5.1 INTRODUCTION In the nucleophilic substitution reactions a group attached to a carbon is replaced by another group which may involve several mechanisms. Bimolecular nucleophilic substitution 5,2 along with its unimolecular counterpart are the most important and involve reactions of alkyl halides, alcohols, and related compounds, Gaod nucleophiles ( ‘OH, CHO”) encourage S,2 reactions, while poor nucleophiles (H,0, CH,OH) courage Sy1 reactions, ‘Competition between S,1 and 8,2 Reactions + Sg reaction has high synthetic value since it leads to a single substitution produc. cn Sq reactions fas afar less sypthetic oalue sine it Tends to tun substitution products if the leaving group is bonded ta stereogenic carbon, + An Syl reaction is further complicated by carbocation rearrangements, + An Sql reaction patsy (the initial species formed isa carbocation is frvowred whem the carbocation is stabilized (tertiary or resonance stabilized carbocations, and the solvent i polar (10 stabilize the transition state + The Sy2 pathwuy (a concerted pathoay) & favoured wher the electrophilic carboa i nol sterically kinderedt and dhe solvent i aprotie (lo make the nucleopiie mare reactive) +The rate lew for the reaction of w reactant ©, am allo! Katide that care display both $2 and §,,1 reactions simuldarevusty is ye sum of the inaividual rate faws Rete law {ali halite] [rackeopiite] Rate law (S41 reaction) =k; [alkyt fala) 2 Peaction) sikte| Inuctecphite) ©, [alkyl halidevata ae +} NeeN + SHOOOO'HD que aetbie ugg aurayog) uate sic yo aouasaid axp ov anp s} Aaragpeas ypiny ayy qUARe SyeTAUaU DANIAN A 3} samios uojead v yo anuasud ay ur auryyaMEZeE uoneredaid aty #1 ajdiuexa uv pur sdvweped aqaqnuds pryast -suedap dneug Suraney © ypiya wodp wore uOGuED poyeAMES ‘attudoappna ay 30 uOMeLAATE an St Togue> parernges at nngnasqns arrydoayanu ayy Sawai {c-g immaypg) uot apraeds nie aprrey [AE Aaepuozas typi oF waDs st sna. sas sojnydoayony ype aouts ‘suogzea: uoeurus Woy uoygadutes e aves suoRdeAl LOKI fuonezusoe suena) ofw zs fs pert ae SR | HoH | (1°S Buoys) amas ang fo weep Sijieas— | yp 0} aaaqeyae oxyasnBifod popaanes yyiae 42170 341 Suny poussian fo | jonpoid suo sai mony .3ije ayy 10 woes 1% aay “TunyTeaa ait fo UoUsEANSylunD 2yi 01 | aarrojas tongound yuo fo wenssaaui 5! aywaysgns paLT Pwo MOH aRa 2% we fo sUUKQYNO ALL + | spasoagl yo st waxgoeas 23 fo apa ays mg L awowatas 2%5 wo jo o4es ays sosmauouuy aeydaagomy aq fo woxeuyuanuian ayy Suse uo sry | (uoneinbyico yo worsreau 0H AST , and “C=C—H makes these reagents good bases and only moderately active nucleophiles. Its important to select the reagents which will give substitution products in high yield with less elimination, the nature of the nucleophile ceflects on the desired outcome of the substitution reaction, To convert an alky! halide to an alcobol. the nucleophile must be OH or HO. It is therefore, sometimes difficult te achieve only substitution, without a competing elimination reaction, The following points may be nated: + Alcohols can be synthesized from alkyl halides by the use af either water or hydroxide ion as the nucleophile (Scheme 5.26) ov Ho REL > Rt SCHEME 5.2 * Good yields are obtained from S,.2 neacsions of hydroxide ion with secondary alkyl halides that are allylic, benzylic, or adjacent te a carbonyl geoup (Scheme 5.2) CNA non FS oH Yao no LS SCHEME, * Hydroxide ion is not normally employed as a nucleophile with unactivated secondary halides and never with tertiary halides due to competing E2 elimination reactiens. Far these reactants replacement of the halide with OH can be accomplished by using water asa nucleophile and 5,1 conditions (Scheme 5.24) HO 4 Reto — ROH G He ‘SCHEME 52d“Aliphatic Nucleophille Subsiitution and its Synthetic Applications 183 [7 Brereise 5.1 a z | Wikick of the following routes (Scherue 5.20) is suitable for the synthesis of ethyl | isovroput ether? | SCHEME 5.2 ANSWER. The route (Il) using the primary halide, In either route, the base employed is un alkoxide whieh is a strong base. Ln route (I) therefere, using 2 secondary alkyl halide would mean that the major reaction would be E2 | elimination rather than §,,2 sulsstitution. The conversion of aleobls into alkyl halides is another important substitution reaction, As seen in E2 eliminations, a hydroxy group is not displaced as its anion, it being af high energy. ‘Consequently aleohals are inert to nucleophiles, unless special conditions are employed. Thus, a hydroxyl group ean be displaced from an alcohol, wien itis protonated using a strong acid and the process termed as electrophilic catalysis (Scheme 5.3}. = wonvendn AG. ge + GHACH UH | in Substitution at primary carbon weet cnc%5H, eee CH). LOERE Sey raRE = 3 repay Sulphonate esters, ¢g., prtoluenesulphonate esters known as tosylates (represented as -OTs in structures) are excellent leaving groups and react very much fike alkyl halides in both Sy] and $2 reactions (Scheme 3.4}. in fact p-toluenssulphonate ion is about 100 times better than a chloride ion as a leaving group. Another related ester is methane sulphonate estes, During tosylate formation from an alcehol, the C—O bond of the alcohol remains intact and the alcohol, {as its tosylate ester) retains its stereochemical configuration. As expected during the $2 reaction on a tosylate the inversion of configuration is observed (Scheme 3.4). ‘The inversion of configuration was confirmed from the ester prepared from the parent alcohol by reaction with acetyl chloride (this ester has the same relative configuration as the alcohol or its tosylate ester} and comparing its [a] with that prepared by the acetolysis of the A sudphonate lay fosvintat A wary gona iaviag group ROR * Tec! An alechol Tosylchbride ‘tosylate aster ‘Huenesapnony anion: oO An ace (2 oe Pyridine | CLeCH, ti 4 ° 9 Hu CHICK r i FfCH, eH ho bn, ieee + or wc jaesons ein of conto (seri a anton WR eH © fom UNI, Hyereaton