Phenol reacts with thionyl chloride


11. Carboxylic acids and their derivatives - nucleophilic substitutions

If a hydroxyl group is bonded to the carbon atom of the carbonyl group, a new functional group results, the Carboxy groupthat for the Carboxylic acids is characteristic. While there are numerous carboxylic acid derivatives, we will only consider four here. The nitrile group is also formally the derivative of a carboxylic acid:

11.1 Nomenclature

11.1.1 Carboxylic acids

The common names of many carboxylic acids are common. In the IUPAC system, the name of a carboxylic acid is derived from the name of the parent alkane by adding the word -acid derived. The stem of the alkanoic acid is numbered so that the carbon of the carboxy group is numbered 1. All substituents along the longest chain that contains the functional group are then provided with a corresponding number. The carboxy group has a higher priority than any other group discussed so far. Saturated cyclic acids are called Cycloalkanecarboxylic acids. Dicarboxylic acids are systematically called Alkanedioic acids, but often named by their common name.

Carboxylic acid Acyl group
structure Surname Natural occurrence Surname structure
HCOOH Formic acid (Formic) Ants Formyl HCO-
CH3COOH Acetic acid vinegar Acetyl CH3CO-
CH3CH2COOH Propionic acid (propionic) Dairy products Propionyl CH3CH2CO-
CH3CH2CH2COOH Butyric acid rancid butter Butyryl CH3(CH2)2CO-
CH3(CH2)3COOH Pentanoic acid (Valeric) Valerian roots    
CH3(CH2)4COOH Hexanoic acid (Caproic) Goat smell    
HOOC-COOH Oxalic acid   Oxalyl -OCCO-
HOOC-CH2-COOH Malonic acid (Malonic)   Malonyl -OCCH2CO-
HOOC-CH2CH2-COOH Succinic acid   Succinyl -OCCH2CH2CO-
CH2= CHCOOH Acrylic acid   Acryloyl CH2= CHCO

11.1.2 Alkanoyl halides

The compounds of the RCOX type are named according to the IUPAC nomenclature in such a way that the name of the parent alkane of the carboxylic acid from which they are derived has the ending -oyl halide appends. In the nomenclature that is still mostly used, the name is formed from the name of the stem of the acid group and the ending halide. According to the latest nomenclature, the chloride of acetic acid would then be called ethanoyl chloride, in the other case acetyl chloride:

11.1.3 Carboxylic acid anhydrides

Carboxylic acid anhydrides are formed from the carboxylic acids by dehydration. Accordingly, they are also named by adding the word anhydride simply appending to the name of the acid:

11.1.4 Esters

According to the latest IUPAC nomenclature, esters are called alkyl alkanoates. In the German-speaking area, however, three different nomenclatures are used, e.g .:

Cyclic esters are called Lactones.

11.1.5 amides

Amides are systematically referred to as Alkanamides, in the case of the trivial names, the ending -amid attached. Substituents on nitrogen are identified by the prefix N- or N, N-, depending on the number of bound groups. Depending on the number of groups bound to the nitrogen, a distinction is made between primary, secondary and tertiary amides. Cyclic amides are called Lactams :

11.1.6 nitriles

This class of compounds is systematically referred to as Alkane nitriles. In the case of the trivial name, the ending is usually added to the root of the word for acid -nitrile attached. Occasionally one also appends the ending to the name of the alkyl group -cyanide at :

11.2 Structure and properties of carboxylic acids

As with ketones, the carboxyl carbon atom is sp2-hybridized and therefore planar:

The carboxyl group is strongly polar due to the polarizable carbonyl double bond and the hydroxyl group. As pure liquids and even in very dilute solutions, carboxylic acids are mostly present as dimers bound by hydrogen bonds:

Due to their ability to form hydrogen bonds in the solid and in the liquid state, carboxylic acids have relatively high melting and boiling points.

e.g.

11.3 Acidity of Carboxylic Acids

As the name suggests, carboxylic acids are acidic. The acidic behavior is much more pronounced than with the alcohols, although the acidic proton in both cases comes from a hydroxyl group:

Carboxylic acids are medium-strength acids : See HCl and acetic acid.

connectionpKa
HCl-7
CCl3COOH0.64
HCOOH3.75
PhCOOH4.19
CH3COOH4.72
CH3CH2OH16

Why are carboxylic acids more acidic than alcohols when both have OH groups? Let us compare the relative stability of alkoxide anions and carboxylate anions:

The negative charge in carboxyl groups is delocalized over two O atoms. A Resonance stabilization of the resulting carboxylate ion takes place.

