Carboxylic acid deprotonation

The galacturonic acids of a plant cell wall mainly belong to smooth chains of homopolygalacturonic acid (PGA) and to hairy regions of rhamnogalacturonan I (RGI). In green plants, other uronic acids can be found in hemicelluloses. Provided they are not methylesterified, all these carboxylic acids deprotonate at the more or less acidic pH of wall water. The electrostatic charges of these polyanions are then compensated by cations ultimately derived from the environment. 

Introduction of the auxiliary 52 to the substrate required the acylation of the oxazolidinone nitrogen with various carboxylic acids. Deprotonation and subsequent alkylation with different electrophiles (R2X) were performed. Through LiOOH mediated hydrolysis, the a-branched carboxylic acids 53 were obtained in 50-70% yield and enantiomeric excesses of 84—97% (Scheme 12.20). The resin-bound chiral auxiliary 52 could be recovered and recycled, thereby maintaining stereoselectivity. 

Watch out Carboxylic acids are called acids because they are acidic. They will deprotonate in base before they do any other reactions typical of compounds containing carbonyl groups. Everyone forgets that seemingly simple fact, and problem writers may try to trap you. Always remember A carboxylic acid deprotonates in base. 

Now, let s draw the forward scheme. Radical bromination of 2-methylbutane produces the tertiary alkyl hahde, selectively. Then, elimination with NaOEt, followed by awti-Markovnikov addition (HBr / peroxides), and then elimination with iert-butoxide, followed by another awri-Markovnikov addition (HBr / peroxides) produces l-bromo-3-methylbutane. This alkyl hahde will then undergo an Sn2 reaction when treated with an acetylide ion to give 5-methyl-1-hexyne. Ozonolysis of this terminal alkyne cleaves the CC triple bond, producing the carboxylic acid. Deprotonation (with NaOH) produces a carboxylate nucleophile that subsequently reacts with bromomethane in an Sn2 reaction to give the desired ester. 

Section 19 5 Although carboxylic acids dissociate to only a small extent in water they are deprotonated almost completely m basic solution... 

Once formed the tetrahedral intermediate can revert to starting materials by merely reversing the reactions that formed it or it can continue onward to products In the sec ond stage of ester hydrolysis the tetrahedral intermediate dissociates to an alcohol and a carboxylic acid In step 4 of Figure 20 4 protonation of the tetrahedral intermediate at Its alkoxy oxygen gives a new oxonium ion which loses a molecule of alcohol m step 5 Along with the alcohol the protonated form of the carboxylic acid arises by dissocia tion of the tetrahedral intermediate Its deprotonation m step 6 completes the process... 

In base the carboxylic acid is deprotonated giving a carboxylate ion... 

Section 20 11 Ester hydrolysis m basic solution is called saponification and proceeds through the same tetrahedral intermediate (Figure 20 5) as m acid catalyzed hydrolysis Unlike acid catalyzed hydrolysis saponification is irreversible because the carboxylic acid is deprotonated under the reac tion conditions... 

The dianions derived from furan- and thiophene-carboxylic acids by deprotonation with LDA have been reacted with various electrophiles (Scheme 64). The oxygen dianions reacted efficiently with aldehydes and ketones but not so efficiently with alkyl halides or epoxides. The sulfur dianions reacted with allyl bromide, a reaction which failed in the case of the dianions derived from furancarboxylic acids, and are therefore judged to be the softer nucleophiles (81JCS(Pl)1125,80TL505l). 

Unsubstituted 3-alkyl- or 3-aryl-isoxazoles undergo ring cleavage reactions under more vigorous conditions. In these substrates the deprotonation of the H-5 proton is concurrent with fission of the N—O and C(3)—-C(4) bonds, giving a nitrile and an ethynolate anion. The latter is usually hydrolyzed on work-up to a carboxylic acid, but can be trapped at low temperature. As shown by Scheme 33, such reactions could provide useful syntheses of ketenes and /3-lactones (79LA219). 

