Conjugate addition (Connections Conjugation changes the reactivity of carbonyl groups To stat this chapter, here are four reactions of the same ketone. For each product, the principal a absorptions in the IX spectrum are listed. The pair of reactions on the lef should come asno surprise Hyeuneestorew R epeeoseny, to you: nucleophilic addition of cyanide or a Grignard reagent to the ketone produces productwith messmo cement a =I ot empeancs ars ChaperS ih be ae ut instead an O-H peak at 3600 em, The 2250 em" peak is CaN; Sampeinse an Cran 9 whe IR: 3600 trout, 2250, 1650 WR: 2250, 2735 no absorston rear 2700 no absorston at 3600, e 2.BUMEBr gy on ° 1. BuMgBr, 2% CuCl Ja 2.Ha0 2.120 Me Mm M —— ® i: 3600 ca, 2640 we 2730 ro asoratonneor700 ro absorgin a 2600 But what about the reactions on the right? Both products A and B have kept their eazbonyl group JA (GR peak at 1710 em!) but have lost the C=C. Yet A, at least is definitely an addition product ma cn because itcantains a C=N peak at 200 em", ‘Well, the identities of A and B are revealed here: they are the products of addition, not to a the carbonyl group, But to the C=C bond, This type of reaction i called conjugate addition, and is gy wha ths chapter ill about, The cape wl so how expsn how such small difrences in| e reaction conditions (temperature, or the presence of CuCl) manage to change the outcome je completely iret addon tothe C=0 group228 > Thea and Breer tothe distance tthe double bond tam the C=0 ‘troup: the ccarbonis the one ext to 0-0 (natthe carbons Catbon sel, tne Beatonis one furtnerdown the chan, and 0 on, - 5 urvanetcitre 20 - Conjugate addition conjugate action tothe C=C double bong \jugate addition to the C=C double bond follows a similar course to direct addition to the C=O group, and the mechanisms for both are shown here, Both mechanisms have two steps: addi- tion, followed by protonation, Conjugate additions only accur to C=C double bonds next to C=O groups. They don’t occur to C=C bonds that aren't immediately adjacent to C=O (see the box on p. 000 for an example). ‘Compounds with double bonds adjacent to a C=O group are known as «,B-unsaturated carbonyl compounds. Many ct,-unsaturated carbonyl compounds have trivial names, and some are shown here, Some classes of o,f-unsaturated carbonyl compounds also have names such as ‘enone’ or ‘ena, made up of ‘ene’ (lor the double bond) + ‘one’ (for ketone) or ‘ene’ + ‘al (lor aldehyde). an afansaturated aldehyde an o.iunsaurates ketone an abunsaturated acd anc,bunsaturated ester Ose Ae ee Wh sos wacmaote noel pane A range of nucleophiles will undergo conjugate additions with 0,.8-unsaturated carbonyl com- pounds, and six examples are shown below. Note the range of nucleophiles, and also the range of car- bony! compounds: esters, aldehydes, acids, and ketones. ‘ypes of meleopile which dergo eorugate ation cyaniae KON + amines EtNH + Naot its MesH + A. a A yn A ehtorde Hel +Polarization is detectable spectroscopically ‘The reason that o,-unsaturated carbonyl compounds react differently is conjugation, the phe- nomenon we discussed in Chapter 7. There we introduced you to the idea that bringing two 7 sys- tems (two C=C bonds, for example, or a C=C bond and a C=O bond) close together leads to a stabilizing interaction, I also leads to modified reactivity, beacuse the ® bonds no longer react as independent functional groups but asa single, conjugated system, Termite self-defence and the reactivity of alkenes Sober termies ofthe spcies Schedorhinotemnes iamananus ‘ests by produeng tis eompound when ery fective a a ‘onjugeteaacitoneartona with hols (RSH). This makes thigh tox, sce ‘many mportant biochemicals carry SH groups. The worker termites athe same eee Species who bulls the nests—need be ableto ao beingeaughtinthenoteacive. grate soasesaes | 229 ‘toss, so they ae equipped with an ename that alows them torechee a ae ate ey Sompsuns:toconpou 2. Ths tilhasadeile bon atte coslesond— SNe ae isComphnurveatne ova rlophissbechne ansreonsgsnewee ‘oarbenyl group The warkars escape winamed » Alkenes conjugated with carbonyl groups are polarized wl Ce we yn , . ME’ cc double bond acts This is quite different to the reactivity of a C=C curt rows indicate double bond conjugated with a carbonyl group, eloalation of electrons wich, at you ave jst ee, race with nucleophiles ee system is different from the sum of the isolated parts, ™ with the C=O group profoundly affecting the reactvi- "Westin datibuten tes semewnere ty of the C=C double bond. To show why, we can use curly arrows to indicate delocalization ofthe electrons over the four atoms in the conjugated sys- tem, Both representations are extremes, and the true structure lis somewhere in between, but the polarized structure indicates why the conjugated C=C bond i electrophilic. © Conjugation makes alkenes electrophilic Isolated C=C double bonds are Cdoublebonds conjugated nucleophilic ‘with carbonyl groups are lectrophilic CQ Lor Polarization is detectable spectroscopically IR spectroscopy provides us with evidence for polarization in C=C bonds conjugated to C=O bonds. ‘An unconjugated ketone C=O absorbs at 1715 cm™ while an unconjugated alkene