SCHEME 54Aliphanic Nucleophitic Substttation inc tte Synthetic Applications 198 rnsylate (5,2.reaction). Conversion of an alcahol to its hydrocarbon via reduction ofits tosylate occuts via $,2 attack by a hydride ion, H”; on the tosylate (eq, 1, Scheme 3.4), ‘The Mitsunobu reaction (also see Scheme 7.18) isa powerful tool to invert the configuration of an aicohol to its stereoisomer. The reaction involves conversion of the alechel into a good yeaving group which can be displaced by a relatively weak nucleophile, generally a carboxylate jon (RCOO™). The product of sterecchemical inversion in an. ester. This on saponification leads fo the alcohol of opposite configuration. The Mitsunobu reaction involves an aikoxyphosphonium intermediate which undergoes 5,2 inversion. | SCEME SS ry ake Missunnbe ceactions ‘Complexation with the oxygen of hydroxy! grup by adding Lewis acid, ZnCl, creates an even better leaving group than that formed by protonotion of the axygen. The complex either reacts with the nucleophile by Si or 2 mechanism (Scheme 5.6) Chloroatkanes can be made the same way as bromoalkanes (see Scheme 5.3) using hydrochiorie acid, but hydsechloric acid is net as reactive with alechols as is hydrobromic186 Organic Reaction’s and their Mechanisms acid, Hydrogen chloride is a weaker acid than hydrogen bromide and formation of the Protonated alcohol (an exunium jan) is less favourable with ICI as the reagent. Moreoves, chloride is a pooter nucleophile than bromide and thus the displacement step is also lec favaurable. A Lewis acid «g.. zine chloride is often added to bring about an enhancement a the reaction of aleohots with HCI (Scheme 5.5). S,1 rtactions Involve the formation of |: carbocations. therefore rearrangements are often observed during thest reactions. (see Scheme 4.32) 3.2 SYNCHRONOUS SUBSTITUTION—: (A) Mechanism—s, 2 PROCESS Proves ‘The mechanism of an 5.2 reaction is a converted one ‘step process without an intermediate and involves backside displacement of the leaving group by a nucleophile (see Scheme 5) The configuration atthe carbon atom unsergving substitution inverts Walden inversion) sines the nucleophile approaches along a line diametrically opposite the bond to the leaving group. ‘This stereochemical eusteome of the reaction points to a transition state (Scheme 3 7) ft wrhita the carbon undergoing substitution involves a temparary rehybridization from sp tosp? and finally back to sp", sp-hybridized carbon has ap orbital Perpendicular to the plane of the bonds which partly overlaps with an orbital of the leaving group as well as with that af the incoming nucleophile. * Thus the $.2 reaction transition state with a given reactant may be represented praperly (Scheme 5.71) SCHEME So |Saliphate Nucigophine Substitution andl its Symlwite Applications 197 (B) Seructure of the Substrate The rate of direct displacement ic., an $2 reaction is highly sensitive to the sterie bulk of the substituents present on the carbon undergoing this reaction. As expected the degree of coordination increases at the reacting carbon atom and from the steric point of view, the optimum substeate would be CH,—X, Each replacement of hydrogen by a more bulky alkyt group should decrease the rate of eaction, Consequently, the order of reactivity of alkyl groups isexpected to be methyl > primary > secondary > tertiary and this is cbserved. Table 5.1 gives the relative rates of typical $2 reactions. Methyl halicles react most rapidly and tertiary halides react so slowly as to be unreactive by the 5,2 mechanism, [t may be noted that in E2 reactions the order of reactivities (see Scheme 12.11) is the oppasite to this, therefore, the S,,2/E2 ratio is largest for 4 primary halide while it ig least for a tertiary halide and this is seen during the reactions of alkyl bromides with ethoxide ion in ethanol at 55°C (Table 5.1). Thus tertiary halides do not give any significant yield in the $,2 reactions. One fails to prepare ¢g., t-butyl cyanide from t-butyl chloride and cyanide ion as the product is derived only fram elimination, (CH), C = CH, Table 5.1 Relative rates of reactions of alkyl halides in at —& CH) CH, OF + CH=CH, YT etatioe | Amok ance 10% Sulacituent | Compound) | 1 pe | | | Matty | CHK aw SEL —o (GHy,CHe EL» CH CH Cy ; ov [Seca 1 cH as Pragemanart F fichyci—x | om » [emer | a ie Char em (CH). cH, My (anty product) Neopentyt halides being primary halides arealso unceactive in'S,2 reactions. This situation shows that steric hindrance effeds operate even if the carbon is substituted by alkyl groups. Ageneral statement is therefore, that 5,2 type displacements are retarded by increased steric ‘epulsions at the transition state. In substrates of the type R—-CEL,—X, where X js a leaving group, showed that steric effects af R are the dominant factor in determining rates (good yields of neopentyl iodide can be obiained via Grignard reagent, see Scheme 7.82). The bulky substituents on oc near the carbon atom undergoing 2 reaction hinder the approach of the nucleophile to a distance within bonding range. In an extreme case within The senes fe.. in neopentyl system (compared to methy!), the approach of the nucleophile along the line of the C—X bond is hindered by a meshyl group, whatever geometry is attained by ratation about the single bonds (Scheme 5.8). The halocycloalkanes show considerable rate differences during $,2 reactions depending on the size of the ring (for detailed discussion (see Table 1.1), Halocyclohexanes although seemingly mare capable of attaining sp? hybridization at the reacting carbon are however,“ Hoocenty|naletos Bocitaie all, relay nhieone Steric affects in acyciie systoms in the 8,2 reaction SCHEME 5.4 slower in S,2 reaction (see Table 1.1), When a nucleophile approaches an equatorial Malide, it faces an inhibiting effect. steric hindrance by the two axial hydragens at C-3 and C-5 carbons (Scheme 5.9). In.a