rganic hemistry, 5 th Edition L. G. Wade, Jr. hapter 6 Alkyl alides: Nucleophilic Substitution and Elimination lasses of alides Alkyl: alogen, X, is directly bonded to sp 3 carbon. Vinyl: X is bonded to sp 2 carbon of alkene. Aryl: X is bonded to sp 2 carbon on benzene ring. Examples: Jo Blackburn Richland ollege, Dallas, TX Dallas ounty ommunity ollege District 2003, Prentice all alkyl halide l vinyl halide aryl halide hapter 6 2 I Polarity and Reactivity alogens are more electronegative than. arbon-halogen bond is polar, so carbon has partial positive charge. arbon can be attacked by a nucleophile. alogen can leave with the electron pair. δ+ δ- hapter 6 3 lasses of Alkyl alides Methyl halides: only one, 3 X Primary: to which X is bonded has only one - bond. Secondary: to which X is bonded has two - bonds. Tertiary: to which X is bonded has three - bonds. hapter 6 4 lassify These: 3 3 3 2 F l Dihalides Geminal dihalide: two halogen atoms are bonded to the same carbon Vicinal dihalide: two halogen atoms are bonded to adjacent carbons. ( 3 ) 3 3 I hapter 6 5 geminal dihalide vicinal dihalide hapter 6 6 1
IUPA Nomenclature Name as haloalkane. hoose the longest carbon chain, even if the halogen is not bonded to any of those s. Use lowest possible numbers for position. 3 2 3 2 2 l 3 ( 2 ) 2 ( 2 ) 2 3 2-chlorobutane 4-(2-bromoethyl)heptane hapter 6 7 Systematic ommon Names Name as alkyl halide. Useful only for small alkyl groups. Name these: ( 3 ) 3 3 2 3 l 3 3 2 F hapter 6 8 Trivial Names 2 X 2 called methylene halide. X 3 is a haloform. X 4 is carbon tetrahalide. Examples: 2 l 2 is methylene chloride l 3 is chloroform l 4 is carbon tetrachloride. Uses of Alkyl alides Solvents - degreasers and dry cleaning fluid Reagents for synthesis of other compounds Anesthetic: alothane is F 3 l l 3 used originally (toxic and carcinogenic) Freons, chlorofluorocarbons or F s Freon 12, F 2 l 2, now replaced with Freon 22, F 2 l, not as harmful to ozone layer. Pesticides - DDT banned in U.S. hapter 6 9 hapter 6 10 Dipole Moments µ = 4.8 x δ x d, where δ is the charge (proportional to EN) and d is the distance (bond length) in Angstroms. Electronegativities: F > l > > I Bond lengths: -F < -l < - < -I Bond dipoles: -l > -F > - > -I 1.56 D 1.51 D 1.48 D 1.29 D Molecular dipoles depend on shape, too! hapter 6 11 Boiling Points Greater intermolecular forces, higher b.p. dipole-dipole attractions not significantly different for different halides London forces greater for larger atoms Greater mass, higher b.p. Spherical shape decreases b.p. ( 3 ) 3 3 ( 2 ) 3 73 102 hapter 6 12 2
Densities Alkyl fluorides and chlorides less dense than water. Alkyl dichlorides, bromides, and iodides more dense than water. hapter 6 13 Preparation of RX Free radical halogenation (hapter 4) produces mixtures, not good lab synthesis unless: all s are equivalent, or halogenation is highly selective. Free radical allylic halogenation produces alkyl halide with double bond on the neighboring carbon. hapter 6 14 alogenation of Alkanes All s equivalent. Restrict amount of halogen to prevent di- or trihalide formation + 2 hν + ighly selective: bromination of 3 3 3 3 3 + 2 hν 3 3 + 90% hapter 6 15 Allylic alogenation Allylic radical is resonance stabilized. omination occurs with good yield at the allylic position (sp 3 next to =). Avoid a large excess of 2 by using N-bromosuccinimide (NBS) to generate 2 as product is formed. N + N + 2 hapter 6 16 Reaction Mechanism Free radical chain reaction initiation, propagation, termination. hν 2 2 + + hapter 6 17 Substitution Reactions X + Nuc: - Nuc + X: - The halogen atom on the alkyl halide is replaced with another group. Since the halogen is more electronegative than carbon, the -X bond breaks heterolytically and X - leaves. The group replacing X - is a nucleophile. hapter 6 18 3
Elimination Reactions X + B: - + X: - + B The alkyl halide loses halogen as a halide ion, and also loses + on the adjacent carbon to a base. A pi bond is formed. Product is alkene. Also called dehydrohalogenation (-X). hapter 6 19 S N 2 Mechanism + Bimolecular nucleophilic substitution. oncerted reaction: new bond forming and old bond breaking at same time. Rate is first order in each reactant. Walden inversion. hapter 6 20 - S N 2 Energy Diagram Uses for S N 2 Reactions Synthesis of other classes of compounds. alogen exchange reaction. ne-step reaction. Transition state is highest in energy. hapter 6 21 Nucleophile Product lass of Product R-X + I - R-I akyl halide R-X + - R- alcohol R-X + - R' R-R' ether R-X + - S R-S thiol R-X + - SR' R-SR' thioether R-X + N3 R-N3 + X - amine salt R-X + N3- R- N3 azide R-X + - -R' R- -R' alkyne R-X + - N R- N nitrile R-X + R- - R--R' ester hapter 6 22 S N 2: Nucleophilic Strength Stronger nucleophiles react faster. Strong bases are strong nucleophiles, but not all strong nucleophiles are basic. hapter 6 23 Trends in Nuc. Strength f a conjugate acid-base pair, the base is stronger: - > 2, N 2- > N 3 Decreases left to right on Periodic Table. More electronegative atoms less likely to form new bond: - > F -, N 3 > 2 Increases down Periodic Table, as size and polarizability increase: I - > - > l - hapter 6 24 4
