Chapter 11, Part 1: Polar substitution reactions involving alkyl halides

Transcription

1 hapter 11, Part 1: Polar substitution reactions involving alkyl halides Overview: The nature of alkyl halides and other groups with electrophilic sp 3 hybridized leads them to react with nucleophiles and bases Two types of reactions covered in h 11, which often compete with each other: 1. Substitution: H 3 H 2 l + Nu- H 3 H 2 Nu + l- 2. Elimination: H 3 H 2 l + B:- H 2 =H 2 + HB + l- Both are common in compounds where the sp 3 -carbon is bonded to an electronegative atom alkyl halides, alcohols, ethers due to electronegativity of the halogen, -X bond breaks easily: the halogen is a good leaving group Part 1: Substitution reactions Two possible scenarios lead to substitution products: A nucleophile is attracted to the polar -X bond; as it approaches and begins to bond with, the - X bond breaks and the halide ion leaves Under certain conditions, a weak - X bond breaks to form a carbocation. As X - leaves, a nucleophile is able to bond to the carbocation Which pathway actually occurs depends on several factors: the nature of the nucleophile the nature of the leaving group the structure of the molecule at the sp 3 carbon reaction conditions

2 Scenario #1: A one-step reaction with the nucleophile = The S N 2 reaction S N 2 = substitution, nucleophilic, bimolecular The rate law for this process: Rate = k [alkyl halide] [nucleophile] Two key aspects of S N 2 mechanism: HO- + H 3 Br HO H 3 + Br- One step process (concerted) Back-side attack of the nucleophile at the carbon produces an inversion in stereochemistry at the carbon: Four key factors that increase the likelihood of an S N 2 type substitution: 1) Easy access to the substrate (alkyl halide): 1 o works best The pathway occurs much more slowly for substituted (2 o or 3 o ) alkyl halides due to steric hindrance by the alkyl groups attached to the Reactivity: methyl > 1 o RX > 2 o RX > 3 o RX

3 2) A strong attacking nucleophile This is a key factor since rate depends on both R-X and Nu. Nucleophilicity = ability of a nucleophile to speed up the reaction: Factors influencing reactivity of the nucleophile: A. Basicity: When comparing nucleophiles that have the same attacking atom, the stronger the base, the better it is as a nucleophile Base strength increases as pk a of conjugate acid increases *NOTE: Acting as a base is NOT the same as acting as a nucleophile B. harge: Negatively charged species are usually better nucleophiles than neutral Some atoms (such as ) aren t nucleophilic at all unless they are (-) charged Basic reaction conditions can help keep nucleophile negatively charged. Size: Within a group in the periodic table, the larger the size of the attacking atom, the better the nucleophile, due to increased polarizability ompare I - vs. l - ; SH - vs. OH -

4 3) A good leaving group The better the leaving group, the faster an S N 2 reaction occurs Poor leaving groups raise the energy of the TS while good ones lower ΔG + Example: for the halide ions, the weaker bases are better leaving groups: Increasing basicity For any R-X, reactivity by S N 2 pathway: R-I > R-Br > R-l > R-F Good leaving groups: I-, Br-, -OTos So-so: l- Poor leaving groups: F-, OH-, NH 2 -, OR- (Alcohols, ethers, amines do not react directly by the S N 2 mechanism!) 4) A solvent that doesn t interfere with the process (aprotic is best) Protic solvents: an donate a hydrogen in a hydrogen-bonding interaction Examples: water, alcohols (H 3 OH, H 3 H 2 OH) They prevent the nucleophile from getting to its destination by solvation Result: Slower reaction rate, particularly for normally good nucleophiles Aprotic solvents: annot donate a hydrogen in a hydrogen-bonding interaction and therefore are not attracted to the nucleophilic species. Examples: H 2 l 2, diethyl ether, THF, toluene, acetone In aprotic solvents, the nucleophile is not affected; in fact the solvents help to stabilize the transition state, thus lowering activation energy S N 2 reactions can proceed more quickly in aprotic solvents!