In the discussion of the relative acidity of carboxylic acids in Chapter 1, the thermodynamic acidity, expressed as the acid dissociation constant, was taken as the measure of acidity. It is straightforward to determine dissociation constants of such adds in aqueous solution by measurement of the titration curve with a pH-sensitive electrode (pH meter). Determination of the acidity of carbon acids is more difficult. Because most are very weak acids, very strong bases are required to cause deprotonation. Water and alcohols are far more acidic than most hydrocarbons and are unsuitable solvents for generation of hydrocarbon anions. Any strong base will deprotonate the solvent rather than the hydrocarbon. For synthetic purposes, aprotic solvents such as ether, tetrahydrofuran (THF), and dimethoxyethane (DME) are used, but for equilibrium measurements solvents that promote dissociation of ion pairs and ion clusters are preferred. Weakly acidic solvents such as DMSO and cyclohexylamine are used in the preparation of strongly basic carbanions. The high polarity and cation-solvating ability of DMSO facilitate dissociation... 

A number of studies of the acid-catalyzed mechanism of enolization have been done. The case of cyclohexanone is illustrative. The reaction is catalyzed by various carboxylic acids and substituted ammonium ions. The effectiveness of these proton donors as catalysts correlates with their pK values. When plotted according to the Bronsted catalysis law (Section 4.8), the value of the slope a is 0.74. When deuterium or tritium is introduced in the a position, there is a marked decrease in the rate of acid-catalyzed enolization h/ d 5. This kinetic isotope effect indicates that the C—H bond cleavage is part of the rate-determining step. The generally accepted mechanism for acid-catalyzed enolization pictures the rate-determining step as deprotonation of the protonated ketone ... 

The acid-base reactions that occur after the amide bond is broken make the overall hydrolysis ineversible in both cases. The amine product is protonated in acid the carboxylic acid is deprotonated in base. 

The reaction mechanism involves deprotonation of the carboxylic anhydride 2 to give anion 4, which then adds to aldehyde 1. If the anhydride used bears two a-hydrogens, a dehydration takes place already during workup a /3-hydroxy carboxylic acid will then not be isolated as product ... 

Lster hydrolysis occurs through a typical nucleophilic acyl substitution pathway in which hydroxide ion is the nucleophile that adds to the ester carbonyl group to give a tetrahedral intermediate. Loss of alkoxide ion then gives a carboxylic acid, which is deprotonated to give the carboxylate ion. Addition of aqueous HC1 in a separate step after the saponification is complete then pro-tonates the carboxylate ion and gives the carboxylic acid (Figure 21.17). 

Basic hydrolysis occurs by nucleophilic addition of OH- to the amide carbonyl group, followed by elimination of amide ion (-NH2) and subsequent deprotonation of the initially formed carboxylic acid by amide ion. The steps are reversible, with the equilibrium shifted toward product by the final deprotonation of the carboxylic acid. Basic hydrolysis is substantially more difficult than the analogous acid-catalyzed reaction because amide ion is a very poor leaving group, making the elimination step difficult. 

The 20 common amino acids can be further classified as neutral, acidic, or basic, depending on the structure of their side chains. Fifteen of the twenty have neutral side chains, two (aspartic acid and glutamic acid) have an extra carboxylic acid function in their side chains, and three (lysine, arginine, and histidine) have basic amino groups in their side chains. Note that both cysteine (a thiol) and tyrosine (a phenol), although usually classified as neutral amino acids, nevertheless have weakly acidic side chains that can be deprotonated in strongly basic solution. 

Although lithium aldolates generally display a rather moderate preference for the u/f/z-isomer4, considerable degrees of diastereoselectivity have been observed in the reversible addition of doubly deprotonated carboxylic acids to aldehydes20. For example, the syn- and uw/z-alkox-ides, which form in a ratio of 1.9 1 in the kinctically controlled aldol addition, equilibrate in tetrahydrofuran at 25 C after several hours to a 1 49 mixture in favor of the anti-product20. 