As with alcohols and phenols, the acidity of the carboxylic acid is influenced by substituents in the vicinity of the carboxy group:

connection pKa   connection pKa
CH3COOH 4.72 CH3CH2CH2COOH 4.9
ClCH2COOH 2.86 ClCH2CH2CH2COOH 4.5
Cl2CHCOOH 1.26 CH3CHClCH2COOH 4.1
Cl3CCOOH 0.64 CH3CH2CHClCOOH 3.8
F.3CCOOH 0.23    

Where do such effects come from? The dissociation of a carboxylic acid is an equilibrium process. A substituent that does Carboxylate-Anion can stabilize, leads to an increase in acidity because the dissociation coefficient is increased. Electron-withdrawing substituents in the vicinity of the carboxy group therefore increase its acidity:

The inductive effect is much less pronounced when the substituent is some distance from the functional group.

11.4 Manufacture of carboxylic acids

Most of the procedures we describe here have already been mentioned when describing the chemistry of other functional groups.

11.4.1 Oxidation

Alkyl groups on aromatic rings can be oxidized to carboxyl groups with potassium permanganate: (see Chapter 5.10)

Primary alcohols as Aldehydes can be oxidized to carboxylic acids: (see chapter 9.7.3)

11.4.2 Hydrolysis of nitriles

Nitriles are hydrolyzed to the corresponding carboxylic acids by aqueous acids or bases:

Because nitriles are often made from haloalkanes, haloalkanes can be converted to carboxylic acids in two steps:

This method works best with primary alkyl halides. With secondary and especially with tertiary alkyl halides, eliminations can occur.

11.4.3 Carboxylation of Grignard reagents

In Section 10.4.3 we saw how Grignard reagents react with aldehydes and ketones with nucleophilic addition. Similarly, carbon dioxide is also attacked by Grignard reagents. A carboxylate is formed, from which the acid is obtained after aqueous work-up and acidification:

Here we have a second method for the preparation of the carboxylic acids from the corresponding haloalkanes:

11.5 Reactions of the carboxylic acids

How can acid chlorides, anhydrides, esters and amides be produced from carboxylic acids in the laboratory?

Conversion into acid chlorides

The reaction of a carboxylic acid with thionyl chloride (SOCl2) or phosphorus pentachloride (PCl5) gives the corresponding Alkanoyl chlorides. This replaces the OH group with a -Cl group:

The hydroxy substituent is not unique to S.N2-, but also a poor leaving group in addition-elimination reactions. Since the halogens in the alkanoyl halides are good leaving groups and activate the adjacent carbonyl function, these carboxylic acid derivatives are valuable synthetic intermediates in the preparation of other carboxylic acid derivatives.

Conversion into acid anhydrides

As can be seen from the name, the anhydrides of the carboxylic acids are formally derived from these by splitting off water. Only with certain cyclic dicarboxylic acids In this way, intramolecular water splitting is easy cyclic anhydrides possible:

Conversion into ester

Esters are the most important carboxylic acid derivatives. We will consider two methods by which esters can be made from carboxylic acids.

An important method is nucleophilic substitution (pN2) of haloalkanes with carboxylate ions:

Carboxylate ions are nucleophiles that form esters via SN2-reactions form, especially when the substrates primary haloalkanes are.

If you put a carboxylic acid and an alcohol together, no reaction takes place. When adding catalytic amounts of an inorganic acid (H.2SO4, or HCl), however, both components react slowly with one another, whereby a Ester and water are formed, e.g .:

The equilibrium can be shifted in the direction of the products by using either one of the two starting compounds in excess or by selectively removing the ester or the water from the reaction mixture. Esterifications are often carried out in the corresponding alcohol as a solvent (Fischer esterification).

Mechanism:

An addition-elimination mechanism (cf. 11.6.)

