NUCLEOPHILIC SUBSTITUTION REACTIONS HL Organic Chemistry: NUCLEOPHILIC SUBSTITUTION REACTIONS

Types of Halogenoalkanes methyl primary secondary tertiary The carbon attached to the halogen determines whether the haloalkane is considered: methyl [only hydrogens] primary (1°) [one methyl or alkyl] secondary (2°) [two methyls or alkyls] tertiary (3°) [three methyls or alkyls]

SUBSTITUTION REACTIONS One group takes the place of another. Y + R X R Y + X Y takes the place of X ( Substitution ) Y “displaces” X

NUCLEOPHILIC SUBSTITUTION NUCLEOPHILIC DISPLACEMENT leaving group substrate nucleophile product The nucleophile “displaces” the leaving group. This is a “substitution” reaction : Nu substitutes for X (takes its place).

EXAMPLE 1 * (s) soluble insoluble iodide displaces bromide at carbon * NaI is soluble in acetone, NaCl and NaBr are not

EXAMPLE 2 solvolysis of t-butyl chloride in water 3 E1 competes EXAMPLE 2 solvolysis of t-butyl chloride in water water displaces chloride at carbon * The extra proton is taken by a second water molecule.

DISPLACEMENT REACTIONS NUCLEOPHILIC SUBSTITUTION REACTIONS ( substitution at carbon ) can be compared to ….. ACID-BASE REACTIONS ( substitution at hydrogen )

COMPARE THESE SUBSTITUTIONS DISPLACEMENT AT CARBON nucleophile substrate product leaving group DISPLACEMENT AT HYDROGEN base acid conjugate acid conjugate base

THESE REACTIONS HAVE A WIDE RANGE OF SUBSTRATES

COMMON SUBSTRATES ( Leaving group varies ) alkyl halides alcohols require acid and then H2O leaves tosylates ABBREVIATION alkyl p-toluenesulfonate

WIDE RANGE OF NUCLEOPHILES THERE ARE ALSO A WIDE RANGE OF NUCLEOPHILES A WIDE VARIETY OF COMPOUNDS CAN BE MADE

NUCLEOPHILES Nucleophile Product Class alkyl halides alcohols ‘ ‘ A WIDE SELECTION OF NUCLEOPHILES MAKES POSSIBLE THE SYNTHESIS OF MANY TYPES OF ORGANIC COMPOUNDS: R-Y + Nu R-Nu + Y Nucleophile Product Class R X alkyl halides alcohols R O H ‘ ‘ R O R ethers R C N nitriles O esters R ' C O R R ' C C R alkynes R S H thiols

THE NUCLEOPHILE DOES NOT HAVE TO BE CHARGED + - H O + R B r H O R + B r H H O H Under some circumstances water will react. H + - H O R + H O + B r 3 Nucleophile Product Class R O H alcohols ‘ ‘ ethers R O R amines R N H 2 amines R ' N H R

REACTION 1 THE SN2 REACTION

SN2 - rate = k2 [RBr] [NaOH] bimolecular concerted substitution 55oC rate = k2 [RBr] [NaOH] k2 = 0.022 liter/mole-sec - bimolecular concerted SN2 substitution nucleophilic bimolecular

SN2 Concerted (one step) reaction Concerted (one step) reaction transition state TS SN2 E N E Ea R G Y starting D H material product

REACTION 2 THE SN1 REACTION

SN1 rate = k1 [RBr] unimolecular two steps slow fast substitution 55oC rate = k1 [RBr] k1 = 0.010 liter/mole-sec unimolecular two steps slow SN1 fast substitution also alkene (via E1) nucleophilic unimolecular

SN1 TWO STEP REACTION carbocation intermediate TS E TS N E Ea R G Ea Y 2 N E Ea 2 R G Ea 1 Y starting step 1 step 2 D H material product

TWO SUBSTITUTION REACTIONS A QUICK SUMMARY OF TWO SUBSTITUTION REACTIONS SN1 / SN2

SN2 RBr + NaOH ROH + NaBr 1) First Case rate = k2 [RBr] [NaOH] Two similar reactions, different kinetics. RBr + NaOH ROH + NaBr 1) First Case 55oC methyl SN2 rate = k2 [RBr] [NaOH]

2) Second Case 55oC tertiary SN1 rate = k1 [RBr]

MANY PARAMETERS INFLUENCE NUCLEOPHILIC SUBSTITUTION

NUCLEOPHILIC SUBSTITUTION MANY FACTORS INFLUENCE SN1 AND SN2 REACTIONS SOME PARAMETERS : a) solvent b) temp. c) pH d) DH a) structure a) structure of R, stereochemistry a) bond strength a) nature of X b) atom used b) atom used b) concentration c) concentration c) base strength c) bond strength d) base strength e) solubility f) size