conformation where the leaving group is axial, then its exit itself faces steric hindrance, SCHEME 39 A bridgehead helide is inert since the three bridges prevent the backside attack necessary fot S,2 reaction. Moreover, inversion of such a system is impossible. Epoxides are mest important three-membered heterocycles which undergo reactions with nucleophiles such as hydroxide ton or alkoxides. The nucleophile attacks the less hincered carbon as expected from an Sy2 attack {1” > 2° > 3°) and the alkyl group is transferred with a heteroatom in the f-position (Scheme 5.94). SCHEME 395 The C—O bond of an epoxide is weaker than those of other ethers due to strained three membered ring, Organolithium and organomagnesium campaunds, therefore, act as nucleophiles in $,2 reactions with epoxides and otherwise these reagents are normally peor nucleophiles and being very strong bases promote elimination reactions (see Scheme 7.78)." ‘Aliphatic Nucteophilic Substitution ane its Syntietic Applications 199° (€) Nucleophites ane their Relative Nucleaphilic Strength—Nucleophilicity— Polarizabiliry of an Atom The rateof an S,,2 reaction is directly related tethe effectiveness of the nucleophile in displacing the leaving group. As a consequence, of a pzir of nucleophiles containing the same reactive tome g., methanol and methaxide ion, the species with a negative charge is the more powerful nucleophile. Put in other words, of a base and its conjugate acid, the base is always more nucleophilic. Therefore, OH" is a stronger nucleophile than H,O, SH a stronger nucleophile than (CH,), SH and NH} is stronger nucleophile than NH. This finding is reasonable as a stronger bond between the nucleophilic atom and carbon would lead toa more stable transition stare and thus a reduced activation energy. Because the 5,2 reaction is concerted the strength cf che partially formed new bond will be rellected in the energy of the transition state; the snore negative the attacking species, the faster will be the reaction, There seems to be a good correlation berween basicity and nucteaphilicity. However, it would be a mistake to explain that methoxide is a much better nucleophile since it is much more basic. Basicity and nucleophilicity are two fundamentally different properties. Basicity (a measure of a thermodynamic phenomenon) is defined by the equilibrium constant for abstracting a proton (Scheme 5.10). On the other band, nucleophilicity (a measure of a kinetic phenomenon! is defined by the rate of attack on an electrophilic carbon, [Remomraaty] y | Base: SCHEME 5.10 The hydroxide ion (OH7) is a stronger base than a cyanide ion (CN>), at equilibrium it has & greater affinity for a proton (the pX, of H,0is « 16, whereas the pX, of HCN is” 10). However, cyanide ion is a stronger nucleaphile.ie.,it recets more rapidly witha carbon having a leaving gfoup than a hydroxide ion. In both cases (Scheme 5.10) however, a new bond is formed When the new bond is twa proton, the species has reacted as a bast; in case the bond is to a carben it has reacted as a nucleophile, Moreover, since nucleophilicity is used to describe trends im the kinetic aspects of reactions, the relative mucleophilicity of a given species may differ from substrate to substrate. Asterically bulky nucleophile is less reactive than a smaller one, An $2 reaction is net oly sensitive te the bulky groups on theelectrophile, but te the bulky groups on the nucleuphile as well. This is due to nonbondesd Rpulsions which would develop in the transition state. Thus although t-butoxide ion is a stronger base that ethoxide ion, but the bulky Hbutoxide isa weaker te neon nuucleophile, Basicity is little effected by steric hindrance, ‘rong sase since the attaek is on an unhindered proton. The strength of a base depends only on how well the base shares its SCHEME ST electrons with a proton (Scheme 5.11)Nucleophilicity decreases on going from left to right in the periadic table. This follows the increase in clectronegativity from lett to right, Thus high electronegativity is unfavourable, due to tightly held electrons which are therefore, relatively less available for donation to the substrate for S,,2 pracess, Thus OH" is mare nucleophilic than F; NEL, is more eueleophili: than H,0. Nucleophiiteity increases going down the petiedic table ie., Br° is more nucleophilic than Cr and SH is more nucleophilic than OH. For the halide ions the nucleophilic reactivities follow the order: beBrschs ‘Thus I is the best nucleophile while Fis poorest. This order is the reverse of the kasicity order of the halide ions: Pech Brot ‘Thus one finds that the correlation between basicity and nucleaphilicity does not hold for the halides. Down a column in the periodic table the atoms become larger. Thus one has more electrons at a greater distance from the nucteus, These electrons are rather loosely held and the atom with this situation is more polarizable. The increase in polarizability leads to an ease of the distortion of the electrun cloud of the attacking atom af the nucleophile to allow far more effective overlap in the transition state, with the back lobe of the slowly rehybridizing sy hybrid used to maintain bonding to the leaving group. For these very reasons the basicity ol the larger elements is relatively poor than smaller elements as the overlap with the hydrogen | s orbital is poor. Thus. ane can use successfully the extent of polarizability to explain as to why [is a better nucleophile than F (Scheme 5.12). ft is only with Iv that the partial band formation begins at relatively large distances as the electron cloud of the nucleophile gets “pulled” to the carbon atom where the S,2 reaction accurs. Thus the activation energy of the | substitution is decreased. This however, is not the case with F- which has tightly bound electrons a= | 7 j I ~ — |@o eran: hie awicteons nf fw ite san ca | oe 2 fartar may with oti af enrban