The reverse of the esterification is that Ester hydrolysis (saponification). This reaction is carried out under the same conditions as the esterification, the only difference being that an excess of water is used to shift the equilibrium and that a water-miscible solvent is used, e.g .:

Conversion into amides

Amines are more nucleophilic and basic than alcohols, and they can react with carboxylic acids in both ways. If you put an acid and an amine together, it forms immediately Ammonium salt (not the amide!):

Since the carboxylate anion has a negative charge, it is now not attacked by nucleophiles. Such salts lose H only at much higher temperatures2O and then form amides. That is why it is usually necessary via an acid chloride, a Acid anhydride or going to an ester to form an amide.

reduction to alcohols

An extremely strong nucleophile is lithium aluminum hydride (LiAlH4). This reagent reduces carboxylic acids to the corresponding alcohols, which are obtained after aqueous work-up:

Mechanism (see chapter 10.4.6):

11.6 The addition-elimination mechanism

Carboxylic acid derivatives react to the carbonyl group in a similar way to aldehydes and ketones: the carbonyl carbon is attacked by nucleophiles. A nucleophilic attack on the carbonyl group, however, proceeds differently than with aldehydes and ketones.

In general:

Nucleophilic addition to aldehydes and ketones

Nucleophilic substitution on carboxylic acid derivatives

In contrast to the addition products of the aldehydes and ketones, the intermediate alkoxide can be eliminated by splitting off X- disintegrate. This process, in which the nucleophile enters the molecule in place of the X group, is called Addition-elimination reaction.

Compare with the SN2 substitution sp3-Centers:

No intermediate product, just a single transition state.

If we compare the reactivity of different acyl derivatives, the following order of reactivity is observed:

This order partly corresponds to the leakage capacity and the electron-withdrawing properties of the substituent bonded to the carbonyl group as well as the strength of its mesomeric effect (strong for -OR, -NHR; weaker for -Cl). An important consequence of this reactivity sequence is that it is usually possible to convert a more reactive derivative into a less reactive derivative by an addition-elimination reaction:

This scheme gives us an overview of the reactivity of carboxylic acid derivatives.

But let's also remember that that Hydroxy proton of a carboxylic acid reacts acidic and most nucleophiles are basic. Therefore, with carboxylic acids even an acid-base reaction can compete with the nucleophilic attack.

11.7 The chemistry of the alkanoyl halides

Manufacturing

We have just seen how carboxylic acids are treated with thionyl chloride (SOCl2) or PCl5 give the corresponding alkanoyl chlorides (acid chlorides).

Reactions

Alkanoyl chlorides react with nucleophiles via an addition-elimination mechanism. Acid chlorides are some of the most reactive carboxylic acid derivatives and can be converted into numerous other functional groups. Acid chlorides, for example, react very quickly with water and then form carboxylic acids. Such reactions are not reversible:

The reaction of acid chlorides with alcohols proceeds via a similar mechanism and is a very good option for the preparation of esters, e.g .:

Usually a base (e.g. pyridine) is added to neutralize the by-product hydrogen chloride.

Secondary and primary amines and ammonia react with alkanoyl chlorides to form amides. The resulting HCl is in turn neutralized by the added base (which can be an excess of amine), e.g .:

The reduction with lithium aluminum hydride (LiAlH4) also takes place via an addition-elimination mechanism (see above Reduction to alcohols)

11.8 The chemistry of carboxylic acid anhydrides

Manufacturing

One method of making carboxylic acid anhydrides is by dehydrating carboxylic acids:

Reactions

The reactions of the carboxylic acid anhydrides proceed - albeit less violently - analogously to those of the alkanoyl halides. The leaving group is a carboxylate ion instead of a halide ion.

Some examples follow:

11.9 The chemistry of esters

The esters are the most important class of derivatives of the carboxylic acids. Many esters have a characteristic pleasant odor. They are important components of natural and artificial fruit flavors. Esters of long-chain carboxylic acids and alcohols are the main components of animal and vegetable Waxes. Waxes and fats are among the Lipids (Chapter 17). They serve as "fuel" and energy depot and are biological components Membranes.

Manufacturing

Esters can be prepared from carboxylic acids using the methods already mentioned:

Reactions

The same reactions that we have seen with other acyl derivatives can be carried out with esters. However, the conversions are much slower, so that an acid-base catalyst is usually needed to accelerate the reaction.

hydrolysis

In contrast to the alkanoyl halides and the carboxylic acid anhydrides, esters do not react with water and alcohols in the absence of a catalyst. If esters are heated in an excess of water in the presence of mineral acids, so HYDROLYZE you. The mechanism is the reverse of acid catalyzed esterification. THE HYDROLYSIS of esters is also catalyzed by bases:

In contrast to the acid-catalyzed hydrolysis is the base-catalyzed reaction no Equilibrium process:

The last step, in which the acid is converted into the carboxylate ion, is irreversible under these reaction conditions.

Amides from esters (cf. the ribosome)

Esters react only slowly with the more nucleophilic amines without adding a catalyst to form amides, e.g .:

This reaction also takes place via an addition-elimination mechanism.

