CHEM331/333 RBL 6 Nucleophilic Substitution at Carbonyls (CGW some of chapters 10, 12, Maskill chapter 4, Carey and Sundberg p 465). 1. Tetrahedral intermediates Nucleophilic substitution at carbonyl carbon with displacement of leaving group X is a common reaction in synthesis. The reaction is also called 'acyl transfer', since an acyl group (RCO) is being transferred from X to Nu. The order of reactivity is similar to SN2, with good nucleophiles rapidly displacing good leaving groups. O Nu: + R O X R + X Nu The main difference from SN2 is that a tetrahedral intermediate is involved because the nucleophile's filled orbital has to overlap with the unfilled (*) carbonyl orbital i.e. it has to come from above the plane of the carbonyl. Nu Nu O The preferred angle of attack is ~ 110º (the tetrahedral angle) due to repulsion between incoming nucleophile and antibonding lobe of * orbital. O Nu Nu Nu 2. Two main mechanisms for ester hydrolysis The two common mechanisms are one for basic hydrolysis called BAc2 (Base-induced, acyl-oxygen cleavage, bimolecular), and one for acid catalysed hydrolysis AAc2 (Acid-catalysed, acyl-oxygen cleavage, bimolecular). The 'bimolecular' means that two molecules are involved in the RLS. OH R BAc2 O O R' R O O R O O + R' R'OH OH2 A Ac2 R R OH O O O O R' R R R' OH R' HO O + R'OH BAc2 (Base-induced, acyl-oxygen cleavage, bimolecular). Not a base catalysed reaction, since the hydroxide is used up – the initially formed alkoxide immediately deprotonates the acid to give a carboxylate. OH k1 R O R' k –1 OH R R' k2 O OH O R R O + + O R'H R' Evidence for mechanism: Hindered acids react more slowly, so reaction likely to be bimolecular. Kinetics: Rate = kobs[ester][HO–]. Steady state on tetrahedral intermediate gives rate k 1k 2 – [ester ][HO ] (k –1 k 2 ) so kobs = k1k2/(k–1 + k2). Since kobs is just a number, the kinetic expression provides no evidence for an intermediate – a simple bimolecular displacement with a single TS would have the same rate equation. Hammett: +ve (probe in R) Isotopic labelling: There are three oxygens in the tetrahedral intermediate, and these can be tracked by labelling them with 18O. We will consider two possibilities. Labelling the OR' group (R') produces labelled alcohol, HR', showing that the O–R' bond has not been broken (no alkyl–oxygen cleavage). Labelling the hydroxide by running the reaction in 18OH2 produces labelled carboxylate, and not labelled alcohol, confirming that the CO–O bond has been broken. If hydrolysis using labelled hydroxide is stopped before completion, analysis of remaining unhydrolysed ester shows that some of the 18O label has got into the ester carbonyl. This means that the initial tetrahedral intermediate can equilibrate (via protonation to the neutral species and deprotonation) with a tetrahedral intermediate with the charge on the other oxygen (proton transfers between charged heteroatoms in water are very fast). Reversion to the ester then introduces the label. This experiment provides a way of measuring the relative heights of barriers for forward and backwards reactions from the tetrahedral intermediate, k -1 and k2. It turns out that little label normally ends up in unreacted ester, showing that the forward reaction usually has the lower barrier (i.e. k2 > k-1). As might be expected, RCOX with a good leaving group (e.g. X = OPh) has a higher k2/k–1 ratio than RCOX with a bad leaving group (e.g. X = NHR, an amide). OH R X O R X O OH R X O O OH R X OH AAc2 (Acid-catalysed, acyl-oxygen cleavage, bimolecular). Water is a poor nucleophile, so will only attack at an appreciable rate if the carbonyl is activated by protonation. All the steps in acid–catalysed ester hydrolysis are reversible, and the reaction continues until it reaches equilibrium (the reverse is acid–catalysed ester synthesis). The overall equilibrium constant for synthesis/hydrolysis of esters is ~ 1, i.e. with equal concentrations of reactants, the reaction goes about half way starting from either side. For kinetic measurements, only rates in the early stages of the reaction are analysed, so that back reaction from the ester (k–2) does not have to be considered. O H2O + R O R' KH+ R OR' R k1 R O H OH R' k –1 OH + R'OH OH2 R R' OH OH OH k2 R R H R' OH + O R'H Evidence for mechanism similar to BAc2: Hindered acids react more slowly, so reaction likely to be bimolecular. Kinetics: Rate = kobs[ester][H3O+]. Steady state on the tetrahedral intermediate gives