1 Effect of nucleophile on reaction H H H H H H H RDS H H RDS + Nuc R H Nuc X R X R Nuc R X Nuc R X • Nucleophile not involved in RDS of SN1 so does not effect the reaction (well obviously it controls the formula of the product!) • Nucleophile has a big effect on SN2 • Large nucleophiles are poor in SN2 reactions due to steric hindrance Large nucleophile (t-BuOH) suffers steric interactions Small nucleophile (MeOH) can easily approach 2 Nucleophile strength • The stronger the nucleophile the faster / more efficient the SN2 reaction • Nucleophilic strength (nucleophilicity) relates to how easily a compound can donate an electron pair • The more electronegative an atom the less nucleophilic as the electrons are held closer nucleophilic strength Anion more nucleophilic H O than its neutral analogue (basicity) HO > 2 nucleophilic strength R C (basicity) 3 > R2N > RO > F As we move along a row the electronegativity electronegativity C < N < O < F increases and nucleophilic strength nucleophilicity decreases (basicity) R NH2 > R OH > R F As we go down a group both anions and neutral atoms get more nucleophilic strength H2S > H2O (basicity) nucleophilic - electrons I > Br > Cl > F not held as tightly as size increases 3 Solvent effects SN1 • Intermediate - the carbocation - is stabilised by polar solvents • Leaving group stabilised by protic solvents (encourages dissociation) • Water, alcohols & carboxylic acids good solvents for SN1 Br H O H O H H Br O H O H O cation hydrogen stabilised O bonds SN2 • Prefer less polar, aprotic solvents • Less charge separation in TS‡ so less need for polar solvent • Need aprotic solvent so that nucleophile is not solvated O H O H H H H O H O CH3Br O δ– δ– H H I H H H I Br H H H H needs H H O loss of O one H2O 4 Leaving group SN1 Nu SN2 X Nu or Nu X Nu • Leaving group (X) is involved in RDS of both reactions - very important • Better leaving group - faster both reactions are • Bond strength - stronger the bond worse the leaving group • Stability of X - neutral or stable anions (more electronegative) make good leaving groups H2O > HO leaving group I > Br > Cl > F ability weak strong base base 5 Alcohols as leaving groups • Poor leaving group as they react directly with nucleophiles • Observe deprotonation O Nu O H Nu R H R • But they are readily converted to good leaving groups! • We can protonate them SN1 SN2 OH Br OH HCl Cl conc. HBr H2SO4 Br Cl H H Ph OH Ph OH2 OH OH2 6 Alcohols as leaving groups II Alcohols can be converted to good leaving groups with oxophilic reagents like SOCl2, PCl5, P(O)Cl3 & PBr3 OH PBr3 Br O P Br Br Br Br Br OH P P Br O Br Br Addition of an electron-withdrawing group can make alcohols good leaving groups TsCl Nu R OH pyr R OTs R Nu O O O O S Tol S O Tol S O Tol S O O O O O Ts = tosyl = toluenesulfonyl good leaving group due to delocalisation 7 Ethers as leaving groups • Normally ethers are stable under most conditions • They are commonly used as solvents • But with strong protic acids or Lewis acids they can be cleaved O OH Me HI + Me I SN2 O OH 1. BBr 3 + Et Br 2. H2O B = group 3 so empty p orbital H2O BBr3 Br Br Br BBr2 O B O O Br 8 Epoxides as leaving groups • Epoxides are excellent electrophiles • Reason - O & 2 x C are sp3 so bond angles should be 109˚ but are forced to be closer to 60˚ • The ring is under a lot of strain (ring strain) • This can be released if the epoxide reacts and we get ring opening O OH HNR2 R2N O H O R N HNR2 2 Why do you think this isomer is formed? 9 Amines as nucleophiles • Amines are good nucleophiles, readily attacking electrophiles • But we have a problem (as always)... H H R + H N R X H N R H N NH4 H H3N H H R R R + H N R X H N R R N NH3R H RH2N H H more nucleophilic R = electron donating R R R + R N R X R N R R N NH2R2 H R2HN H R even more nucleophilic R = electron donating R R In reality we tend to R N R X R N R produce a mixture! R R 10 The solution... • Fortunately there are ways around this problem • Use "masked" amine - a functional group that is readily converted to an amine • Azide is very good as it is small an will attack most electrophiles LiAlH4 R X + Na N N N R N N N R NH reducing agent 2 or... O O NH2NH2 R X + K N R N R NH2 hydrolysis O O.