STRUCTURE OF THE SUBSTRATE SN1

SN1 - SUBSTRATE AND CARBOCATION slow R-X R+ X- + R+ Nu- R-Nu + fast The energy of the carbocation intermediate is an important factor for an SN1 reaction. The better ion will have the lower energy pathway. 3o < 2o < 1o

SOLVOLYSIS OF tert-BUTYL BROMIDE acetone SN1

SOLVOLYSIS OF t-BUTYL BROMIDE tertiary + H3O+ + Br-

EFFECT OF INCREASING SUBSTITUTION - SN1 100% RBr + H2O ROH + HBr HCOOH methyl primary secondary tertiary 108 1.0 1.7 45 Guess ? relative rate increasing rate rate rel rate = rate CH3Br EFFECT OF SUBSTRATE ON RATE

STRUCTURE OF THE SUBSTRATE SN2

SN2 - SUBSTRATE .. R H O : .. C : Br R R H O : .. H C : Br H H large groups introduce steric hindrance .. C : Br R R H O : .. H easy access no steric hindrance C : Br H H

EFFECT OF DEGREE OF SUBSTITUTION - SN2 methyl primary secondary tertiary 150 1 0.01 0.001 decreasing rate rel rate = rate EtBr rate EFFECT OF SUBSTRATE ON RATE

EFFECT OF BULKY SUBSTITUENTS - SN2 ( substitution on the a carbon ) NEOPENTYL slower than t -butyl a a a a 17 1 0.03 3 x 10-6 decreasing rate rel rate = rate EtBr rate ALL ARE PRIMARY !

Summary for Substrates Notice that benzyl and allyl are good for both SN1 and SN2 SN1 SN2 (fastest) tertiary methyl (fastest) BEST BEST benzyl benzyl allyl allyl secondary primary primary secondary WORST bridgehead tertiary (slowest) (bicyclic) neopentyl APPROXIMATE RATE ORDERS bridgehead WORST (bicyclic) (slowest)

IS THE NUCLEOPHILE IMPORTANT IN BOTH SN1 AND SN2 REACTIONS ?

SN1 rate = K1 [RX] SN2 rate = K2 [RX][Nu] NUCLEOPHILES IMPORTANCE IN SN1 AND SN2 REACTIONS Nucleophiles are unimportant in an SN1 reaction; they are not involved in the rate-determining step. SN1 rate = K1 [RX] The nature of a nucleophile is only important to an SN2 reaction. SN2 rate = K2 [RX][Nu]

WHAT IS A GOOD NUCLEOPHILE ? SN2 REACTIONS

.. : Y WHAT IS THE IDEAL NUCLEOPHILE ? R : .. C : Br R R - X SN2 REACTIONS Y : .. LARGE STERIC PROBLEMS no way ! bad R SMALL : .. X - C : Br good R R Smaller is better ! For an SN2 reaction the nucleophile must find the back lobe of the sp3 hybridized orbital to which the leaving group is bonded.

EXPECTED “IDEAL” NUCLEOPHILES cyanide - ROD OR SPEAR SHAPED :C N: - + - :N N N: azide SMALL SPHERES These types should be able to find the target ! .. :F: :Cl: .. - - etc. Generally this idea is correct.

OUR EXPECTATION ……. - - - - F Cl Br I We would expect the halides to be good nucleophiles: ionic radii: 1.36 A 1.81 A 1.95 A 2.16 A smallest ion - - - - F Cl Br I and we would expect the smallest one (fluoride) to be the best nucleophile, ….. however, that is not usually the case.

SN2 CH3-I + NaX CH3-X + NaI Rate = k [CH3I] [X-] k slowest fastest F- RELATIVE RATES OF REACTION FOR THE HALIDES MeOH CH3-I + NaX CH3-X + NaI Rate = k [CH3I] [X-] SN2 k F- 5 x 102 slowest Cl- 2.3 x 104 Br- 6 x 105 fastest I- 2 x 107 * MeOH solvates like water but dissolves everything better.

COMPETITIVE NUCLEOPHILES

SN1 REACTIONS - - - IN SN1 REACTIONS ALL NUCLEOPHILES REACT EQUALLY WELL HOH, H+ .. - solvolysis + :Br: .. slow .. - :Cl: .. .. - : I : .. All react equally with the carbocation. The amounts of RCl, RBr and RI reflect their starting concentrations in the solution.

SN2 REACTIONS - - - FOR SN2 REACTIONS, THE SIZE AND NATURE OF THE NUCLEOPHILE IS IMPORTANT - Cl - - Br I Different amounts of RCl, RBr, and RI are found even when they are equi- molar in the original solution.

