In this process, the acyl transfer from the azlactone 40 to the nucleophilic catalyst 21d is rapid relative to both direct transfer to the substrate and to the transfer from the acylated catalyst to the substrate amine. Under these conditions, which implies use of low reaction temperatures, selectivity factors as high as 27 were achieved (Scheme 12.19) [41]. 

In the benzoin condensation, a new stereogenic center is formed, as the product is an a-hydroxy ketone. Consequently, many chemists aspired to develop heterazolium-catalyzed asymmetric benzoin condensations and, later, other nucleophilic acylation reactions [9]. For example, Sheehan et al. presented the first asymmetric benzoin condensation in 1966, with the chiral thiazolium salt 7 (Fig. 9.2) as catalyst precursor [10]. 

Taylor and Morken extended the use of IR-thermography to the monitoring of the change in the heat of reaction on and in the surroundings of a bead carrying an active catalyst (Figure 5.4.4) [13]. In a search for acylation catalysts an encoded library of 3150 different potential nucleophilic catalysts was prepared by the split-and-mix procedure and tested for their acylation properties. The library beads were spread in a reaction solution of chloroform-ethanol-triethylamine-acetic anhydride, 40 6 6 3, and monitored with an IR camera. Whereas no detectable thermal... 

The Fischer esterification mechanism (Key Mechanism 20-2) is an acid-catalyzed nucleophilic acyl substitution. The carbonyl group of a carboxylic acid is not sufficiently electrophilic to be attacked by an alcohol. The acid catalyst protonates the carbonyl group and activates it toward nucleophilic attack. Attack by the alcohol, followed by loss of a proton, gives the hydrate of an ester. 

Some reactions that can go as basic nucleophilic acyl substitutions actually work much better with an acid catalyst. For example, aspirin is made from salicylic acid and acetic anhydride. When these reagents are mixed, the reaction goes slowly. Addition of a drop of sulfuric acid accelerates the reaction, and it goes to completion in a minute or two. 

One particular amino-pyridine has a special role as a more effective acylation catalyst than pyridine itself. This is DMAP (DiMethylAminoPyridine) in which the amino group is placed to reinforce the nucleophilic nature of the... 

Referring to a mechanistic classification of organocatalysts (Seayad and List 2005), currently the two most prominent classes are Brpnsted acid catalysts and Lewis base catalysts. Within the latter class chiral secondary amines (enamine, iminium, dienamine activation for a short review please refer to List 2006) play an important role and can be considered as—by now—already widely extended mimetics of type I aldolases, whereas acylation catalysts, for example, refer to hydrolases or peptidases (Spivey and McDaid 2007). Thiamine-dependent enzymes, a versatile class of C-C bond forming and destructing biocatalysts (Pohl et al. 2002) with their common catalytically active coenzyme thiamine (vitamin Bi), are understood to be the biomimetic roots ofcar-bene catalysis, a further class of nucleophilic, Lewis base catalysis with increasing importance in the last 5 years. 

Recently, the asymmetric variants of the Stetter [114-118], crossed-benzoin [114, 117-120], and transeslerification [121] reactions have attracted great interest as asymmetric nucleophilic acylation processes. A prerequisite for asynunetric catalysis is the availability of a chiral catalyst. Introduction of chirahty into the thiamin framewoik follows the same principles as that for the related imidazoUum systems, mainly the introduction of a chiral centre next to the nitrogen atom of the thiazole ring [117]. 

Esters can also be synthesized by a nucleophilic acyl substitution reaction of a carboxylic acid with an alcohol. Fischer and Speier discovered in 1895 that esters result simply from heating a carboxylic acid in alcohol solution containing a small amount of strong acid catalyst. Yields are good in this Fischer esterification reaction, but the need to use excess alcohol as solvent limits the method to the synthesis of methyl, ethyl, and propyl esters. 

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