A completely different dipolar cycloaddition model has been proposed39 in order to rationalize the stereochemical outcome of the addition of doubly deprotonated carboxylic acids to aldehydes, which is known as the Ivanov reaction. In the irreversible reaction of phenylacetic acid with 2,2-dimethylpropanal, metal chelation is completely unfavorable. Thus simple diastereoselectivity in favor of u f/-adducts is extremely low when chelating cations, e.g., Zn2 + or Mg- +, are used. Amazingly, the most naked dianions provide the highest anti/syn ratios as indicated by the results obtained with the potassium salt in the presence of a crown ether. 

On the other hand, syn-carboxylic acids are obtained from a deprotonation of the /5-silyl ester, giving the (E)-enolate, followed by reaction with different aldehydes and subsequent hydrogenolysis. No diastereomers of the aldol product are detected720. 

A similar case of enolatc-controlled stereochemistry is found in aldol additions of the chiral acetate 2-hydroxy-2.2-triphenylethyl acetate (HYTRA) when both enantiomers of double deprotonated (R)- and (S)-HYTRA are combined with an enantiomerically pure aldehyde, e.g., (7 )-3-benzyloxybutanal. As in the case of achiral aldehydes, the deprotonated (tf)-HYTRA also attacks (independent of the chirality of the substrate) mainly from the /te-side to give predominantly the t/nii-carboxylic acid after hydrolysis. On the other hand, the (S)-reagcnt attacks the (/ )-aldebyde preferably from the. S7-side to give. s wz-carboxylic acids with comparable selectivity 6... 

As suggested by Roberts and Moreland many years ago (1953), the acidity constants of 4-substituted bicyclooctane-l-carboxylic acids provide a very suitable system for defining a field/induction parameter. In this rigid system the substituent X is held firmly in place and there is little possibility for mesomeric delocalization or polarization interactions between X and COOH (or COO-). Therefore, it can be assumed that X influences the deprotonation of COOH only through space (the field effect) and through intervening o-bonds. On this basis Taft (1956, p. 595) and Swain and Lupton (1968) were able to calculate values for o and crR. 

It has been found that the tris(tert-butyloxycarbonyl) protected hydantoin of 4-piperidone 2, selectively hydrolyses in alkali to yield the N-tert-butyloxycarbonylated piperidine amino acid 3. The hydrolysis, which is performed in a biphasic mixture of THF and 2.0M KOH at room temperature, cleanly partitions the deprotonated 4-amino-N -(tert-butyloxycarbonyl)piperidine-4-carboxylic acid into the aqueous phase of the reaction with minimal contamination of the hydrolysis product, di-tert-butyl iminodicarboxylate, which partitions into the THF layer. Upon neutralization of the aqueous phase with aqueous hydrochloric acid, the zwitterion of the amino acid is isolated. The Bolin procedure to introduce the 9-fluorenylmethyloxycarbonyl protecting group efficiently produces 4.8 This synthesis is a significant improvement over the previously described method9 where the final protection step was complicated by contamination of the hydrolysis side-product, di-tert-butyl iminodicarboxylate, which is very difficult to separate from 4, even by chromatographic means. 

Heteroarylphenylalanines could be smoothly obtained via microwave-promoted Suzuki reaction of heteroaryl halides with 2-amino-3-[4-(dihy-droxyboryl)phenyl]propanoic acid (Scheme 28) [46]. Interestingly, the free amino acid could be used without any protection of the amine and carboxylic acid fimctionahty. When 4-(dihydroxyboryl)-L-phenylalanine was used as organometallic partner no racemization was observed. The carboxylate anion and free amino group seem to shield the a-C - H from deprotonation and thus hmit racemization. 

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