5 Practical applications of the S N 2 reaction: A wide range of nucleophiles can react with alkyl halides, replacing the halide with new functional groups and making substitution a versatile synthetic tool: Alkynes: H 3 H 2 Br + H 3 H 3 H 2 H 3 + Br- Alcohols: H 3 H 2 Br + OH H 3 H 2 OH + hers: H 3 H 2 Br + OH 3 H 3 H 2 OH 3 + Br- Br- Amines: H 3 H 2 Br + NH 3 H 3 H 2 NH 3 Br O O Esters: H 3 H 2 Br + H 3 H 3 H 2 O H 3 + Br- HO Nitriles: H 3 H 2 Br + Thiols: H 3 H 2 Br + SH 3 H 3 H 2 SH 3 + N H 3 H 2 N + Br- Br- oupling: H 3 H 2 Br + RMgBr H 3 H 2 R + MgBr 2 Intermolecular reactions (above examples) involve two separate molecules Intramolecular S N 2: If the alkyl halide also contains another nucleophilic group, it can undergo an intramolecular reaction between the halide and the Nu, forming a ring: Br NH 2 H N H Br- Using S N 2 reactions: Will reaction proceed spontaneously in the forward direction? Yes, if The halide to be replaced is a better leaving group than the incoming group This usually requires that the incoming group is a stronger nucleophile If incoming and outgoing groups are nearly equal in basicity, reaction is reversible; can be driven forward by removing product as it forms (Lehatelier's principle)

6 Scenario #2: A two-step substitution reaction with a carbocation intermediate = The S N 1 reaction A 3 o R-X isn t likely to react by S N 2 pathway, but 3 o alkyl halides do react with bases to produce substitution products, and conc. of Nu has no effect on rate An alternate mechanism: S N 1 = substitution, nucleophilic, unimolecular rate = k [alkyl halide] Two step reaction: 1) Slow step: Loss of leaving group to form carbocation intermediate 2) Faster step: Reaction of carbocation with nucleophile A typical S N 1 reaction H 3 H 3 H 3 H 3 Br H 3 H 3 + Br- H 2 O H 3 H 3 HO H 3 3 o alkyl halide 3 o carbocation 3 o alcohol What affects S N 1 reactivity? 1 o, 2 o, 3 o RX: Relative reactivity by S N 1 depends on structure of carbocation 1 o RX < 2 o RX < 3 o RX Leaving group: How good is it at leaving?

7 Strength of the nucleophile doesn t matter so much! The ability of the solvent to stabilize the carbocation: Protic solvents that hinder S N 2 rxns actually help S N 1 rxns Additional considerations when dealing with carbocation-based mechanisms: 1) Stereochemistry: Recall stereochemistry of addition reactions: simple carbocations form racemic mixture: HBr Br- + H H H 3 Br H 3 H 3 Br S N 1 reactions that produce a chiral center also give a racemic mixture of products Br H 3 H 3 + Br- H 2 O HO H 3 + H 3 OH 2) Resonance makes carbocations more stable, favors S N 1 pathway 3) arbocations are prone to rearrangement, may affect final product of S N 1 Ex: H 3 H 3 H H Br H 3 H 2 O

8 S N 1 mechanism S N 2 mechanism

9 So, a substitution product has formed was it S N 1 or S N 2? Both pathways are possible. Which one is favored? In a competition, the pathway which occurs most rapidly will be favored. Some factors that may influence pathway 1. Structure of alkyl halide: 3 o 2 o 1 o S N 1 S N 2 2. oncentration of nucleophile: Rate of S N 1 pathway does not depend on [Nu] Rate of S N 2 = k [RX][Nu] 3. Reactivity of nucleophile: affects rate of S N 2 but not rate of S N 1 S N 2 pathway is favored by higher concentration and more reactive nucleophile. onversely, low concentration or use of weaker nucleophile may favor S N 1 4. hoice of solvent: S N 1 reactions are favored by solvents capable of stabilizing a transition state that closely resembles the (+)-charged carbocation intermediate - polar solvents best S N 2 reactions are favored by aprotic solvents and slowed down by protic solvents Summary: S N 2 is favored by: High conc. of strong nucleophile A polar aprotic solvent Less bulky & 1 o R-X S N 1 is favored by: A weaker nucleophile A polar protic solvent Substituted R-X that form stable carbocations Outcome of S N 2: Outcome of S N 1: Inversion of configuration Products are racemic mixtures No rearrangement of skeleton Rearrangements are likely