waergostg nueteaprrit attack The ighiy bound fuorise iow! exam electrons ssn ta SCHPME sethat cannot begin to form a C—F bond until the atoms are very close together One may appreciate that the degree of mucleophilicity increases on going down in the periodic table even for uncharged nucleophiles ie., H, Se > H,S > H,O and PH, > NH, In these cases particularly, the Fact that the increasing polarizability improves nucieophilic power explains ‘he nucleaphilicity trend. In these uncharged nucleophiles, the solvent effects must, however, be less pronounced, ‘synthesis of amines involves the reaction of nucleophiles like NHy ar an amine on alkyl halides or sulphonate esters in an §,2 reaction (Scheme 5.12a). The product of the reaction with ammonia ot an amine is an amine salt. The free amine js isolated on treatment with a base such as NaOH, rl 2 - i apl ea: Se HR CH, Br Ammon Gromaetane Ezwlammaniue oromice ‘an amuse CHCH.NHj8r + QH —— CH,CHAIH, © 1,0 © Br enmamne SCHEME 5.123 ‘The order of reactivity of alkyl halides is typical for $2 reactions: CH. alkyl halides react with ammonia or amines to give elimination product ‘A disadvantage of this route te amines is that the product amine salt can exchange a proton witht the starting ammonia or amine (Scheme 5.12), This leads to twa or more nucleophiles X31" > B. Tertiary CH,CH.NHY r+ Ny SE CHLCH.NK, + NZ Br lism 2 ino SCHEME 5.12b ‘competing in the eaction with the reactant. Recall that a primary amine is a stronger base and 4 stronger nucleophile than is NH}, For these reasons ., methy! iodide and ethylamine Ln basic solution lead to quaternary ammonium iodide as the final product (Scheme 5.12c). CHGH,AK, © ao > CH CH NH,CH, REF CHLCHLNHCH, [eo = caycr inc, OH | t oH, ls. CH,CH.NCH, Ls SCHEME 5.12TF 202° Grganic Reaetians an their Mechartisms EXERCISE 5.2 ij How unt alkyl alive reacts cith the azide tau? How this method can be used fo | syiithesise rrianary amine | ANSWER. Azide ion is a very goad nucleophile which reacts with an alky! halide to giv® an alkyl azide. An alk! azide is not however, nucleophilic and its catalytic hydrogenation gives the primary amine in good yield (Scheme 5.124) + 40H, NH. N, SCHEME | EXERCISE 5.3 | Explain the Gatrried synthesis of u prienary anrine ANSWER. In phthalimide the electron pair on the nitrogen is | nucleophilic (due to resonance). Recall that the hydrogen on nitrogen is very acidic | and can be removed by a base to yield phthalimide anion which is a good | neither basic nor nucleophile. Reaction with an alkyl halide gives an N-alkylphthalimicle which does not alkylate further, Hyelrolysis then produces the allcylamine (Scheme 5.12e)- | 5 ot (Gem SCHEME 5.1% {D) Nucleophilicity and Solvent Bifects Nucleophilicty is impeded by solvation. A molecule of a solvent ¢g., water ar an alcotl {protic solvent) can form hydrogen bonds to an anionic nucleuphile (Scheme 5.13). Smaller anions (concentrated charge) aze more strongty solvated than larger ones. This phenomeno®. therefore, creates a solvent induced barrier to attack at the substrate. For a solvated anion © act ag a nucleophile in an 5,2 reaction energy is required to “strip off” some of the solvent— dliphatic Miclkophilic Substitution and ils Synthetic Applications” 208 4 . A } wf i hoof ne fac A arrmres. 78] [ison maven scm ree | Basses [ris iicen soluetean secoee 2 DMC bs polar apratie solvent and dissolves many organic Compounds ane sais. Mucieapnies ara lags. solvated! andi ars more trae to reat SCHEME 5.13 molecules. This energy ip much langer in the case of a small strongly solvated ion c.g., Fas compared to I". Consequently an inclide ion is a better nucleophile than fluoride ion in protic solvent in an $2 reaction. Table 3.2 lists some common nucleophiles which are listed in decrensing order of nucieophilicity in protic solvents ., water or aleohol. [tis found that Table $2 Some common nucleophiles ‘Strong nacheophiles Wonk imcleophites | —————| | SHO j Fo | | ‘ Ma | | (CH.CHJ,NH | cHOH j | c= (CH.CHY,N ou CHO" iiciara maiopeas Bry NH. CI) ONE when benzyl tosylate is heated ia methanol, then benzy! methyl ether is formed (Scheme 5.13a). On adding bromine te the reaction, the reaction rate does not change but, new yor PhGH, OCH. SCHEME 5.130204 Oranic Reactions anel tisir Mechanisms” benzyl bromide is formed. [tis an 81 action, therefore, the rate does not depend! on nucleaphile, Bromide ion isa better nucleophile than methanol and in the presence of this jon the product ¢_ benzyl bromide and not benzyl methyl ether Several aprotic solvents ¢ ., dimethyisulphowide (DMSO) and dimethylformamide (DMA) (Scheme 5.14) are used. An aprotic solvent is not a hydrogen bond donor since it does nothave 3 hydrogen attached to an oxygen o¢ to a nitrogen. Thus they de not solvate anions to any appreciable extent: Consequentiy with anionic nucleophiles, reaction rates are tae gzeater in the polar aprotic solvents, There is lack of stabilization of these nuclesphiles by iaydrogen bonding, these are therefore, almost “naked” ta be highly wactive as nucleophiles. Fluor de ton, therefore, is a better nucleophile ir. OMSO than in water during an S,? reaction, The 8 is on the suvfaoa] AL_oline museca | mec, ee | fRereme | F | [cease ai | Simetnysuaosde 8, Ascimedtyiarmarie CMs DAF SCHEME 3.14 A polar aprotic sofvent dissolves ianic compounds and it solvates cations, the way similar to protic solvents by orienting the negative end of its dipole around the cation (Scheme 5.14), {tis however, unable to solvate the anion by H-bonding. Moreover, methyl groups in the case of DMSO shield the $ which is the positive end of the dipole, -his prevents the solvation wf fw anion, and same is the case with DMF, Consider the $y2 reaction on methyl iodide by a Br-and an uncharged nucleophile Me,N [Scheme 3.15) in ar alcohol, ie the reaction of Br the oucluophile is solvated by hyerogen bonding. Thus the rate of an $,2 reaction involving a negative nucleophile is slower in a more polar solvent. The transition state, however, behaves as a much larger ion and is thus muck ‘ess stabitized by hycirogen bonding. In the case of neutral reactants a passage to the transition Slot reaction in a palar grote solver, Faster mest ita paar p80e sobvect. the ucleapnie is suated ane mat ee Doth *velant we cuarges 30 staovhzee. SCHEME 5.15 state involves the generation of epposite charges. Consequently the transition state is stabilized more than the reactants as the solvent is changed to more polar one. Thus the rate of an soo mwaction involving @ neutval nucleophile [s faster in a mone polar solvent.i EXERCISE 5.4 (a) Explain whether the reaction of 1-chloroprapane with NH, would be faster in CH,OHIG0% HO or in CH,OH 40%160% HO. (6) Whether the reaction af 1 chloropropame aeith CN willbe faster in EtOH or DMSO. ANSWER. (a) This is an §,2 reaction and the reactants are neutral, the transition { ae state, CH,—CH, -CH,C] + NH, —® CH,CH,CH, is polar. The reaction will be NH, faster in a more polar salvent. Since water is more polar thax CH,OH, so the reaction will be faster in 20% CH,OH/80% HO. ib) Reaction is faster in DMSO. iii iene {E} Leaving Groups A good leaving group is the one which becomes a stable fon after its desarture. As most leaving groups leave asa negative ion, the good leaving groups are thase ions which stabilize this negative charge most effectively. The weak bases do this best, thus the best leaving groups are weak bases, In an5,.2 reaction the leaving group begins to gain negative charge as the transition state is reached. The move the negative charge is stabilized, the lower is the energy of the transition state; this lowers the energy of activation and thereby increses the rate of reaction. The weak bases arv the best leaving groups since weak bases are stable bases, since these can readily hold om to elections which were earlier shared with a proton. Moeeaver, a weak base is not bonded as strongly to the carbon as would be the case with a strong base and consequently a weaker bond is more easily broken. When one considers 5? reactians on the CHyCrt | HOT + CHICH.Sr——® CH,CHLOH + ‘ong toto Sa] ge, wore ay SE | SCHEME 5.153ra similar reactants but with different leaving groups (Scheme 5.15a) one finds that is the best leaving group while Fis the worst, This is in keeping with the above discussion. One may also remember that larger atoms can better stabilize their negative change An alkyl chloride or bromide reacts with Nal in acetone under §,2 mechanism due to the presence of 4 strong nucleophile "and an aprotic solvent acetone. NaCl/NaBe formed is not soluble in acetone and therefore. the appearance of a precipitate in a test for alkyl chloride er bromide. As expected the compound (Il, Scheme 5.152) ives a precipitate immediately since bromide ion is a better leaving group than chloride ion Sulphonic acids. R SO,OH are similar to sulphuric acid i acidity and the sulphonate ion RSO; is a very good leaving group. Aiky! benzenesulphonates, alkyl p-toluenesulphonates are therefore, very good substrates in $,,2 reactions (see Seheme 5.4}. The riflate ion (CE,S0,-) is one of the best leaving groups known, tis the anton of CE,SO,H which isa strong acid auch stronger than sulphuric acid Recall that an alcohol can be converted into an alkyt halide on treatment with a hydogen halide (see Schemes 5.3 and 5.5). A hydrogen halide protonates the alcohol as well as provides the rueleophile for the reaction, Other alternative could be the canversion of an alcohol into its sulphonate ester followed by an §,2 substitution employing, halide natcleophile (Scheme 5,154, i Ph. SF oy ymca, MN, Ph (2) LB. acetone Ph OTs Be oso ee ee eee SCHEME 5.15% The sulphonate ester method requires twa steps far the conversion af an alcohol into an alkyl chloride. A one step method employs the use of a ceagent thienyl chloride (SOCI) or a phosphorus trihalide ¢.g., PBr,. These reagents convert the OH group af an aleohol into good Jeaving groups chlorosulphite and bromophosphite groups respectively (Scheme 5.15c}. These reagents replace the Hof the alcohol graup which makes the oxygen a Weaker base and a better leaving group. Chloro-and bromoalkanes are generally used as reaction intermediates and since alcohels are widely available, the role of SOC1, and PBr, for their one step conversion into alkyl halides is synthetically very important. The mechanism may be 5,1 or $2 depending t tot ala CH~OH + C-S— cages ci cH, t0ts+o, —e a Thien # chen| yuaajos spaide ie Suysn uopsear gNg aup ur appgdoarany ay se vo} HO 402. ] worue ayrage sasn Eni auc) “(UOT aDURUOEAT) aeRO A UT ADASeg, | np asearsap fa (OD'HD) dar8 (Ai9>" dq HO Jo H Aq Suede pu Aygeens | | | quaBeas ay) Anpow smut “auoyausig aug -mns30 fi YoHeUHUITIA Jo ALoUr 'asea, ‘Suions v Stag yt sours sumoean Arepuoaas v YIM IQ ASR WMTEED UC "YEMSNY ays asada HD 0 9309 | oS aslowaxa {gig ourayg aos) suoTpUeS sap]/u spun sana90 pure anpDa]as aI0U! & rmdug pur aurydsoydduayden yo apoy wae so din pring ay) plone o1 auasjos se pasm owe =} aurpIad -punocuo> ays yo arrgonaas af 20z suommanddy auayutis sy pup uaymamsars amydozany ane208 Organic Reactions ard their Mechanisms fase 3 r like DMSO. The acetate ester is formedt in an 8,2 reaction in high yield which is | then hydrolyzed OF /H,0 in a separate step (Scheme 5.15) wt) ae oF couse. One | oH,ch, Lic, = ck, ch be cH, SSS och tn, + See 3 : 52 owes 28uura SCHEME 8 180 (F) Electrophilie and Nucleophilic Catalysis S\2 reaction rates can be increased both by electrophilic and nucleophilic catalysis, A hydroxyl group |uONE ui jauooye ays Jo UoRaGAL ayE UIOay apo 1 pOLaAAuOD ag APU [OYODTE By | susmag Ig aug, (O} at uonsear gg ay yo yeordéa 81 yore UOEANSt7UIOD Jo UOHSAAAUT OL oq yscauo ur st sy -(az's ALANS) uogTeD re UOMEANSyUD Jo VoHUATAL ypLA MIO prem -oueSso- ue uO AU SMU, “SfePBUE “7) swe anAEsOdoKDAje ATBUANS oy PAYEE S137 uaym woHoear 245 se paws Tepsdafoung oy|TYdeLIDFS UORMUNSGNs OBsopu URS UOgIEDY uonsexy 72g EL (8) 81e. summanddy qpeunilig

