4.1] SN1 MECHANISM Let us take the example of alkaline hydrolysis of butyl bromide to give t-butyl aleobol Me Me I ° | Me Cr 40H > Me aes Me Me butyl bromide ‘-buty! alcoho! This is an SN1 reaction and involves the SN mechanism discussed below SNI mechanism is a two-step process. The first step is slow heterolysis of the substrate to give an intermediate carbocation. This is rate-determining step. Me Me. Me es | ‘c@ Me—C—Br I + Br | Me Me t-butyl carbocation ‘butyl bromide The second step is fast combination of the intermediate carbocation with the nucleophile. Me: Me Me pe es @ Fast | | + OH ——+ Me—C—OH Me | Me Substitution product Evidence for the SN1 mechanism 1. Kinetics : The SN1 reaction is a first order reaction following the rate-law given below: Rate = k [substrate] That is, the rate of the SNI reaction depends only on the concentration of the substrate and it is independent of the concentrition and uncleophilicity of the attacking nucleophile. Thus, kinetics is a very strong evidence for SNI mechanism. 2. Stereochemistry : The SN1 reactions proceed with partial racemisation and some invet In SNI reactions an intermediate carbocation is formed which is planar, and the nucleophile should k with equal facility from either side of the plane, resulting in complete/racemisation. However, in practice the expected complete racemisation is rarely observed. Usually( there is 5 to 20% inversion. This may be explained by considering that the attack by a nucleophile occirs before the leaving. group has completely. departed from the neighbourhood of the carbocation, thus, to a certain extent the leaving group shields the front-side of the carbocation from attack. Consequently, the backside attack is preferred to some exteng resulting in the inversion of configuration, more stable the carbocation, the greatér is the proportion of racemisation) This is because in propor such eases the leaving group gets time to leave the neighbourhood of the carbocation’ before the attack by 4 nucelphile occurs, thus, there is almost equal facility for attack from either side of the carbocation plane leading to a greater degree of racemisation, For example, the solvolysis of (+)PhCHMeCl, which Ean fortn 4 stabilised benzylic carbocation, leads (0 98% racemisation, while (+)CgH xCHMeCI (2-octy! chloride), ii In solvolysis reactions, the This Ts due to the fast attack of hilic the solvent, the greater is the proportion of inversion) f the front-side which is shielded ‘where no comparable stabilisation can occur, leads to only 34% racemi molecule from the backside but, not == more aucleop! the more nucleophilic solvent vivo Y22 Dr NERY KEtY.SVie oy) UNM Yas et}a ADVANCED ORGANIC CHEMISTRY wch faster than smaller bicyclic systems, though the reaction is still 80% aqueous ethanol at 25°C - Br \ X se hese />~ LN? th eee ibe i ¥ Rate: x10 =10 [42] sn2 MECHANISM Let us take the example of alkaline hydrolysis of methyl bromide to. give methanol Open chain system (2,2,2}bieyetie sysiem (Cebutyl bromide) (+-bromobicyclo(2, 2, 2joctane! CH;Br+OH —> CH;OH + B® (Direct displacement) ‘Tis is an SN2 (direct displacement) reaction and proceeds through the SN2 mechanism discussed below ‘SN2 mechanism is a one-step (concerted) process and involves no intermediate. In this reaction the nucleophile attacks the substrate from the just opposite (back) side (at 180°) to the leaving group. ‘The C—OH bond is formed as the C—Br bond is broken : H oy & \/ & 9 HO + H -Br| —+HO—CCH + Br nH” SH Transition state Substitution product “The energy necessary to break the C—Br bond is supplied by simultaneous formation of the C—OH bond. In the transition state (TS) the nucleophile and the leaving group are both 50% bonded to the carbon being attacked. The three nonreacting groups and the central carbon atom are appoximately coplanar in the TS, ie. the central carbon atom has" gone from its initial sp? hybridisation to an sp? state with an approximately perpendicular p orbital. One lobe of this p orbital overlaps