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A2 Advanced Organic Chemistry - Carboxylic Acids and Derivatives


Carboxylic acids - Nomenclature

Take the prefix that corresponds to the total number of carbon atoms in the molecule (see naming alkanes in the alkanes page) and add anoic acid to form the name, e.g. CH3COOH is ethanoic acid.

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Carboxylic acids - Reactions

(1) With metals and bases :

Carboxylic acids will react with metals (such as sodium),

2RCOOH(aq) + 2Na(s) → 2RCOO-Na+(aq) + H2(g)

and with both weak and strong bases such as sodium carbonate (weak) and sodium hydroxide (strong),

RCOOH(aq) + NaOH(s) → RCOO-Na+(aq) + H2O(l)

2RCOOH(aq) + Na2CO3(s) → 2RCOO-Na+(aq) + H2O(l) + CO2(g)

With all these reactions a metal carboxylate salt is formed (e.g. sodium ethanoate).


(2) With alcohols :

When carboxylic acids are mixed and heated with alcohols, with a little concentrated sulphuric acid as a catalyst to remove the water product, esters are produced.


(3) Formation of acyl chlorides :

Carboxylic acids can be turned into a much more reactive molecule, called an acyl (or acid) chloride by reacting them with a chlorinating agent such as phosphorus pentachloride (PCl5) or thionyl chloride (SOCl2) :

2RCOOH + PCl5 → 2RCOCl + POCl3 + H2O

2RCOOH + SOCl2 → 2RCOCl + SO2 + H2O

The reaction needs to be conducted in distillation appartus so that the product can be separated from the carboxylic acid starting material.

To name an acyl chloride take the prefix that corresponds to the total number of carbon atoms in the molecule (see naming alkanes in the alkanes page) and add anoyl chloide to form the name, e.g. CH3CH2COCl is propanoyl chloride.

Acyl chlorides perform the same reactions as their parent carboxylic acids, except that they react at room temperature and generate hydrogen chloride as a byproduct. They give very exothermic reactions. They must be kept in a dry atmosphere as they will react with the slightest amount of moisture to regenerate the carboxylic acid.

RCOCl + NH3 → RCONH2 + HCl

RCOCl + R'NH2 → RCONHR' + HCl

RCOCl + R'OH → RCOOR' + HCl

RCOCl + H2O → RCOOH + HCl


(4) Formation of acid anhydrides :

Another way to make a more reactive derivative of a carboxylic acid is to dehydrate (i.e. remove H2O) a pair of molecules:

2RCOOH → (RCO)2O + H2O

The carboxylic acid is refluxed with a dehydrating agent, such as phosphorus pentoxide (P2O5) and the product is distilled from the reaction mixture.

To name an acid anhydride take the prefix that corresponds to the total number of carbon atoms in the parent carboxylic acid (see naming alkanes in the alkanes page) and add anoic anhydride to form the name, e.g. (CH3CH2CO)2O is propanoic anhydride.

As with acyl chlorides, they perform the same reactions as their parent carboxylic acids, just at room temperature. They give less exothermic reactions than acyl chlorides. They must be kept in a dry atmosphere as they will react with moisture to regenerate the carboxylic acid.

(RCO)2O + NH3 → RCONH2 + RCOOH

(RCO)2O + R'NH2 → RCONHR' + RCOOH

(RCO)2O + R'OH → RCOOR' + RCOOH

(RCO)2O + H2O → 2RCOOH

The formation of an acid anhydride can also occur intramolecularly, for example with 1,2-benzenedicarboxylic acid (commonly known as phthalic acid) :


(5) Reduction :

Carboxylic acids cannot be reduced with sodium borohydride (NaBH4), as carbonyls are, but can be reduced with lithium aluminium hydride (LiAlH4), a more powerful reducing agent. They are reduced to primary alcohols :

RCOOH + 4[H] → RCH2OH + H2O

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Carboxylic acids - Hydrolysis of esters

This is simply the process of adding the elements of water (H2O) to an ester to reform the carboxylic acid and alcohol used to form the original ester.