rear snokeoues a ase The reaction products can be farmed by attack by the nucleophile at any stage. In case the products arise from tight ion pair one expects inversion of configuration. This is because in the case of tight ion pait R° is not completely irve, there is still significant bonding between R* and Xe and asymmetry of the substrate is reasonably maintained to a considerable extent. AS a sonsequence in tight ion pais, X-solvates the cation on the side of its departure and therefore itcan only get solvation from the solvent molecules from the apposite side, This process will lead to inwersion of configuration. In case the peeduct arise from the solvent separated ion pair extensive racemization will result since here the stereochemistry is not swintained as tightly as in intimate ion pair The product from the dissociated cation 8” will give complete rieemization, Thus in summary the following points may be noted: Consider the reaction of optically pure lephenylethy! ehleride af ($) configuration with water in aqueous acetone (Scheme 5.27) which as a whole shows First order kinetics (Sy1 ‘eaction}, The 2% net iawersion of configaration af the substrate is due to the invelvement of anion pair mechanism (Scheme .28). Inthe initially formed intimate ion pair the carbocationic partis solvated on the side opposite to the leaving group and the product from these species will have inverted configuration. Thus many §,1 actions inwalve the formation of ion pairs. + Anion pair is a closely associated eation and an anion and behaves a a single unit + Ina tight ion pais, the individual ions retain their stereochemical configuration + A solvent separated ion pair has ils ions separated by solvent molecules and the ions thay and may oot retain their sterecchemical coniguration. rie —ae tes =228 Omenie Renetions and their Mechanisms: 2 =| L cay sh | fevateiy coo Hoes \ ‘CH, inverse re SCHEME 5.28 Other evidence also. proves the formation of ion pairs. When 2-ectyl brosyiate (labelled at the sulphone oxygen with '40} was subject to solvolysis, the un-eacted brosylate isolated from various stages of solvolysis had the '"O considerably (but not completely) scrambled {Scheme 3.29). SCHEME 5.29 In this case the ceaction involves the formation of an intimate ion pair, where the three oxygen atoms become equivalent, [f may be remembered that an ion pair can recombine to afford the original substrate {an internal return, Scheme 5.29), ‘The addition of an ineet salt like NaC1O, o¢ LiBr at a very low concentration to the solution of some substrate undergoing solvalysis leads to an initial large rate inerease. This rate subsequently fails off to become a normal ionic strength effect and the effect is called special salt effect, In the absence of the added salt, the solvolysis proceeds with intimate ion pair formation with considerable return to the starting substrate. The CIO; or Br exchanges with the leaving group to prevent this return. Consequently the amount of the solvent separated ion pair that vould have returned to the substrate is reduced. This leads to an overall increase int the reaction rate| 7 dtphealic Nscteophulte Substitution and ike Sipthetie Applications 215: 5.7 NEIGHBOURING GROUP PARTICIPATION AND NONCLASSICAL CARBOCATIONS: One has seen that aueleophilic substitution take place with racemization or with inversion of configuration. However, in several cases such reactions accur with everall retention of configuration, One factor which leads to retention of configuration during a nucleophilic substitution is neighbouring group participation. The neighbouring group is an electron rich substituent (Z:, Scheme 5.3() present in the proper position for backside attack i.e,,anui attack othe leaving group (X). The pracess infact is a twe step process. In the first step (Scheme 3.30) wie ey tod R ¥e “Tha paving eu 5.) The neighbouring group mechanise bs oF the configuration at 2 i racemized 05,2 substitutions, crch brings about an iversion genic carbon. Configuration isretained and ant inverted or the neighbouring group (acting as an intemal nucleophile} attacks carbon at the reaction center 1Sy2 attack} and the leaving group is lost to give a bridged intermediate, This is then attacked in the second step by an external nucleophile {Y:, another 5,2 attack) and the internal rucleophile goes back to where it came from, the net result is two consecutive Sy2 reacti¢ns ieading to retention of configuration at the reacting carbon. 'A graphic example of neighbouring group participation is found in the conversion of Poromapmpanoie acid into lactic acid (Scheme 5.31), In the presence of concentrated sodium CH.CHOO.H —® CH.CHCOL br The normal stereochemical result for an 3,2 reaction SCHEME 5.31 hydroxide, ($}-2-bromopropanoic acid (shawn as its ion, Scheme 3.32) undergoes a bimolecular displacement with inversicn of configuration as expected from the normal 5,2 reaction, The same reaction when cartied out in the presence of Ag,()and a low concentration of hydroxide ion, however, occurs with retention of canfiguration (Scheme 5.32), The reaction now invalves220 Orocnte Reerions. art thai Mdeharéstns if is Pith iy hwo steps, in the first step the carboxylate Breup acts as a neighbouring group to displace bromide ian wa backside attack on the stereoventer. The silver ion here acts as an electrophilic catalyst and aids the removal of bromine. [n the second step, the a-lactone is attacked by » ‘Sater molecule. Both the steps involve an utversion of configuration on the attacked carbon Thus, the net result of twa inversions in wo Steps is an overall retention of configuratic iP p o Se Go Aa oe ie CH, . CH, Ag Aa nisctne (BEET) cornwraton of 9 sereocener ivan ‘Sie0 