with the nucleophile, and the ther with the leaving group. Evidence for the SN2 mechanism 1. Kinetics : The SN2 reaction is a second-order reaction following the rate-law given below Rate = k [substrate] [nucleophile] ‘That is, the rate of the SN2 reaction depends on both the concentration of the ubstrate and that of the attacking nucleophile. This rate law has been found to apply in many ce( I a large excess of nucleophile is present, e.g., in solvolysis, the mechanism may still be bimoYecular, although the experimentally determined kinetics will be first order R=k {substrate} Such kinetics ae called pseudo frst ondgy. Thus, the kinetic evidence does not necessarily lead to correct conclusions in all the cases. We have noted that the 2 in SN2 denotes bimolecular. It must be remembered that it is not always the same as second order. moh oy)SN TEACH inversion of configuration in view of the one. ‘ocess, This inversiorf of configurat ong before 3, Formation of a single substitution product + s evidence that these are one-step reactions, i.e» ediates. This is unlike SN1 reactions which are often aecompanies Jucts. This ation intermediate. 4. No substitution at bridgehead carbons potential leaving groups at bridgehead carbons SN2 mechanism requires the ba because ‘and coplanarity of the three_nonreacting. carbons duz To gid cage like structures of under SN2 conditions tack of the nucleophile ide atta groups. L-bromo-3,3-dimethylbicy tthoxide ion, whereas the open-chain analogues un M " ore 0° + Ph—— C1 | | H 100% R n the SN2 reaction an enantiomerically vi SA er This ya very sitong evidence Tor the SNZ mechanism | inthe light of the parti light of additional expe specile Fe fe + EO —}— Ph + H 100% § pure reactant leads to an enantion from the backside of th 's called Walden inversion (1893) ani SN2'mechanism was proposed by Hughes and Ingold (1937) 'SN2 reactions usually yield single substitution they do not proceed via reactive -d by rearrangement, and involve Ifthe SN2 mechanism is correct, the compounds with chould not be-able to react by this-mechanism. This is .cleophile. inversion of configuration. : bridgehead ihe TS all of which are prevented at the Ee expounds containing the brdigehead carbons. For exampig rlo(2.2.2Joctane is resistant towards reaction with \derwent the reactions readily. ° £:0___, Noreaction 'SN2 conditions| Br Problem 1. Explain mechanisms? Solution : Because of the following rigid cage aU Vioh yy) shy f-bromotriptycene is inert 1o nucl SNI reactions proceed throu like structure of 1-bromotriptycene, ophilic substitution by both the SNI and SN2 gh cabocation intermediate which has planae ste the bedigehead carbon cannotvivo Y22 UMN yas tL‘ALIPHATIC NUCLEOPHILIC SUBSTITUTION \ ee ) a oo In the case of cis isomer, the nucleophilic —O® is not in a favourable position for the backside src. Hore Cl sd H are sens wo ent ott sal ures iis give a vinyl alcohgl which automerises to a ketone. : ou 9 fa On if The backside attack by nucleophile is an essential requirement of SN2 without which these reactions are not possible. i [45] NEIGHBOURING GROUP PARTICIPATION (NEIGHBOURING GROUP MECHANISM) A number of nucleophilic substitution reactions are Known which occur with complete retention (not inversion or racemisation) of configuration and with uriexpectedly greater rate of reaction) In these cases usually there is an atom or group with an unshared electron pair B to the leaving group) (or sometimes farther away). The mechanism operating in such cases is called neighbouring group.mechanism or neighbouring group participation. 