REDUCTION

The reduction of esters to alcohols requires 0.5 equivalents of lithium aluminum hydrides per ester function:

The nucleophile can be described here as a hydride donor (H.-) consider (see above).

With Grignard reagents

Esters react with two equivalents of Grignard reagent to form alcohols. In this way, secondary alcohols are formed from formic acid esters and tertiary alcohols from all other esters:

Mechanism:

This reaction proceeds, like the reduction with lithium aluminum hydride, via a nucleophilic addition-elimination mechanism to an aldehyde and then further via a nucleophilic addition to the alcohol.

11.10 The chemistry of amides

Of all the carboxylic acid derivatives, the carbonyl group of the carboxamides is least easily attacked by nucleophiles. The amides are due to the special ability of the lone pair of electrons on nitrogen, in resonance to step, the most inert carboxylic acid derivatives:

For this reason, amide groups are PLANAR! (see peptides and proteins).

Therefore, stringent conditions (high temperature) are required for nucleophilic addition-elimination reactions on amides.

Manufacturing

Amides are usually made from acid chlorides (or anhydrides) and a corresponding amine:

Reactions - HYDROLYSIS

For example, hydrolysis only takes place after prolonged heating in a strongly acidic (aqueous HCl) or basic (caustic soda) aqueous solution:

Mechanism:

In an aqueous solution at pH7, amides are hydrolyzed with a half-life of approx. 500 years (!).

11.11 The chemistry of nitriles

Nitriles, R-CN, are counted among the derivatives of carboxylic acids because the carbon in the nitriles is in the same oxidation state as in the carboxyl group, and because nitriles can easily be converted into other derivatives of carboxylic acids or prepared from them.

In the nitriles, both atoms are the functional groups sp-hybridized, the lone pair of electrons on nitrogen occupies the sp-Hybrid orbital:

The electron-withdrawing force of the N atom in the nitrile group can be represented by a dipolar resonance structure.

The lone pair of electrons on N can also be easily protonated.

Manufacturing

The easiest method to produce nitriles is through the SN2-reaction on haloalkanes, e.g .:

Reactions

A comparison between carbonyl compounds and nitriles shows a great similarity in their reactivity towards nucleophiles. The most important chemical properties are:

Examples:

11.12 nylon, polyester and related polymers

We have already considered the radical polymerization of alkenes. The production of polyethylene, PVC and related polymers takes place via chain reactions (Chain growth polymerization). Step growth polymers arise from a reaction between two different monomers. This is often one nucleophilic acyl substitution reaction. Some examples follow:

The PET drinking bottles are made of polyethylene terephthalate. This polymer is produced in two stages. First, ethylene glycol and terephthalic acid (or dimethyl terephthalate) are converted to bis (2-hydroxyethyl terephthalate (BHET). Then BHET is polymerized with an Sb / Ge / Ti catalyst. At the moment, around 9.5 million tons of PET are produced annually.

11.13 Thioesters in biological chemistry

In nature, acid chlorides and carboxylic anhydrides are not used (why not?). Nevertheless, nucleophilic acyl substitution reactions often take place in the metabolism. In nature, however, thiol esters are used instead of acid chlorides or anhydrides. If we have the pKaValues ​​of Alkyl thiols we can see that their acidity lies between alcohols and carboxylic acids:

This means that a thiolate anion is not just one very good nucleophile, it is also involved in nucleophilic acyl substitution reactions a very good leaving group. In terms of their reactivity, thioesters lie between carboxylic acid anhydrides and normal esters.

Coenzyme-A is the most abundant thiol in nature. Acetyl-CoA fulfills exactly the same role in nature as acetyl chloride or acetic anhydride, although the structure of acetyl-CoA is a little more complicated:

Acetyl-CoA is often (but not exclusively) used in nature as an acetylation reagent:

An example can be found in the biosynthesis of N-acetylglucosamine, an important component of bacterial cell membranes:

Thioesters play a very important role in the immune system - in the so-called complement cascade. The plasma protein C3b contains a thioester group. A post-translational modification converts a glutamine residue in C3b into a thioester. The thioester group is very reactive and can, for example, react with nucleophiles (alcohol or amine groups) on the cell surface. C3b reacts best with bacteria or viruses. This decorates the surface of the microorganism with many copies of C3b. Then other proteins from the complement cascade bind to this membrane-bound C3b and finally the membrane of the microorganism is destroyed.