THE BOTTOM LINE SN1 CARBOCATIONS REACT WITH ALL NUCLEOPHILES EQUALLY The nucleophile is not involved in the rate-determining step. SN2 BETTER NUCLEOPHILES REACT FASTER GIVING MORE PRODUCT The nucleophile is involved in the rate-determining step.

HOW CAN YOU TELL IF IT IS SN1 OR SN2 ? 1) LOOK FIRST AT THE NUCLEOPHILE You cannot do a reasonable SN2 reaction without a good Nu. If you have a poor nucleophile, SN1 is probable. 2) NEXT CHECK THE SUBSTRATE Primary is bad for SN1 ….. Tertiary is bad for SN2 3) FINALLY LOOK AT THE SOLVENT SN2 is best in nonpolar and polar aprotic solvents, but can also happen in water or EtOH. SN1 needs a polar solvent.

* SOME HELPFUL HINTS ! DECISION CHART LOOK FIRST AT THE NUCLEOPHILE, THEN THE SUBSTRATE GOOD NUCLEOPHILE * Good Nucleophile in high concentration = SN2 unless it is a strong base however, 1o substrates can give SN2 at low T RO- HO- H2N- …. however, SN2 needs a 1o or 2o substrate (or 1o benzylic) not 3o SUBSTRATE …. prefers a nonpolar solvent but will proceed even in a polar solvent (aprotics best) SOLVENT strong bases like all substrates with a beta hydrogen (anti-coplanar) 3o >> 2o > 1o STRONG BASE

* SOME HELPFUL HINTS ! DECISION CHART LOOK FIRST AT THE NUCLEOPHILE, THEN THE SUBSTRATE POOR NUCLEOPHILE * Poor nucleophile (solvolysis) = SN1 or low concentration …. however, the substrate needs to be 3o or benzylic or allylic (or 2o) SUBSTRATE …. also, in SN1 the carbocation needs a reasonably polar solvent SOLVENT watch for rearrangements REARRANGEMENT

Summary of material you MUST know for the HL Chemistry exam

IB Style Rxn Pathways Haloalkanes are the starting reactants for all substitution reactions SN1 uses slow heterolytic cleavage of the carbon – halogen bond to form a carbocation intermediate as the rate limiting step The intermediate then reacts rapidly with a nucleophile (Nu-) to form the final product The energy profile for an SN1 reaction shows two humps in the reaction pathway (see slide) You MUST USE CURLY ARROWS to show this process for IB exam credit!

SN1 General Example L = “Leaving Group” (in this case a halogen)

SN1 General Example (IB Version)

SN1 NaOH Example (IB)

SN1 TWO STEP REACTION carbocation intermediate TS E TS N E Ea R G Ea Y 2 N E Ea 2 R G Ea 1 Y starting step 1 step 2 D H material product

IB Style Rxn Pathways The SN2 reaction involves the simultaneous breaking of the carbon-halogen bond and the formation of the carbon-nucleophile bond The transition state has a 5 bonded metastable carbon complex which releases the halogen while the covalent bond to the nucleophile remains Again, you must be able to use CURLY ARROWS to write out this mechanism

SN2 General Example The halogen is a specialized case of a “leaving group” (L) Note the 5 bonded carbon in the single step mechanism transition state The double cross on the center diagram is the symbol for transition state The energy profile only has a single curve

SN2 General Example (IB)

SN2 NaOH Example (IB)

SN2 Amine Example (IB)

SN2 Nitrile Example (IB)

SN2 Concerted (one step) reaction Concerted (one step) reaction transition state SN2 E N E Ea R G Y starting D H material product

Summary of IB SN Information (1) Slightly positive charged carbons are attacked by negative nuclophiles Primary halogenoalkanes react via SN2 Rate = k[R-X][OH] Tertiary halogenoalkanes react via SN1 Rate = k[R-X] Secondary halogenoalkanes can react via either route, and will probably not be asked on the DP exam

Summary of IB SN Information (2) As the halogen changes from Cl→ Br→ I, carbon-halogen bond polarity decreases, whereas reaction rate increases SN1 reactions occur faster than SN2 The rate of reaction for halogenoalkanes is: Tertiary > Secondary > Primary Nitriles can be converted into: (1) amines using hydrogen gas (with a nickel catalyst) or (2) carboxylic acids using an acid (typically HCl)

20.2.6: Reactions of Nitriles (IB)

Words to the Wise You have just seen the minimum you need to know about Nucleophilic Substitution Reactions in this mini-review Read your IB Text Book and review material.