1t consists of two consecutive SN2-substitutions with inversion of configuration, thus, the net result is retention of configuration; In the first step_of this reaction the neighbouring group acts as a nucleophilie pushing out the eaving group, tn the Second step the external nucleophile pushes out the neighbouring group. A common feature ofall neighbouring group mechanisms is the formation of a cyclic intermediate. ‘Step 1. Slow Intermolecular SN2 inwamolecuar SN2 Step 2 Fest inversion) inversion) 2 Ra Netresultiseention ‘of configuration ince, the neighbouring group acting asthe nucleophile (Z) is present in the same molecule and is eine available for the attack, sych reactions ooeur thousands times faster than comparable ul philic substitutions( This rate enhancement by nel nbouring group participation is i such reactions are called anchimerically assisted reactions ‘echanism follows the first-order rate law shown below . Rate = k [substrate] NC That is, the external nucleophile (Nu®) does not take part in the rate-determining steP- T Oxygen as a neighbouring group : The ealssic example cof neighbouring group participation * aline hydrolysis of 2-bromopropanoate anion to lactate anion in which the carboxylate anion A Be a x ax a reetbonias, Brey Wee 2 Orca acid is treated with dilute alkali, it gives eR es with complete retention of configuration lactate Us LRT 4e sa Oo) intermolecular nucleo} called.anchimeric assistance an “The neighbouring gfoup micube Me 6 A EH CHCH,OEt [44] THE si mecHaNism There are certain nucleophilic substitutions which proceed with retention of configuration even ugh no neighbouring group is involved. These reactions proceed through SNi (substitution nucleopfitic mechanism, and follow the second—order Kinetics. For example, the conversion of renylethanol into (S)-L-phenylethy| chloride on treatment wih thronyTchloride Ph, OH + SOCh ——* Me w Retention configuration This reaction has been shown to follow the second order kinetics, but clearly cannot proceed by a simple SN2 mechanism because it would lead to inversion of configuration, whereas in the present reaction retention of configuration has been observed 1g SNi mechanism involving an ion-pair has been proposed for the above reaction: ‘Alky chlorosulpite ‘cc +50, w nae the same side a the orginal ofthe geometry ofthe ion-pi, the leaving group aacks from aaa, ot Cerkequent retention of configuration, The above mechanism has been supported bythe C—O bond with conse following factsgon RONAN CCA CHEST “i The uve intermediate alkyl ehlorosulphite has been isolated when the reaction is cared under The te tone The ehlorosulphie ts formed with retention of configuration because C—O tnd is-not broken during the reaction Annet mnversion of the alky| chlorosulpite into the product increases with increasing polarity of the solvent and also with inereasing stability of the carbocation (PRCHMe), This Shows that an ion-pair és almost certainly involved. (iii) When (S)-L-phenylethanol and thionyl chloride react in the presence of a base, e.g. pyridine, Us) L phenylethyl chloride is obtained, .e., inversion of configuration occurs, Inversion results because pyridine reacts with the alky! chlorosulphite to give I before anything further can take Ph, 9 \ | Mec—0-S—NQ)) ' Inversion of onion place. The CI® freed in this reaction is an_ effective nucleophile which attacks from the backside bf the C—O bond in a normal SN2 reaction leading to inversion of configuration. 11 was previously believed that the mechanism was a one-step (concerted) process : 6 ws & The fact that the chlorosul phite MeyCHCHMeOSOCI gives rearranged product Me7CCICH)Me on heating indicates that an ion-pait must be involved because there is no other way to explain the formation of the rearranged product ° I @ e Il Me—CH—CH—Me | O—S. | Me cl 0 —> R—CI + 0; Rearranged ion-pair explains the formation ‘of the rearranged product The SNi mechanism is relatively rare, its another example is the decomposition of ROCOCI (alkyl chloroformate) as follows: 0, y eis oe 4.5 | MIXED SN1 AND SN2 MECHANISMS Certain nucleophilic substituion reactions under a given set of conditions show all the characteristics of SN2 mechanisms; other seem to proceed by SN1 mechanism, but there are certain cases which cannot be characterized so easily. There seems to be something in between, a mechanistic borderline region where it ic not clear whether the reaction