A catalyst is needed to increase the rate of this process and either an acid (H+(aq)) or a base (-OH(aq)) will work.

The following notes are taken from the introduction to my PhD thesis :

The hydrolysis of esters has been classified by eight different reaction mechanisms - being divided into

i) acid (A) or base (B) catalysed reactions,
ii) alkyl-oxygen cleavage (AL) or acyl-oxygen cleavage (AC)
iii) a unimolecular or bimolecular pathway in the rate determining step (1 or 2).

The two most common reaction mechanisms followed in ester hydrolysis are the acid catalysed AAC2, shown below,

and the base catalysed BAC2, shown below -

The acid catalysed process is fully reversible reaction, driven to completion by an excess of water, whilst the base catalysed reaction is essentially a fully complete process once the carboxylate ion has been formed.

Both these mechanisms involve a tetrahedral transition state and apply to the hydrolysis of most esters, including lactones, providing access to the carbonyl carbon atom is not sterically hindered. Reactions following these mechanisms are also more common due to the excellent electron sink the carbonyl carbon makes, because of the electronegative oxygen atoms bonded to that particular carbon atom.

The SN1-like(unimolecular) mechanisms involving acyl carbon-oxygen cleavage, AAC1 and BAC1, shown below, are uncommon because of the formation of an acylium ion, R-C=O+, requiring a strongly electron donating group as R, for example a trimethylphenyl group, to stabilize the positive charge of the ion,

The other possibility for cleavage in an ester (chain or ring) is the breaking of the alkyl carbon-oxygen bond, though this is not as common as acyl-oxygen cleavage, and requires a sterically hindered carbonyl carbon atom in general to be achieved.

The acid catalysed reaction mechanisms for alkyl-oxygen cleavage, AAL1 and AAL2, rely on the protonation of the oxygen atom in the carbonyl bond to begin with, and then either the expulsion of either a stable alkyl carbocation (for example a tertiary, allylic or benzylic group ) (AAL1), shown below,

or the R'OH group (for non-stabilizing alkyl groups, R') (AAL2), shown below,

Of the remaining general reaction mechanisms - the base catalysed alkyl-oxygen cleavage mechanisms - BAL2 is extremely rare and is only observed when the alkyl structure of the ester group is prone to SN2 inversion (e.g. R'= methyl or ethyl in the equation shown below ),

The final mechanistic possibility, BAL1, involves alkyl-oxygen cleavage as the first step, shown below,

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Carboxylic acids - Uses

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Carboxylic acids - Lactones

(1) Formation of lactones :

Lactone is the name given to the special group of esters in which the ester linkage forms part of a ring system. They conform to the general structural formula,

The minimum value for n is 0, for α-acetolactone, with n = 1 for β-propiolactone, n = 2 for γ-butyrolactone (or furan-2-one), n = 3 for δ-valerolactone (or pyran-2-one) and n = 4 for ε-caprolactone.

The simplest synthetic route to producing a cyclic ester ring system is to allow a hydroxy-carboxylic acid to react intramolecularly. As with any normal esterification reaction the process of closing the ring system is a dynamic equilibrium, and so in general requires the use of an acid catalyst (e.g. sulphuric acid or phosphoric acid), to remove water and thus move the esterification equilibrium over to the right (Scheme 1).

Scheme 1

To guard against the intermolecular attack of one molecule with another, which would result in the formation of a polyester, the concentration of the hydroxy-carboxylic acid needs to be kept low.

Another major method of producing the lactone ring is a reaction called a Baeyer-Villiger oxidation. This is the oxidation of a ketone, specifically a cyclic ketone, to an ester, by the use of reagents such as m-chloroperbenzoic acid (ClC6H4COOOH), perbenzoic acid (C6H5COOOH), peracetic acid (CH3COOOH), or hydrogen peroxide (HOOH). (scheme 2).

