Nomenclature Common: named as if derived from hydrogen halide, H–X CH 3 –Cl methyl chloride (CH 3 ) 2 CH–Br isopropyl bromide Br R–X alkyl halide grouped into 1 E , 2 E , 3 E classes based on identity of R
Nomenclature IUPAC: named as substituted alkanes substituent name for X is halo R–X haloalkane 3-fluoroheptane F ( S )-3-fluoroheptane F (1 R ,3 S )-1-bromo-3-methylcyclohexane Br
Some essential properties of haloalkanes • R–X are polar H δ− δ + C X H H 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 Cl bp - 0.5 E C bp 79 E C • R–X are toxic • R–X are relatively rare as natural products
Synthetic and Naturally Occurring Haloalkanes Cl Cl Cl Cl H O OCH 3 Cl Cl Cl Cl CH 3 DDT (insecticide) methyl ether of a trichloroorcinol LD 50 = 115 mg/kg (fungicide produced by water lillies) (compare LD 50 acetaminophen = 338 mg/kg) O - O Cl OSO 3 Cl OH Cl OH OH Cl OH Cl Cl Cl OH Cl Cl Cl Cl cytotoxic sulfolipid from Mytilus galloprovincialis IC 50 = 13 µ M
OH Cl Cl O H O OH O HO O OH Cl sucralose (Splenda™) 400-800 times as sweet as sugar OH OH O OH H O H O O HO O OH OH sucrose
Are all nucleophiles created equal? Consider the S N 2 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- N / C- good Br- HO-, RO- N 3 - fair Cl-, F- RCO 2 - NH 3 poor H 2 O, ROH very poor RCO 2 H
Trends in nucleophilicity: BASICITY Consider the S N 2 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- N / C- good Br- HO-, RO- N 3 - NH 3 fair Cl-, F- RCO 2 - H 2 O , ROH poor very poor RCO 2 H in the same row of the periodic table, stronger bases are better nucleophiles
Trends in nucleophilicity: BASICITY Consider the S N 2 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- HO-, RO- N / C- good Br- N 3 - fair Cl-, F- RCO 2 - NH 3 H 2 O, ROH poor very poor RCO 2 H in the same row of the periodic table, stronger bases are better nucleophiles
Trends in nucleophilicity: BASICITY Consider the S N 2 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- HO-, RO- N / C- good Br- N 3 - RCO 2 - fair Cl-, F- NH 3 poor H 2 O, ROH very poor RCO 2 H in the same row of the periodic table, stronger bases are better nucleophiles
Trends in nucleophilicity: SIZE AND SOLVATION Consider the S N 2 reaction of various nucleophiles in a polar protic solvent, holding R–X constant: Nu- + R–X 6 Nu–R + X- Relative Nucleophilicity Nucleophile I- very good HS-, RS- Br- N / C- good HO-, RO- N 3 - Cl- , F- fair RCO 2 - NH 3 poor H 2 O, ROH very poor RCO 2 H in the same column of the periodic table, bigger is better
Trends in nucleophilicity: SIZE AND SOLVATION Consider the S N 2 reaction of various nucleophiles in a polar protic solvent, holding R–X constant: Nu- + R–X 6 Nu–R + X- Relative Nucleophilicity Nucleophile HS-, RS- very good I- HO-, RO- N / C- good Br- N 3 - fair Cl-, F- RCO 2 - NH 3 poor H 2 O, ROH very poor RCO 2 H in the same column of the periodic table, bigger is better
Why might this be so? SOLVATION MATTERS Polar protic solvents H . .. . O . .. . .. O O N H H H H H H O . .. . water alcohols ammonia, carboxylic acids amines Polar aprotic solvents O O O O H 3 C S O N H H 3 C CH 3 H 3 C CH 3 CH 3 ethers acetone DMF DMSO
relative desolvation in polar aprotic solvents increases the E of the E a nucleophile: given about the same pK a , smaller is better HO- + CH 3 Br HOCH 3 + Br- relative solvation in polar protic solvents decreases the E of the nucleophile: little nucleophiles are more strongly solvated, so given the same pK a , bigger is better
H S δ− δ+ S S S H H H S H Nu- S H H H H S S S E S H S H S H Nu- H S H S H S H S H S
H S δ− δ+ S H S Nu- H S H H S E S H S H S H Nu- H S
While S N 2 is favored in polar aprotic solvents, S N 1 is favored in polar protic solvents. This is because the polar transition state is stabilized by polar protic solvents, lowering the E a of the rate limiting step: CH 3 OH + (CH 3 ) 3 C+ + Br- + (CH 3 ) 3 COCH 3 H E a + Br- CH 3 OH + (CH 3 ) 3 CBr (CH 3 ) 3 COCH 3 + HBr
Leaving group ability is a function of the basicity of the leaving group Compound Corresponding acid pK a Corresponding conjugate base O O O O O O -11 H S R S S - O CF 3 O CF 3 O CF 3 ( - OTf) (R–OTf) (H–OTf) I - R–I H-I -11 Br - R–Br H–Br -9 Cl - R–Cl H–Cl -7 O O O O O O H S S R S - O O O -3 ( - OTs) (R–OTs) (H–OTs) + H H + R H O -2 H 2 O O H H + + R R' H R' O O -1.5 ROH H H O O O 5 H R - O O O HO - R–OH H–OH 16 RO - R–OR’ H–OR’ 16 - 18 - R–NH 2 H–NH 2 36 NH 2
+ H PDS O . . RLS H H H O O O O .. .. .. .. H .. .. + H H . + .. . O . O . .. . . + + .. .. .. .. .. .. H O O O H H H O + H O + Br
The substitution continuum R R R R S N Z H + X- H + Z- X R R R R What factors influence the balance between S N 1 and S N 2 for a given class of haloakanes?
Primary haloalkanes: • S N 2 for all Z- • Increased steric hindrance in ‡ decreases the rate α -branching in haloalkane P P bulky nucleophiles H H H H O- Na+ H H OH O H H X
Secondary haloalkanes: • S N 2 for all Z- less basic than HO- • Increased steric hindrance in ‡ decreases the rate of S N 2 α -branching in haloalkane P P bulky nucleophiles • S N 1 Z: is neutral and the solvent P expect rearrangement CA of Nu: pK a K+ -CN H-CN 9.2 DMSO CN Br H-OH 15.7 H-CH 2 CH 3 50
Tertiary haloalkanes: • Don’t see S N 2 • S N 1 for most Z: and the anions of strong CA P expect rearrangement O O O-Na+ O X + O O O OH
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