is proceeding through SN1 or SN2 mechanism. Two theories have been devised for explaining these borderline cases: 1, Simultaneous SNI and SN2 mechanisms : According to this theory borderline behaviour is caused by simultaneous occurring of both the SN1 and SN2 mechanisms in the some vessel, i-e., some ool de eact by the SNI, while others react by the SN2 mechanism. Ds teats OL)AUPHATIC NUCLEOPHILIC suesriTuT suastirumion a pot ony i inermediate mechanism theory ( Sncen, 1968) : This theory is very broad ahd apis Samy 1 ordering eases but aot all nclophic sbsiions ata saturated carbon, All SN and SN2 reactions can be accommodated by only one basic mechanism (the in pair mechanism), The fy by RX = 2 PX? = products The difference between SNI and SN2 mechanisms is that inthe former ease the formation of the ion pair (4) is rate-determining, whereas in SN2 mechanism its destruction (la) is rate-determining. Le when kz > 4), the mechanism is SN1, and when kj > k2, the mechanism iy SN2. The borderline behaviour is found when ky = ky. 44.6] THE SET MECHANISM In some nicleophilic substitution reactions where SNI mechanism is highly probable, it has been shown, by esr detection of the intermediate, that free radicals are actually involved. In such cases a carbocation is a good electron acceptor and nucleophile is an electron donor, The mechanism involved is named as SET (single electron transfer) mechanisms, e.g. the reaction between the triphenylmethyl cation and f-butoxide ion Ph3C® + -BuO® —> PhyC’ +1—BuO" —> 1—BuOCPhs [47 | FACTORS AFFECTING REACTIVITY IN SN REACTIONS 1. Effect of substrate structure : The rate-determining step in SN1 reactions is the formation of a carbocation. Thus, the order of reactivity of substrates in SNI reactions is the same as the order of stability of carbocations they can form. The stabler a carbocation, the more readily it is formed. The following is decreasing order of reactivity of some substrates in SN1 reactions : | AryCX> ArgCHX > RjCX > ArCHpX > —C=CHCH3X > R2CHX > RCH2X R= simple alkyl group like Me or Et: Ar=e.. Ph “The order of stability-of carbocations can be explained by + 1,+M and hyperconjugative effects (a) Unsaturation/ft the d-carbon ~ Vinyl, acetylenic and aryl are very unreactive in SN reactions ecaune the CX bfod acquires partial double bond character, i. strengthened through resonance, Thus breaking of C—X, bond becomes difficult resulting in the inertness ofthese substrates toward SN reactions (b) Unsaturation at the B-carbon ; SNI reactions are highly favoured if there is unsaturation at the rcarbon, This because the resulting allyl or benzyl cations are stabilised by resonance : ° 2 CH, CH) CH; CH er ‘= Oo eG ‘ Os : oe cad 1 3 enzyleation Coeom ADVANCED ORGANIC CHEMISTRY In general, SN1 rates at an allylic substrate are increased by any substituent in the 1 oF 3 position which cam stabilize the carbocation, ¢.g. alkyl, aryl or halo group, Rates of SN2 reactions for allylic and benzylic systems are also in sased because of resonance in in) The presence of a heteroatom at the c-carbon : SNI reactions are highly favoured if there is heteroatom at the a-carbon because it highly stabilises the carbocation formed, ¢.8.» Ao\a—> o— Bin > 8c id) Steric acceleration of 1 reactions: For some tetiary substrates the rate of SNJ reactions is ci it the Brcarbon is highly substituted. The formation of earbocations in such cases is resi aed because in this process the bond angle increases from 109.5" to 120° thereby reducing the aclponded repulsive interactions (steric strain). For example, the rate constant for the solvolysis oft sonny) methyt chloride is 600 times larger than that of r-buty! chloride under identical reaction conditions 1 SN reactions at bridgeleads : "Nucleophilic substitutions at bridgeheads are impossible or very slow as discussed in Sections 4.1 and 42. {P) Allo! groups at the cand B-carbons in SN2 reactions : nthe transition state of SN2 reactions, five atoms or groups are attached to the