10 Some substitution reactions involving alkyl halides from h. 10 (Part 2) The polarity of the X bond is key to understanding most RX reactions 1. Transforming alcohols to alkyl halides by polar substitution Alkyl halides and alcohols have in common a polar bond between and functional group: R H 2 Br R H 2 l R H 2 OH However, the OH group of alcohols is a poor leaving group compared to Br, l, or I 3 o alcohols react readily with Hl, HBr or HI by S N 1 mechanism to make 3 o alkyl halides; this works because they form a stable carbocation intermediate, but is unlikely with 1 o or 2 o ROH H 3 OH HBr ether H 3 Br Preparation of 1 o and 2 o alkyl halides from alcohols by S N 2 reaction: 1 o & 2 o alcohols require a bit more encouragement to get rid of the OH group Halogenating reagents help activate the removal of the OH group These reagents reduce the risk of undesired elimination reactions. Reactions proceed with inversion Some advantages to preparing alkyl halides from alcohols The alcohols are often inexpensive and readily available These reactions tend to produce only the desired major product, not mixtures like you would get by radical halogenation

11 2. Organometallic Reagents: Using metals to activate carbon towards S N 2 substitution Alkyl halides have a partial positive charge on the bearing the halogen Reaction of alkyl halides with certain metals results in insertion of metal Produces a new carbon-metal bond in which the carbon now bears the partial negative charge Useful way to make the carbon nucleophilic Earlier example: A nucleophilic is generated in deprotonation of acetylene to make acetylide ions these then react with alkyl halide to form - bond 2A. Grignard Reagents: Used to form new bonds Used in reactions with carbonyl compounds (more on this in HM252) Used in substitution reactions with alcohols to make ethers Magnesium inserts itself into the X bond of 1 o, 2 o or 3 o alkyl halides: H 3 Br + Mg H 3 Mg Br Dry ether bromomethane Methylmagnesium bromide (a Grignard reagent) Grignard reagents react readily with any electrophile which makes them useful, but you can also get unwanted side reactions with any source of H + Since they behave like bases, they react readily with H 2 O to replace X with H: H 3 H 2 H 2 -Mg-Br H 2 O, H + H 3 H 2 H 3 + MgBrOH Note: The formation of a Grignard reagent can be considered an organic reduction since the electron density on the carbon atom increases Reduction: increasing e- density on by forming H, M (metal) or by breaking O, N, or X Reactions that form alkyl halides are considered oxidations

12 2B. Other organometallic reagents with nucleophilic Organolithium reagents Lithium is small and strongly electropositive; makes the bonded carbon strongly basic H 3 H 2 H 2 H 2 -Br 2 Li Pentane H 3 H 2 H 2 H 2 Li + LiBr The resulting organolithium reagents are very strong nucleophiles an be used in many of the same reactions as Grignard reagents RLi reagents are used in the preparation of the Gilman reagent (below), which is a milder form of the nucleophile Gilman reagents: Further reaction of RLi with copper produces: R 2 uli ether 2 H 3 H 2 Li + ui (H 3 H 2 ) 2 uli + LiI 2: S N 2 substitution: organometallic coupling reactions Alkyl bromides, iodides & chlorides can react with Gilman reagents (or Grignards) in a carbon-skeleton building reaction, by S N 2 mechanism: Ex: H 2 I H 2 H 2 H 3 H + (H 3 H 2 ) 2 uli ether 0 o H hoice of halogens in making & using alkyl halides in substitution rxns Our focus has been primarily on alkyl bromides, chlorides & iodides because they contain a good leaving group and are readily available commercially Alkyl fluorides are not readily prepared by the same methods; for example, fluorine radicals are extremely reactive & unpredictable so radical fluorination is impractical Alkyl fluorides also are less useful as starting reagents; F is a poor leaving group and thus not easily substituted out

13 Practice problems: Substitution of Alkyl Halides For each reaction, predict the mechanism (S N 1 or S N 2) and the structure of the substitution product(s). If stereoisomers are possible, indicate which ones are produced. 1) (R)-2-bromopentane 1 M Na + - OH 2 H 3 DMSO 2) (R)-2-bromopentane H 3 H 2 OH 3) trans-1-chloro-2-methylcyclohexane 1 M Na + - OH 3 DMSO 4) trans-1-chloro-2-methylcyclohexane H 3 OH 5) 3-bromo-3-methylpentane H 2 O 6) 3-bromo-3-methylpentane - OH 7) bromocyclopentane Na + - :=-H 2 H 3 ether 8) bromocyclopentane (H 3 H 2 ) 2 uli ether

14 hapter 10 problems