Scheme 2

There have been a number of studies of the Baeyer-Villiger oxidation of cyclic ketones by Friess et al. using perbenzoic acid42,43, and by others using hydrogen peroxide44 and peracetic acid45, to oxidise cyclobutanone, -pentanone, -hexanone, -heptanone, and -octanone, so the viability of this reaction is well known.

N.B.: Note that this reaction goes against the typical teaching at A level - ketones cannot be oxidised. This reaction is not to be used in exams, I include it here as a matter of interest for those keen on Organic chemistry.

(2) Ring Closure Favourability :

Ring closure processes in general have been categorized by Baldwin's rules1. These are a set of guidelines that apply to intramolecular ring closures involving tetrahedral, trigonal and linear carbon atoms - i.e. carbon atoms involved in saturated bonds, double bonds (e.g. C=C or C=O) and triple bonds (C≡C or C≡N) respectively (Scheme 3).

Scheme 3

The rules state whether a particular ring closure process is favoured or disfavoured based on the ease the transition state conformational arrangement may be achieved, providing the electron source (nucleophile) contains either a carbon, nitrogen or oxygen atom. Certain chains are able to twist their carbon-carbon bond structure about, to bring their reactive ends together, more easily than others.

The esterification ring-closure process, of a hydroxy-carboxylic acid, to form a lactone would be assigned the nomenclature n-Exo-Trig, where n refers to the ring size to be formed, Exo refers to the fact that a group is expelled during the ring formation process (OH in the basic esterification reaction between an alcohol and a carboxylic acid) and Trig refers to the trigonal acyl carbon atom - the electron sink for the reaction.

Baldwin's rule 2 states that for n = 3 to 7 Exo-Trig ring closure processes are all favoured conformationally. This however is not the definitive guide to whether a lactone ring may be formed. The closure depends on more factors than simply transition state conformation.

The bond strain produced when the small lactone rings are produced, those of α- and β-lactones, is extremely large. The bonding orbitals used in the ring system are sp3 for the oxygen atom and the saturated carbon atom in the ring, but are sp2 for the carbonyl carbon atom. Figure 1 below shows the poor overlap of sp3 orbitals present in the σ-bonds around the ring system.

α-lactone β-lactone

Figure 1 - Ring bonding orbitals for α- and β-lactones

The internal bond angles in the triangle for the α-lactone molecule should be 60° and for the square shaped β-lactone molecule should be 90°, however the actual bond angles involved in the rings are shown in figure 2 below,

Figure 2 - Optimal bond angles for groups involved in lactones

These bond angles are all a lot greater than the optimal geometrical angles in the α-lactone, and the lack of rotation possible about the carbonyl carbon atom because of the carbon-oxygen p-bonding also adds to the large amount of strain (> 30 kJmol-1) present and this leads to two main properties of the ring,

i) the ring system is extremely difficult to prepare (requiring high temperatures and pressures), and

ii) the ring system is highly reactive - susceptible to attack and ring-opening by nucleophiles.

With the β-lactone ring system the ideal internal geometrical angles of 90° are a lot closer to the actual bond angles present and so, whilst still a strained hetero-ring system and therefore hard to form, no matter favourable transition state conformation, and susceptible to nucleophilic attack, the angle strain is less than in the α-lactone system.

So even though Baldwin's rules state that the formation of 3- and 4-membered lactone rings are favoured processes, the bond strain factor overrides this and makes the formation of α- and β-lactones extremely difficult.

With the γ-lactones, the 5-membered ring system, the optimal geometrical shape would be that of a pentagon, which has internal angles of 108°. This is almost identical to the actual angles present in the ring system and so the angle strain in the ring is largely removed altogether (figure 3 below).