rate k 1k 2 K [ester ][H 3 O ] (k –1 k 2 ) H so kobs = k1k2KH+/(k–1 + k2) assuming the ester is protonated in a fast preequilibrium KH+ = [esterH+][H2O]/[ester][H3O+]. Hammett: ~ 0 (probe in R) Isotopic labelling: As before, 18O labelling shows that the reaction involves acyl-oxygen cleavage, the tetrahedral intermediates can interconvert rapidly, and k2 and k-1 are of comparable size. For simplicity we have shown two tetrahedral intermediates - there is also a third, neutral one, with none of the alcohol/ether groups protonated. This is of lower energy than the other two, but still in rapid equilibrium with them. 3. Two less common mechanisms for acid hydrolysis of esters There are two other mechanisms for esters which can give stable cations in strong acid, called AAc1 and AAl1 (the 1 meaning that the slow step is a unimolecular dissociation like SN1). These mechanisms do not go via tetrahedral intermediates. AAc1 (Acid-catalysed, acyl-oxygen cleavage, unimolecular). Limited to esters which can ionise to form a relatively stable acylium ion (the same intermediate as in Friedel-Crafts reactions), or esters for which the normal AAc2 mechanism is difficult. Protonation on the alcohol oxygen is required to make it a better leaving group (most of the molecules will in fact be protonated on the more basic carbonyl oxygen). R R O H R' R' R O R + HR' O O HO HR' Evidence for mechanism: Promoted relative to AAc2 by steric hindrance around carbonyl (example 1 below). Kinetics: Rate = kobs[ester][H3O+], although a large excess of acid is usually used so that the reaction is pseudo-first order, rate = k'obs[ester]. Hammett: –ve (+, probe in R) Isotopic labelling: Hydrolysis of R' labelled ester gives HR', so not alkyl-oxygen cleavage. + Example 1. The ortho-methyls force the ester group out of the plane of the benzene ring, shielding the carbonyl carbon from attack. Protonation and loss of methanol produces a linear acylium ion which can then react with a nucleophile e.g. water without it having to get in past the methyls. O OMe Me Me O OH Me Me Example 2. Acylium ion particularly stable due to resonance. This ester only hydrolyses by A Ac1 in concentrated acid where the concentration of water is low, otherwise the mechanism is normal AAc2. O OMe OMe O OH OMe AAl1 (Acid-induced, alkyl-oxygen cleavage, unimolecular). Occurs when the alcohol portion can form a stable cation R'+ i.e. From the alcohol's point of view this is an SN1 reaction, with the protonated ester as a good leaving group. Not an acyl transfer reaction. R R' R O R' R R OH OH + R' H + HR' Common types of ester that hydrolyse by this mechanism are triphenylmethyl (trityl) and tertbutyl esters (example 1 below), used as acid labile protecting groups. Evidence for the mechanism: Not sensitive to steric hindrance around carbonyl. Kinetics: rate = kobs[ester][H3O+] as before, promoted by polar ionising solvent (SN1 conditions). Hammett: small (probe in R) Isotopic labelling: Hydrolysis of R' labelled ester gives HO–R', so –R bond must have broken. Example 1. tert-Butyl esters can usually be cleaved in the presence of other functional groups by catalytic amounts of acid. The ester is protonated to a small extent, with the slow step being alkyloxygen cleavage Example 2. Hydrolysis of a series of substituted ethyl benzoates with electron withdrawing substituents in concentrated sulphuric acid. This is an unusual situation in which the concentration of nucleophiles such as water is too low for the normal AAC2 mechanism to be competitive. The esters start off almost completely protonated in concentrated acid with the slow step generating a rather unstable ethyl cation. For this particular reaction the mechanism changes to AAc1 (as mentioned previously) if NO2 is changed to OMe because the acylium ion pathway now becomes lower in energy (the methyl cation is even more unstable). Summary of hydrolysis mechanisms BAc2: Stoichiometric +ve (probe in R) labelling detects tet. intermediate(s) and acyl-O cleavage. AAc2: pre-protonation ~ 0 (probe in R) labelling detects tet. intermediate(s) and acyl-O cleavage. AAc1: pre-protonation, needs stable acylium ion - ve (probe in R) labelling shows acyl-O cleavage R O O R' R O R O O O R' O R O OH R' OH R O O H O R' O R' O R OH O R' R + HOR' R O O R'OH R' R R + OH2 R O R' R AAl1: pre-protonation, needs stable alkyl cation ~ 0 (probe in R) or + ve in strong acid labelling shows alkyl-O cleavage OH R O R' OH O + R' O HO + R'OH