Nomenclature Common: named as if derived from hydrogen halide, HX - - PowerPoint PPT Presentation

Br

Nomenclature Common: named as if derived from hydrogen halide, H–X CH3–Cl methyl chloride (CH3)2CH–Br isopropyl bromide R–X alkyl halide grouped into 1E, 2E, 3E classes based on identity of R

F F Br

Nomenclature IUPAC: named as substituted alkanes substituent name for X is halo R–X haloalkane 3-fluoroheptane (S)-3-fluoroheptane (1R,3S)-1-bromo-3-methylcyclohexane

Some essential properties of haloalkanes

• R–X are polar
• the C of C–X is intrinsically electrophilic. This dominates the chemistry of this functional group
• R–X have bp’s higher than corresponding R–H

bp - 0.5 EC bp 79 EC

• R–X are toxic
• R–X are relatively rare as natural products

C X H H H δ+ δ−

Cl

Cl Cl Cl Cl Cl OCH3 Cl Cl Cl O H CH3 O O Cl Cl OSO3 Cl OH Cl Cl Cl Cl OH Cl OH Cl Cl Cl OH OH

• Synthetic and Naturally Occurring Haloalkanes

DDT (insecticide) methyl ether of a trichloroorcinol LD50 = 115 mg/kg (fungicide produced by water lillies) (compare LD50 acetaminophen = 338 mg/kg) cytotoxic sulfolipid from Mytilus galloprovincialis IC50 = 13 µM

O O OH OH Cl O Cl O H HO OH Cl

O O OH OH OH O O H HO OH OH O H

sucralose (Splenda™) 400-800 times as sweet as sugar sucrose

Are all nucleophiles created equal? Consider the SN2 reaction of various nucleophiles in a polar protic solvent, holding R–X constant: Nu- + R–X 6 Nu–R + X- Relative Nucleophilicity Nucleophile very good I- HS-, RS- good Br- HO-, RO- N/C- N3- fair Cl-, F- RCO2- NH3 poor H2O, ROH very poor RCO2H

Trends in nucleophilicity: BASICITY Consider the SN2 reaction of various nucleophiles in a polar protic solvent, holding R–X constant: Nu- + R–X 6 Nu–R + X- Relative Nucleophilicity Nucleophile very good I- HS-, RS- good Br- HO-, RO- N/C- N3- fair Cl-, F- RCO2-

NH3

poor

H2O, ROH

very poor RCO2H in the same row of the periodic table, stronger bases are better nucleophiles

Trends in nucleophilicity: BASICITY Consider the SN2 reaction of various nucleophiles in a polar protic solvent, holding R–X constant: Nu- + R–X 6 Nu–R + X- Relative Nucleophilicity Nucleophile very good I- HS-, RS- good Br- HO-, RO- N/C- N3- fair Cl-, F- RCO2- NH3 poor H2O, ROH very poor RCO2H in the same row of the periodic table, stronger bases are better nucleophiles

Trends in nucleophilicity: BASICITY Consider the SN2 reaction of various nucleophiles in a polar protic solvent, holding R–X constant: Nu- + R–X 6 Nu–R + X- Relative Nucleophilicity Nucleophile very good I- HS-, RS- good Br- HO-, RO- N/C- N3- fair Cl-, F-

RCO2-

NH3 poor H2O, ROH very poor RCO2H in the same row of the periodic table, stronger bases are better nucleophiles

Trends in nucleophilicity: SIZE AND SOLVATION Consider the SN2 reaction of various nucleophiles in a polar protic solvent, holding R–X constant: Nu- + R–X 6 Nu–R + X- Relative Nucleophilicity Nucleophile very good

I-

HS-, RS- good

Br-

HO-, RO- N/C- N3- fair

Cl-, F-

RCO2- NH3 poor H2O, ROH very poor RCO2H in the same column of the periodic table, bigger is better

Trends in nucleophilicity: SIZE AND SOLVATION Consider the SN2 reaction of various nucleophiles in a polar protic solvent, holding R–X constant: Nu- + R–X 6 Nu–R + X- Relative Nucleophilicity Nucleophile very good I- HS-, RS- good Br- HO-, RO- N/C- N3- fair Cl-, F- RCO2- NH3 poor H2O, ROH very poor RCO2H in the same column of the periodic table, bigger is better

H O H H O H N H H H O O . . .. . . .. .. . . ..

CH3 C H3 O C H3 N CH3 O H S CH3 C H3 O O O

Why might this be so? SOLVATION MATTERS Polar protic solvents water alcohols ammonia, carboxylic acids amines Polar aprotic solvents ethers acetone DMF DMSO

HO- + CH3Br HOCH3 + Br- Ea

relative desolvation in polar aprotic solvents increases the E of the nucleophile: given about the same pKa, smaller is better relative solvation in polar protic solvents decreases the E of the nucleophile: little nucleophiles are more strongly solvated, so given the same pKa, bigger is better

H H H H H H H H H H H H H H H H H

Nu-

S S S S S S S S S δ+ δ− E

Nu-

S S S S S S S S

H H H H H H H H H

Nu-

S S S S S δ+ δ− E

Nu-

S S S S

(CH3)3COCH3 H CH3OH + (CH3)3CBr Ea CH3OH + (CH3)3C+ + Br- + + Br- (CH3)3COCH3 + HBr

While SN2 is favored in polar aprotic solvents, SN1 is favored in polar protic solvents. This is because the polar transition state is stabilized by polar protic solvents, lowering the Ea of the rate limiting step:

S O O O H S O O O CF3

• O

O

• O

H O O R R' H + O H R' H + O R H H + S O O O CF3 R S O O O CF3 H S O O O R S O O O

• O

H H H + O R O

Leaving group ability is a function of the basicity of the leaving group

Compound Corresponding acid pKa Corresponding conjugate base

• 11

(R–OTf) (H–OTf) (-OTf) R–I H-I

• 11

I- R–Br H–Br

• 9

Br- R–Cl H–Cl

• 7

Cl-

• 3

(R–OTs) (H–OTs) (-OTs)

• 2

H2O

• 1.5

ROH 5 R–OH H–OH 16 HO- R–OR’ H–OR’ 16 - 18 RO- R–NH2 H–NH2 36 NH2

Br O H O H O H O H O H O H O H O H O H O H O H O H + + + + . . .. .. .. .. . . . . .. .. .. .. .. .. .. .. .. .. . . + RLS PDS + +

X H R R R R H R R R R Z + Z- + X- SN

The substitution continuum

What factors influence the balance between SN1 and SN2 for a given class of haloakanes?

H X H H H O- Na+ OH H H O H H

Primary haloalkanes:

• SN2 for all Z-
• Increased steric hindrance in ‡ decreases the rate

P α-branching in haloalkane P bulky nucleophiles

Br CN K+ -CN DMSO

Secondary haloalkanes:

• SN2 for all Z- less basic than HO-
• Increased steric hindrance in ‡ decreases the rate of SN2

P α-branching in haloalkane P bulky nucleophiles

• SN1 Z: is neutral and the solvent

P expect rearrangement CA of Nu: pKa H-CN 9.2 H-OH 15.7 H-CH2CH3 50

X O O-Na+ O OH O O O O +

Tertiary haloalkanes:

• Don’t see SN2
• SN1 for most Z: and the anions of strong CA

P expect rearrangement