Figure 3 - Ring bonding orbitals for γ-lactone

With higher members if the series of lactones the internal bond angles gradually increase, but because of the twisting the carbon-carbon bond structure of the ring system can undergo, the angle strain is comparable to that of the δ-lactones. The bond angle around the carbonyl carbon of 120° is still a lot larger than either of the geometrical internal angles of the γ- or δ-lactones, but because of possible non-planar conformations for those molecules, the strain of this group is largely removed (figure 4 below),

Figure 4 - Illustration of non-planar conformations in γ- and δ-lactone

With ring sizes larger than 6 atoms the angle strain element of the ring energy is removed, because the saturated bonds are able to move three-dimensionally to achieve the ideal bond angle, or as near as possible. However, there are other elements, one present in the smaller rings and another present only in these large rings.

This first strain is produced by the eclipsing of carbon-hydrogen bonds on adjacent carbon atoms. In an ideal situation the arrangement of bonds radiating from adjacent carbon atoms would attempt to distance themselves as far apart as possible, shown in Newman representations in figure 5 below,

Figure 5 - Newman projections of bonding in ring systems

A represents an ideal case, in which the bonds are the maximum allowed angle apart (60°) as looked at head-on. B shows how eclipsing of the bonds leads to the hydrogen atoms, and their electron density, coming into proximity with one-another. The natural repulsion of similar electrical charges is prevented by the lack of rotation in the ring system - thereby causing strain.

With ring systems the twisting of the carbon-carbon bond can be extremely restricted, and with the three-, four- and five-membered rings this eclipsing of the bonds leads to torsional strain. This reaches a minimum with the chair configuration of the six-membered ring. The larger rings also have some eclipsing bonds present, but this is not as prominent as with the smaller ring sizes. The other configurational problem that arises with the large rings is the possibility of hydrogen atoms, and other substituents if present, sterically hindering themselves across the ring itself. Figure 6 below shows 2 hydrogen atoms (marked with the asterix) encroaching on each others' space in the ring.

Figure 6 - Diagram showing hindrance of hydrogen atoms across ring systems

(3) Other Methods of Preparing Lactones :

Whilst the esterification reaction might be the simplest method of producing a lactone ring, there have been a large variety of less conventional methods used over the years, some of which are detailed below.

The condensation reaction between a variety of zinc esters and benzaldehyde has been reported by Ochiai et al.2 as a possible route to preparing phenyl substituted lactone rings of varying sizes.

The zinc esters were formed from the reaction between the iodo ester (e.g. ethyl β-iodopropanoate) and a zinc-copper couple, and their reaction with benzaldehyde, catalysed by chlrorotitanium triisopropoxide (Scheme 4).

Scheme 4

The product formed, either the open chain hydroxy-ester or the closed ring lactone, depended on the number of carbon atoms in the ester compound. For ethyl β-iodopropanoate and ethyl γ-iodobutanoate the intermediate oxygen ionic centre formed is able to intramolecularly ring close, by attack on the carbonyl carbon atom, and form 5-phenylfuran-2-one (95% yield) and 6-phenylpyran-2-one (26%) respectively (path B of Scheme 3).

With longer chain length in the esters (n = 2, 3 and 4) the predominant product formed is not the lactone, but is in fact the open chain hydroxy-ester (52% yield for n = 2, 80% for n = 3 and 95% for n = 4) (path A in Scheme 3). The main reason for this would be concerned with the ease of obtaining a ring closure configuration. As already discussed, the closures are all Exo-Trig, and as such are favoured by Baldwin's rules. However, when the ring size is 6 or more atoms the distance between reactive ends is too far for easy lactone formation.

The preparation and decarboxylation of 2-phenylcyclobutane-1,1-dicarboxylic acid by Beard et al.3 showed the production of 5-phenylpyran-1-one (5-phenyl-δ-valerolactone) as a by-product (Scheme 5).

Scheme 5

The yield of the lactone product was only 5% though, and so this would not make a suitable method for the preparation of the 6-membered lactone ring.