C=C absorbs > Youmay be asking yourself why wean’ show the delocalization bbymoving he electrons the over way keris. ney Pe ener ee eee eee eee aoa ete ea ae sees Seas lectrons inthe conjugated system.230 lecvons must move fom THOMG of rcleosile. oP | to LUMO of fectopiie °, > In acreein, the HOMO is infact notthe highest led x orbital you see here, tthe lone parson fnygen. This isnot important hore, tough, because we are ‘only considering acrolein as an electrogite, sowe are only Interest in ts LUMO. 20 - Conjugate addition (usually rather weakly) at about 1650 cm. Bringing these two groups into conjugation in an ,B-unsaturated carbonyl compound leads to two peaks at 1675 and 1615 em™", respectively, both ‘quite strong, The lowering of the frequency of both peaks is consistent with a weakening of both = bonds (notice that the polarized structure has only single bonds where the C=O and C=C double bonds were). The increase in the intensity of the C=C absorption is consistent with polarization brought about by conjugation with C=O: a conjugated C=C bond has a significantly larger dipole ‘moment than its unconjugated cousins, ‘The polarization of the C=C bond is also evident in the !'C NMR spectrum, with the signal for the sp? carbon atom furthest from the carbonyl group moving downfield relative to an unconjugated alkene to about 140 pp.m., and the signal for the other double bond carbon atom staying at about 1oppm. 143 pm. be 122 pom. ' ' 124 ppm. 118 pam. Molecular orbitals control conjugate additions Weave pecuoopiceviec that contd C=C bonis pola we can xen his trincuy vows he aceon step mun vee movenet sn fm the HOMO ofthe ndeopew the LUNOar oe tntertedeenyconpouné The empl nthe marinas mee (c0) se makopbe Sut wha des the LOMO took lke Kwa erainiy be na mote complied tan te TOMO ot ample eaten frou. The ner Ving you Ente so fr Gn her) ar ke erin busene (C=C conjugated with C=C), wich we tn compere wh the o,B-unsaturated aldehyde acrolein (C=C conjugated with SO, Theobiabintc teaver buaieneant aon sreabown bee Thy ae. tem ee ss ol ten perused (dsr by he oxen tn (Char “Bydg 5 wo LE Z|t for the moment just concen- trate on the shape of the LUMO, the orbital that willl accept electrons when a nucleophile attacks. In the LUMO, the largest coellicient is on the f carbon of the c,B-unsaturated system, shown, ‘with an asterisk, And it is here, therefore, that nucleophiles attack. In the reaction you have just seen, the HOMO is the methoxide oxygen’s lone pair, so this will be the key orbital interaction‘Ammonia and amines undergo conjugate addition that gives rise to the new bond. The second largest coefficient is on the C=O carbon atom, soit’ not surprising thal some nucleophiles attack here as well—remember the example right at the begin- ning of the chapter where you saw cyanide attacking either the double bond or the carbonyl group depending on the conditions of the reaction. We shall next look at some conjugate additions with alcohols and amines as nucleophiles, before reconsidering the question of where the nucleophile attacks, me me ew a bond Ammonia and amines undergo conjugate addition “Amines are good nucleophile for conjugate addition reactions, and give products that we can term Beamino carbonyl compounds (the new amino group i tothe carboay! group). Dimethylamine is 4 gas at room temperature, and this rescton has to be carried out in a sealed system to give the Ketone product. ' oP "SBN ‘This is the first conjugate addition mechanism we have shown you that involves a neutral nuele- ‘ophile: as the nitrogen adds it becomes positively charged and therefore needs to lose a proton, We can use this proton to protonate the negatively charged part ofthe molecule as you have seen hap- pening before. This proton-transfer step can alternatively be carried out by a base: in this addition of butylamine to an o,8-unsaturated ester (ethyl acrylate), the added base (HtO™) deprotonates the nitrogen atom once the amine has added. Only a catalytic amount is needed, because iti regenerat- ced in the step that follows. 50% ila - “on non Nom" Maye oft 20°C 90% yela A te | r uly oe wh e—~ my Ammonia itself, the simplest amine, is very volatile (it is a gas at room temperature, but a very water-soluble one, and bottles of ‘ammonia’ are actually a concentrated aqueous solution of ammo- nia), and the high temperatures required for conjugate addition to this unsaturated carboxylic acid can only be achieved in a sealed reaction vessel,232 10 + Conjugate addition M350 Cina seabed tbo eave Amines are bases as well as nucleophiles, and in this reaction the frst step must be deprotonation of the carboxylic acid: it’s the ammonium cazboxylate that undergoes the addition reaction. You ‘would not expect a negatively charged carboxylate to be a very good electrophile, and this may well >be why ammonia needs 150°C to react. mA Be ew SUL, rs The f-amino a product of conjugate addition of an amine is stil an amine and, provided it has a primary or secondary amino group, it can do a second conjugate addition. For example, “erianyamines can't gve eyigetsea as ee ‘methylamine adds successively to two molecules ofthis unsaturated