Effect of nucleophile on reaction

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1 1 Effect of nucleophile on reaction X DS c X c c X DS c + X cleophile not involved in DS of S N 1 so does not effect the reaction (well obviously it controls the formula of the product!) cleophile has a big effect on S N 2 Large nucleophiles are poor in S N 2 reactions due to steric hindrance Small nucleophile (Me) can easily approach Large nucleophile (t-bu) suffers steric interactions

2 2 cleophile strength The stronger the nucleophile the faster / more efficient the S N 2 reaction cleophilic 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 Anion more nucleophilic than its neutral analogue nucleophilic strength (basicity) > 2 nucleophilic strength (basicity) 3 C > 2 N > > F electronegativity C < N < < F nucleophilic strength (basicity) N 2 > > F As we move along a row the electronegativity increases and nucleophilicity decreases As we go down a group both anions and neutral atoms get more nucleophilic - electrons not held as tightly as size increases nucleophilic strength (basicity) 2 S > 2 I > > Cl > F

3 3 Solvent effects S N 1 Intermediate - the carbocation - is stabilised by polar solvents Leaving group stabilised by protic solvents (encourages dissociation) Water, alcohols & carboxylic acids good solvents for S N 1 S N 2 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 I C 3 cation stabilised needs loss of one 2 δ I hydrogen bonds δ

4 4 Leaving group X S N 1 or X S N 2 Leaving group (X) is involved in DS 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 leaving group ability 2 > I > > Cl > F weak base strong base

5 5 Alcohols as leaving groups Poor leaving group as they react directly with nucleophiles bserve deprotonation But they are readily converted to good leaving groups! We can protonate them S N 1 S N 2 Cl Cl conc. 2 S 4 2 Cl Ph Ph 2

6 6 Alcohols as leaving groups II Alcohols can be converted to good leaving groups with oxophilic reagents like SCl 2, PCl 5, P()Cl 3 & P 3 P 3 P P P Addition of an electron-withdrawing group can make alcohols good leaving groups TsCl pyr Ts S Ts = tosyl = toluenesulfonyl Tol S Tol S Tol S good leaving group due to delocalisation

7 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 Me I S N 2 + Me I 1. B Et B = group 3 so empty p orbital 2 B 3 B B 2

8 8 Epoxides as leaving groups Epoxides are excellent electrophiles eason - & 2 x C are sp 3 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 N 2 2 N N 2 2 N Why do you think this isomer is formed?

9 9 Amines as nucleophiles Amines are good nucleophiles, readily attacking electrophiles But we have a problem (as always)... N X 3 N N N + N 4 N X more nucleophilic = electron donating 2 N N N + N 3 N X even more nucleophilic = electron donating 2 N N N + N 2 2 N X N In reality we tend to produce a mixture!

10 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 X + Na N N N N N N LiAl 4 reducing agent N 2 or... X + K N N N 2 N 2 hydrolysis N 2