a-carbon. As the number and size of alkyl groups increases on the cand the Brcarbons, the energy of transition state increases due 10 non-bonded repulsive interactions eric strain), which decreases the rate of SN2 reactions. Thus, SN2 reactions are very sensitive to stenc | facior, For example, tertiary systems seldom react by SN2 mechanism, and neopenty! systems being mary systems react extremely slowly because of the larger sie of-butyl group present on the Qrearbon- The following is decreasing order of reactivity of some substrates in SN2 reactions = AryCX > Ar,CHX'> ArCH:X > — (= simple alkyl goup like Me or Et; Ar= e.g Ph) In general, primary alkyl substrates react by the SN2 mechanism, tertiary by the SNI mechanism. and secondary alkyl substrates form broderline, i.e. they mostly react by the SN2 and sometimes by the SNI mechanism depending on the reaction conditions. 3 Solvent effect : The nature of the solvent has a dominant effect on the rate of an SN reaction and the mechanism it follows. The solvent effect on the rate of SN1 reactions depends on whether the vostrate js neutral or positively charged. For neutral substrates, the greater the polarity of the solvent, the fanet is the reaction, because in such cases the transition state is more polar than the starting materials ind so more stabilised by the polar solvent through solvation. The crwcen a dissolved species and the solvent molecules is known as solvation. Sol ee ilcaion by dispersing partial or full charges through hydrogen Gonding, interaction through dipoles, and through electron donation, & & RX —9 R-~-X —> B+? TS For exp he rat of solvolysis of MesCBr is 3 x 10* times faster in more polar 50% aqueous ethanol th n in ethanol alone. For SN2 mechanism increasing solvent polarity usually decreases reaction rate slightly. For example, in the following general SN2 reaction & Ko Nu R+X° ie | Nu® + R-X —> [Nu---R- Ts 1ot developed but the existing charge of the nucleophile is dispersed in the TS resulting in less charge density as compared to the starting materials, thus the stabilisation of the TS is Ieceer than the starting materials causing slight decrease in the reaction rate. {A very marked effect on the rate of SN2 reactions is observed on changing the solvent from polar hdroxylie (protic) to polar non-hydroxylic (aprotic. For example, water acetone, methanol, ethanol, ete New charge isALIPHATIC NUCLEOPHILIC 28 ‘tic solvents, and acetone, dimethyl sulphoxide, DMSO (Me2S=0), dimethyl formamide, DMF CONMe), hexamethylphosphoric wiamide, HMPT [(Me;N),P=O}, ete. are common aprotic solvents \ nts cannot form hydrogen bonds, thus, they do not solvate anions to any appreciable extent. highly solvated by protic solvents through hydrogen bonding. Consequently, reaction rates are with anionic nucleophiles in aprotic solvents because the unsolvated nucleophiles are almost ed” 1 be highly reactive as nucleophiles. For example, the order of reactivity (nucleophilicity) of I> Br > cl?> Due to smaller size F° is highly solvated through hydrogen bonding, hence, least reactive. In aprotic ts the order of reactivity (nucleophilicity) is: F°> Cl? > Bre> 1? A polar aprotic solvent dissolves ionic compounds and it solvates cations by orienting the negative J of its dipole around the cation. It is unable to solvate the anion through positive end of its dipole, DMSO the two methyl groups shield its positive pole, which prevents the solvation of the anion, Me Me SZ. or Ih 08 Mens: 0: Me Solvation of cation Na® by DMSO, hence anion, e.g., C1° is essentially “free” For most of reactions SNI rates increase and SN2 rates decrease in solvents of increasing polari nus, it is quite possible for the same reaction to proceed by the SNI mechanism in one solvent and the SN? in another, ie, the solvent polarity not only affects rates of SN reactions, but may also change the nechanism of a reaction, If the charge is increased in the TS relative to starting materials then increase in polarity will increase ates of SN