2] Configure Hon of the sieraucentier inverts agin SCHEME 3.2 the neighbouring group participation operates luring the rate determining step of a Ruction. the reaction rate is usually markedly increased, This elect then termed anchimieric wees Sulphur atoms act as powerful nucleophiles and the Participation of sulphur as a neighbouring group is common. On reaction with water both hexyl chloride (1, Scheme 5.33) and 2-chluroethyl-ethylsulphide (1) jive tele c nitesponding alcohols, ata eit i Ne SCHEME 333 However, the rate of reaction of sulphur containing compound (Il) is much greater than that {the alkyl chlorice, The neaction in the case of {11g a simple 5,2 displacement of ehtoride ith water, while in the case of sulphide, it is the sulphur atom, which displaces the leaving, “Oup and acts as a neighbouring Sroup. The intramolecular reaction (fas expected) is much Ster than the intermolecular reaction, The initial product frome {11} i8 an epistelphonium ion (immbibichotecrmean- alipharts Nuteopaile Subscisdion: afch ts Symantec: Appts BI. which is then opened by second §,2 displacement (now intermolecular) ta give the product [Scheme 5.34). ‘Thus a neighbouring group participation is the intramolecular involvement of one functional group in the reaction at other functional group. Anchimeric assistance is the increase in the action rate in the rate determining step of the reaction, +He ay Ay in < : Ja hy £Euiphonsm con ‘Operation of neighbourexy yroub eft ScHEME 534 ina 1, 2disubstituted cyclohexane derivative, for the neighbouring group participation to be operative the groups Nave to be anti to each other é, diaxial as in (I, Scheme 5.25}, A ring fip may be necessary to bring about such an arrangement of the groups. Consider the acetalysis, of cis and trans isomers of Z-acetoxycyclohexyl tosylate (Scheme 5.36) which give the same product ( / bh. SCHEME The cis isomer reacts 0 a direct S,2 mechanism and the trans isamer macts {about 700 times faster) via neighbouring group participation by inva vingan acetaxanium fou (A, Scheme 535), This acetoxonium jon (A, the resonance hybrid structure) fram the trans isomer is, Symmetrical achiral (Scheme 5.37) and can be attacked by the acetate ion at either of the two: ‘equivalent carbons shown by arrows. Thus, if one starts with an optically active trans isomer, the net result is the formation of a racemic mixture of diacetates,gn 4 fe ey Toone bm Lone a2) OF Ome t 4 # Cis-teomer ao Norma $.2 displacement SCHEME 5.36 Tans 2 Asoc ton yete Syme! a i SCHEME 5.37, Among the norbomyl derivatives (on acetolysis) the arti tosylate (ILL, Scheme 5.38) revels 10" times faster than (1) while (If} has U0* times reactivity compared to (I th wy Pes = : wo! 0 SCHEME 5.38 i t | | |Aliphatic Nucteophilie Substitution and its Synthetic Applicatians: 235 The fastest rate of acetolysis of anttitosylate (II) compared to (1, Scheme 5.38) proves the removal of the tasyl group (the rate determining step) with strong anchimeric assistance by the double bond. The resulting non-classical carbocation i. bridged ion can only react with eatate ion from the side apposite to the neighbouring group, with retention of configuration ‘Scheme 5.39), Inthe syn-isomer (Il, Scheme 5.38) the rate is slower because the double bond is not properly situated for participation, Thus this isomer dissociates without anchimeric Msistance to give a homeallylic carbocation which rearranges to allylic carbocation ii, Scheme 5.40) and this reacts to give an acetate. The high reactivity: (10* times) of (11) than (1) ‘pay be because of participation of 2 electrons ot two allylic 1. 6.and 4, § bonds. “Thus the bridged cation (Scheme 5.39) is an unusual situation which involves three-center jwo-electron bonding such species are called non-ciassical carbocations. SCHEME Sa ties ANSWER. The thio substituent acts as an intramolecular nucleophilic catalyst and provides anchimeric assistance. [t displaces the chlaro substituent by the | back side attack on the carbon with chloro substituent, Back-side attack requires both substituents to be diaxial. Subsequent attack by water ar ethanol on the(224. Organic Reactions and their Mechanisms = | aulphontue ion is fast as the positively charged sulphur ia very good leaving ‘group and cleavage of the three-membered ring releases strain (Scheme 5.41) @ Asc ae 3 i S | Evidence has been presented that C=C acts asa Reighbouring group and thata non classical carbocation {a bridged cation) may be focmed. Evicience isalso available toshow ther asuitably located C-—< in a substrate can alsa participate in the depacture of the leaving group and non- classteal carbocations may be involved During the acetulysis of exo and emfv-norbornytosylates (Scheme 5.42) itis found that), | the solvolysis of exo isomer is 350 times faster than the endo isomer: (8), buth the some give | only the exo acetate: (c}, and optically pure exo-tosylate gives 100M racemic product while an, ‘optically pure enda tosylate gives 93% racemic exo-acetate. These observations ane explained: | * In the exo isomer the 1. bo bond is suitably located to act as a neighbouring group to lend anchimeric assistance oia backside attack to give directly a non-classical carbocation {1 Scheme5 43) which is more stable than the carbocation (IL Scheme 5 44) formed inially in the case of endo-isomer. The endo-isomer on the other hand first gives a carbocation (UL Scheme, 5:4) which subsequentiy forms the same non-classical enrhocation aSCHEME 343 + The attack occurs from the exe-side due to the cage structure of the non-cassical carbocation intermediate (I, Scheme 5.43), Moreover, the attack must accur from the direction opposite that of bridging interaction and this is exo-direction, + Recall that a non-classical carbocation involves a three-center two-electron bonding, In a common case three carbon atoms ate involved, two af which are bonded by aa bane! while