γ-Butyrolactones have been produced by Schenck et al.4 using a free radical sensitiser and ultra-violet light as the radical initiator. Tokuda et al.5 have also performed a similar reaction, using 60Co γ-rays as the initiator, on a mixture of ethyl crotonate and an excess of alcohol. The particular combination using benzyl alcohol (α-hydroxytoluene) produced a 5-phenyl-γ-lactone (Scheme 6).

Scheme 6

However, because of the radical chain mechanism initiated by the α-hydroxytolyl radical, the overall yield was a reported as a quite unsatisfactory 23%.

The use of an organometallic reagent was investigated by Pratt et al.6. The addition of tributylstannyl-lithium to crotonaldehyde (2-butenal) and subsequent protection of the hydroxyl group produced, using chloromethoxy methyl ether. The reaction between the organotin reagent and benzaldehyde, in toluene, resulted in the production of a stereospecific enol ether (Scheme 7).

Scheme 7

The subsequent hydrolysis of the enol ether to an aldehyde led to the formation of a tautomeric equilibrium in which the closed chain form of the aldehyde was a cyclic lactol. The oxidation of the lactol with a buffered pyridium chlororchromate reagent, gave a good overall yield of 5-phenyl-4-methylfuran-2-one (72%).

The Michael addition of α-nitrotoluene to methyl acrylate (methyl 2-propenoate) has been reported by Ballini et al.7 as a route to γ-lactones (Scheme 8).

Scheme 8

Though normally requiring the use of a homogeneous basic reagent to act as a catalyst to form the anionic electron source, in this case [PhCHNO2]-, this particular paper was concerned with the use a heterogeneous solid catalyst. The subsequent oxidation of the nitro group and cyclisation by reduction gave an overall yield of 52% for 5-phenylfuran-2-one.

Samarium(II) iodide, a strong single electron transfer reducing agent, has been reported by Fukuzawa et al.8 as means of forming a 5-phenyl-γ-lactone by the addition of benzaldehyde and ethyl acrylate or ethyl methacrylate (Scheme 9).

Scheme 9 - where R = H or CH3

The overall yield of lactone produced by this method was 80%.

References:

1) Baldwin, J.E.; J. Chem. Soc. Chem. Comm. ; 734 ( 1976 )

2) H. Ochiai; T. Nishihara; Y. Tamura; Z.-I. Yoshida; J. Org. Chem. ; 53, 1343 ( 1988 )

3) Beard, C.; Burger, A.; J. Org. Chem. ; 26, 2335 ( 1961 )

4) Schenck, G.O.; Koltzenburg, G.; Grossmann, H.; Angew. Chem. ; 69, 177 ( 1957 )

5) M. Tokuda, Y. Yokoyama, T. Taguchi, A. Suzuki, M. Itohl; J. Org. Chem. ; 37, 1859 ( 1972 )

6) Pratt, A.J.; Thomas, E.J.; Chem. Soc. Perkin Trans. ; 1521 ( 1989 )

7) Ballini, R.; Petrini, M.; Rsoini, G.; Synthesis ; 711 ( 1987 )

8) S. Fukuzawa; A. Nakanishi; T. Fujinami; S. Sakai; J. Chem. Soc. Perkin Trans. I ; 1669 ( 1988 )

42) Friess, S.L.; J. Amer. Chem. Soc. ; 71, 2571 ( 1949 )

43) Friess, S.L.; Frakenberg, P.E.; J. Amer. Chem. Soc. ; 71, 2679 ( 1949 )

44) Jaconson, S.E.; Mares, F.; Zambri, P.M.; J. Amer. Chem. Soc. ; 101, 6938 ( 1979 )

45) Starcher, P.S.; Phillips, B.; J. Amer. Chem. Soc. ; 80, 4079 ( 1958 )

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written by Dr Richard Clarkson : © Saturday, 1 November 1997

Updated : Monday 26th March, 2012

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