este. because they nave no proton to lose ° Me OMe eu ° OMe " MeNH, ———> —__' le ome me Trsyeld ‘Two successive conjugate additions can even happen in the same molecule. In the next example, \./M—yroxplamine isthe naeophile. Hydroxylamine s Both an amine and ansleoboh but i alway acs at niuogen because autogen (being les eectconegatve than oxygen) bas a higher-enrgy 28 more reactive) lne pair. Here it reacts wit acylc enone to produce abiglc ketone which we hycromfamine have also drawn in a perspective view to give a better idea ofits shape. * a On = (fey a. ‘o The reaction sequence consists of two conjugate addition reac- tions. The fist is intermolecular, 10 and gives the intermediate enone. ‘The second conjugate addition is intramolecular, and turns the molecule into a bieyelie structure Again, the most important steps aze the C-N bond-forming reac- tions, but there are also several proton transfers that have to ‘occur, We have shown a base ‘B: carrying out these proton trans- fers: this might be a molecule of [ydroxylamine, or it might be a molecule ofthe solvent, methanol. \9 These details do not matter.Conjugate addition of alcohols can be catalysed by acid or base Conjugate addition of alcohols can be catalysed by acid or base Alcohols undergo conjugate addition only very slowly in the absence of a catalyst: they are not such, good nucleophiles as amines forthe very reason we have just mentioned in connection with the reac~ tivity of hydroxylamine—oxygen is more electronegative than nitrogen, and so its lone pairs are of lower energy and are therefore less reactive, Alkoxide anions are, however, much more nucleophilic You saw methoxide attacking the orbitals of actolein above: the reaction in the margin goes at less than 5°C. ‘The alkoxide doesn’t have to be made first, though, because alcohols dissolved in basic solution are at least partly deprotonated to give alkoxide anions. How much alkoxide is present depends on, the pH of the solution and therefore the pK, of the base (Chapter 8), but even a tiny amount is acceptable because once this has added it will be replaced by more alkoxide in acid—base equilibrium with the alcohol. In this example allyl alcohol adds to pent-2-enal, catalysed by sodium hydroxide in, the presence ofa buffer. a 0% you ~~ wat rr | ee | er _— > a * Lona Ho! hoxde produces Only a catalytic amount of base is required as the deprotonation of ROH (which can be water or allyLalcohol) in the last step regenerates more alkoxide or hydroxide. It does not matter that sodium, hydroxide (pK, 15.7) is not basic enough to deprotonate an alcohol (pK, 16-17) completely, since only a small concentration of the reactive alkoxide is necessary forthe reaction to proceed. We can also make rings using alkoxide nucleophiles, and in this example the phenol (hydroxy: benzene) is deprotonated by the sodium methoxide base to give a phenoxide anion. Intramolecular attack on the conjugated ketone gives the cyclic product in excellent yield. In this case, the methoxide (pKagx about 16) will deprotonate the phenol (pK, about 10) completely, and competitive attack by ‘MeO™ acting as a nucleophile is not a problem as intramolecular reactions are usually faster than, their intermolecular equivalents oho aoe 22 ako Naome Z~cno pe Inchapar we eseussed nl ot se end seatasts nthe ce! devon of alesneeto creas Sampounaete form heme. he ‘rensonng-tharbacemtes ‘iklecahies move miei ne mates caer gop ae “rare ae some mortar exceptions tha sepenangontne are ofrne formes erect are234 20 - Conjugate addition Acid catalysts promote conjugate addition of alcohols to 0, -unsaturated carbonyl compounds bby protonating the carbonyl group and making the conjugated system more electrophilic. Methanol adds to this ketone exceptionally well, for example, in the presence of an acid catalyst known as “Dowex 50’. This is an acidic resin—just about as acidic as sulfuric acid in fact, but completely i soluble, and therefore very easy to remove from the product at the end of the reaction by filtration, Moot Dowex 50 “e Me pe ‘Onc th methanol has add to he protonated enone ll ht emis reoeganize the po tons in the molecule to give the product. This takes a few steps, but don't be put off by their com- plexity—as we've said before, the important step isthe first one—the conjugate addition, Conjugate addition or direct addition to the carbonyl group? ‘We have shown you several examples of conjugate additions using various nucleophiles and «4 unsaturated carbonyl compounds, but we haven't yet addressed one important question. When do ‘nucleophiles do conjugate addition (also called ‘I,4-addition’} and when do they add directly to the carbonyl group (1,2-addition’)? Several factors are involved—they are summarized here, and we will spend the next section of this chapter discussing them in turn. Reaction conditions ‘The very fist conjugate addition reaction in this chapter depended on the conditions of the reaction, ‘Treating an enone with cyanide and an acid catalyst at low temperature gives a cyanohydain by direct atlack at C=O, while heating the reaction mixture leads to conjugate addition. What is going ABE LL are eden ear