the third is bonded to the other two by a two-electron three-center bond + The non-classical carbocation intermediate (I, Scheme 5.43) is achiral having a plane of symmetry passing through C-4, C-5, C-6 and midpoint af the C-1 and C-2 bond The C-6 has two hydrogens and is pentacoordinate and is the bridging atom in the cation. Thus the attack at both C-t and C-2is equally tkely which gives equal amounts of enantiomeric acetates—a racemic mixture. In the case of ende-tosylate, tll (IL, Scheme 5.44) collapses to (E), i will give one enaatiomer in excess to explain #3% formation of racemic acetate. Bridging provides only stabilization. If other forms of stabilization are available, ions will then be open classical species. UC NMR spectroscopy is used to distinguish ketween quilibrating structures and bridged species. Thus 2-phenylnorborny! cation (Il, Scheme 5.44) has the clagsical structure. This benzylic cation is stabilized by s-electrons of the benzene ring and thus bridging is not involved. Fizstly consider the resonance-stabilized carbecatian (Scheme 3.45), the two carbons {shawn by dots} which share the positive charge as expected am almost equivalent. fn equilibrating ionie structures (two independent ions) such carbons differ by about 100 ppm.226 Organic Reactions and their Mechanisms: yer f a ne mR SCHEME 5.45 That 2-norbomyl cation is a bridged species has heen shown by detecting it in a highiy polar but non-nuclenphilic solvent (super actd media, SbF,-SO,]. The 5C NMR showed very similar signals for both the deuterated as well as undeuterated positively charged carbons (Scheme 3.46). This evidence excludes the farmation of an eeuilibrating pair of cations where the two boldly shown carbons should have displayed widely separated signals in UC NMR D Euuikbrating paw SCHEME 5.46 Certain properties of a cyclopropane ring are similar to that of an olefin. Cyclopropane rings in particular and cyclobutane ring generally display rate enhancements when these ate suitably placed in a substrate. Thus cyclopropyl-methyl and cyelobuty! substrates undergo hydrolysis abnormally rapidly to yield the same products which include cyclopropy! methyl cyclobutyl and homoallylic compounds (Scheme 5.47). Their formation is due to theHCH,CH,OH ws Deo = = (] ___—— The formation of a common nan-ciassical intermediate SCHEME 3.47 intermediate formation of a non-classical cation (Scheme 5.47}, In cyclic systems related to- nofbomyl system the presence of a suitably placed cyclopropyl group acts as a neighbouring, group. Thus (II, Scheme 3.48) reacts 10! times faster than L [thas been suggested that in (II, Scheme 48) and other eyelopropyl derivatives which display rate enhancement, the developing, porbital af the carbocation is orthogonal to the participating bond af the cvcloprapane ring. ACO, SCHEME S48 5.8 NUCLEOPHILIC SUBSTITUTION AT SILICC (Bor details see Seheme 7.36). i PROBLEMS | SL. A factor which stabilizes an anion would be generally expected to reduce oF enhance the rate of an. nucleophilic substitution? ‘The free enengies of activation for reaction of nucieophiles with CH. at 25°C in methanol and in DMF are given. How do you explain the relative nucleophilicities of the halide ions and thiveyanate ion? N DMF CHAOH ct lao 25.0 Br 173 230 sor 19.9 220 r 209 18.053, 5.6. 52, 5.8, 5.10, Sal, B12, Why displacement of cyanide is never observed? Why azide and aevtate ons are pooe leaving groups? Wity an alcohol reacts with a halide ion only in the presence of a strong acid? 5. Why o-carbony! substituted substrates like BrCH,COCH, and BrCH,CO0 Et react more readily than the corresponding alkyl halides? Why CH,OCH,CI reacts with sedide lon in acetone several thousand times faster than cH cP i Why the inversion of contigueation is much more during the solvolysis of C,H,,CH(CHL JC! than CH.CH (CH,ICI? (Ay the following allylic and benzylic halides react only by Sy] process and not by, mechanism? Why both S,1 and S,2 mechanisms operate when R'ssH or Re R'et?? R R L I I meaty Arce i R R aie Benayic Trans-2-chlorocyciohexanol gives epox yeyclohexane in high yield on reaction with base however, the cis-isomer does not react this way. Explain. Why the epoxice (0 ceacts with avidie methanol to givea optically pure -——~ ‘mixture of Uf and I] (see under answer 5.10) and no racemization is | pbsteved? | Explain the outcome of the following reaction,213, The following nucleophilic substitution reaction proceeds with.a rearrangement, When the reactant is optically active the product is also optically active. Explain. cnc, F CHER, oe _ NOM, wate _NOHCHCH, CHCH HE oHSH, EM. 2-Methyl but-3en-2-ol reacts easily to yield almost exclusively one product through the unsymmetrical allylic carbocation intermediate. Explain. deielniSeen- Dot 0 [Hint: Though the carbocation (I) is unsymmetrical and resonance stabilized it is attacked by the nucleophile almost exclusively at the less substituted end predosinantly. Compare with the explanation in Scheme 2.18] ANSWERS TO THE PROBLEMS | Reduce the rate. | 52, Considering the halide ions, the smaller chioti more hydrogen bonded in methanol \ and langer atoms are less hydrogen bonded in hyséroxylie solvents | 3d. HICN is a weak acid (pK, = drazoic acid (HN. | {CH,COOH) are also weak acids (pX,'s of 5.8 ane 4.8 respectively). 34, The hydroxide ion is a strong base arid thus cannot be a leaving group. The acid protonates the hydroxyl group, and then the , os -ansition states are stabilized by in | lacement the adjacent jai system. 36, the cealkoxy compound the transition state (5,2) is stabilized ‘of the porbitalon the carbon undergoing substitution with the od on to the areal 34. As with tertiary halides, the groups.on the carbon having the halogen prevents these fet ali ud with the presence of three alkyl ic and bengylic halides only by Sy process. carbocation, er the groups can be diaxial or jon} aucleophilie Cr