reactions. If the charge is decreased or dispersed in the transition state relative to the starting material then increase in polarity will decrease rates of SN reactions. For example, in the following SN2 reaction the charge is increased in the TS, hence, polar solvents will increase its rate H | MeN + CH3l —> MeyN®......6 a Hey on the charge is dispersed in the TS, hence, polar solvents will decrease & In the following SN1 react its rate 3 ae R—NMey —+ R* NMey Ts In general, the addition of an external salt affects the rates of SN1 and SN2 reactions in the same way as an increase in solvent polarity. However, there are exceptions; although the rates of SNI reactions wre usually increased by addition of salts (this is called the salt effect), addition of the leaving group ion Often decreases the rate (the common-ion effect), jan 8, 2025, 13:06Voor) Arpi Jan 8, 2025, 13:06ALIPHATIC NUCLEOPHILIC SUBSTITUTION concentration of the nucleophile concenuration of the nucleophile affect the rate of SN2 reaction. The stronger the nucleophile, the faster The onder of fucleophilicity varies and it depends on substrate i solvent, polarisability of the nucleophile, its size : The following main principles govern the rate of the SN2 reaction (A negatively change 5 tively changed nucleophile is stronger than its conjugate acid, ¢.g., OH is stronger than futy> a> OH > RANH > A> NHy> pyridine F> H,0 (ii) On going down in a group of periodic table, nucleophilicity increases, although basicity Jecreases, ¢,g4 1> Br> Cl> F (as we have seen, this order is in protic solvents). Similarly, any Stor mocgophef ronge than oxygen analog. a pospons milephile i no Powerful than its nitrogen analogue. This is mainly because the smaller negatively changed Electrophiles are more solvated by the usual polar solvents. This is most important for prove polar solvents which strongly solvate through hydrogen bonding, hence. nucleophile is net se Tree” to attack the substrate, However, nucleophilicity of small negatively changed nucleophiles ix reversed in aprotic solvents where the solvation is not so strong, hence, the nucleophile is ‘Imost “free” to attack the substrate. For example, the order of nucleophilicity of halides 9 aprotic solvents (€.¢- DMF) is B>Ci> Brot Thus, the freer the nucleophile, the greater is the rate. ranean vation is not the complete answer because nucleophilicity of uncharged nucleophiles also increates on going down in a group. These nucleophiles are not strongly solvated, and solvents do vot greatly affect their nucleophilicity. Similarly, the order of nucleophilicity, ArS> A¥0, fs net affected ao aa. This can be explained on the basis of poarisability of the muclephile ‘The more polarisable the nucleophile, the more easily the electm cloud is distorted, thus, IB nucleophiles can actually bring eae: of electron density to the substrate than the small nucleophiles whose electron clouds are tightly held Hea ove eases may also be explained by hard and soft ackls andl ses principle (HSAB). The proton isa hard acid, but an alkyl substrate is softer aed ‘According the HSAB principle the alkyl group rapected 10 prefer softer nucleophiles than the prown dors Thus, the larger, more polarisable (softer) ae eremphites have a greater attraction toward an alkyl carbo than toward a proton. Basicity involves aren pair donation to hydrogen, whereas aucleophilicty involves electron pair donation to carbon Therefore, basicity and nucleophilicty are not always P el. Tere are exceptions to the above principles. For ‘example, the butoxide ion MeyCO is a stronger use than OH oF OEt, but a much poorer nucleophile ecause its large size hinders it from closely approaching a substrate cate The following overall order of nucleophilicity for SN2 mechanism (in protic solvents) was given DY Edwards agll Pearson (1962) re als > cH > BH > Ny > Br> A> Co pyran» ASD HD good nue teaphile? Taking its example, problem 9. Explain why | is both a ood leaving group and a ih ophilic catalysis. Ney eee NN LO