Polarizability Effect Bulky Nucleophiles Sterically hindered for attack on carbon, so weaker nucleophiles. 3 2 ethoxide (unhindered) weaker base, but stronger nucleophile hapter 6 25 3 3 3 t-butoxide (hindered) stronger base, but weaker nucleophile hapter 6 26 Solvent Effects (1) Polar protic solvents (- or N-) reduce the strength of the nucleophile. ydrogen bonds must be broken before nucleophile can attack the carbon. hapter 6 27 Solvent Effects (2) Polar aprotic solvents (no - or N-) do not form hydrogen bonds with nucleophile Examples: 3 N acetonitrile N 3 3 dimethylformamide (DMF) 3 3 acetone hapter 6 28 rown Ethers Solvate the cation, so nucleophilic strength of the anion increases. Fluoride becomes a good nucleophile. K+ 18-crown-6 S N 2: Reactivity of Substrate arbon must be partially positive. Must have a good leaving group arbon must not be sterically hindered. 2 l KF, (18-crown-6) 3 N 2 F hapter 6 29 hapter 6 30 5
Leaving Group Ability Electron-withdrawing Stable once it has left (not a strong base) Polarizable to stabilize the transition state. Structure of Substrate Relative rates for S N 2: 3 X > 1 > 2 >> 3 Tertiary halides do not react via the S N 2 mechanism, due to steric hindrance. hapter 6 31 hapter 6 32 Stereochemistry of S N 2 Walden inversion hapter 6 33 S N 1 Reaction Unimolecular nucleophilic substitution. Two step reaction with carbocation intermediate. Rate is first order in the alkyl halide, zero order in the nucleophile. Racemization occurs. hapter 6 34 S N 1 Mechanism (1) Formation of carbocation (slow) ( 3 ) 3 ( 3 ) 3 + + - S N 1 Mechanism (2) Nucleophilic attack ( 3 ) 3 + + ( 3 ) 3 Loss of + (if needed) ( 3 ) 3 + ( 3 ) 3 + 3 + hapter 6 35 hapter 6 36 6
S N 1 Energy Diagram Forming the carbocation is endothermic arbocation intermediate is in an energy well. Rates of S N 1 Reactions 3 > 2 > 1 >> 3 X rder follows stability of carbocations (opposite to S N 2) More stable ion requires less energy to form Better leaving group, faster reaction (like S N 2) Polar protic solvent best: It solvates ions strongly with hydrogen bonding. hapter 6 37 hapter 6 38 Stereochemistry of S N 1 Racemization: inversion and retention Rearrangements arbocations can rearrange to form a more stable carbocation. ydride shift: - on adjacent carbon bonds with +. Methyl shift: 3- moves from adjacent carbon if no s are available. hapter 6 39 hapter 6 40 ydride Shift Methyl Shift 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 Nuc 3 Nuc 3 3 hapter 6 41 3 3 3 3 Nuc 3 3 Nuc 3 3 hapter 6 42 7
Primary or methyl Strong nucleophile Polar aprotic solvent Rate = k[halide][nuc] Inversion at chiral carbon No rearrangements S N 2 or S N 1? Tertiary Weak nucleophile (may also be solvent) Polar protic solvent, silver salts Rate = k[halide] Racemization of optically active compound Rearranged products hapter 6 43 E1 Reaction Unimolecular elimination Two groups lost (usually X - and + ) Nucleophile acts as base Also have S N 1 products (mixture) hapter 6 44 E1 Mechanism 3 3 3 3 A loser Look 3 3 3 3 + 3 + 3 3 3 3 + 3 + alide ion leaves, forming carbocation. Base removes + from adjacent carbon. Pi bond forms. hapter 6 45 hapter 6 46 E1 Energy Diagram E2 Reaction Bimolecular elimination Requires a strong base alide leaving and proton abstraction happens simultaneously - no intermediate. Note: first step is same as S N 1 hapter 6 47 hapter 6 48 8
E2 Mechanism Saytzeff s Rule 3 3 3 3 + 2 + - If more than one elimination product is possible, the most-substituted alkene is the major product (most stable). R 2 =R 2 >R 2 =R>R=R> 2 =R tetra > tri > di > mono hapter 6 49 3 3-3 3 3 + 3 minor major hapter 6 50 E2 Stereochemistry E1 or E2? Tertiary > Secondary Weak base Good ionizing solvent Rate = k[halide] Saytzeff product No required geometry Rearranged products Tertiary > Secondary Strong base required Solvent polarity not important Rate = k[halide][base] Saytzeff product oplanar leaving groups (usually anti) No rearrangements hapter 6 51 hapter 6 52 Substitution or Elimination? Strength of the nucleophile determines order: Strong nuc. will go S N 2 or E2. Primary halide usually S N 2. Tertiary halide mixture of S N 1, E1 or E2 igh temperature favors elimination. Bulky bases favor elimination. Good nucleophiles, but weak bases, favor substitution. hapter 6 53 Secondary alides? Mixtures of products are common. hapter 6 54 9
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