Haloalkanes

•

Structure of Haloalkanes

Haloalkane (alkyl halide)

: A compound containing a halogen atom covalently bonded to an

sp

3 hybridized carbon.

• often represented as RX

Nomenclature of Haloalkanes

• Locate the parent alkane.

• Locate each halogen on the parent chain.

• Number the parent chain to give the substituent encountered first the lower number.

• Show halogen substituents by the prefixes fluoro-, chloro-, bromo-, and iodo- and list them in alphabetical order with other substituents.

Common names of haloalkanes

• Several polyhaloalkanes are common solvents and are generally referred to by their common or trivial names.

• Simple haloalkanes can also be named as alkyl halides. • The focus is the halogen atom (fluoride, chloride, bromide or iodide) and becomes the second half of the name.

• The carbon branch attached to the halogen is named as usual and becomes the first half of the name.

F CH 3 CH 3 methyl fluoride IUPAC: fluoromethane H 3 C C I H 3 C H 2 C Br ethyl bromide IUPAC: bromoethane CH 3 t-butyl iodide IUPAC: 2-iodo-2-methyl propane

Some Applications of Haloalkanes

• Refrigerants • Freons are

chlorofluorocarbons (CFCs)

• Release of CFC gases into the atmosphere contributes to ozone destruction.

• Montreal Protocol is an international treaty (1989) to phase-out use of CFCs.

• Much lower ozone-depleting alternatives are the hydrofluorocarbons (HFCs) and the hydrochlorofluorocarbons (HCFCs).

• Solvents • Methylene chloride, chloroform, trichlor, carbon tetrachloride (among others) are used to dissolve grease (in machine shops and dry cleaners!).

• Propellents • HFC-134a (1,1,1,2-tetrafluoroethane) is used as a propellent in “canned air”.

• Anesthetics • Many hydrochlorofluorocarbons are using in anesthesia. • The earliest anesthetics were ethers; thus, many modern anesthetics are halogenated ethers.

Cl F CF 3 F 3 C O isoflurane CHF 2 F 3 C O desflurane CHF 2 F 3 C O sevoflurane CHF 2

Reactions of Haloalkanes

• • Nucleophilic substitution (S N 1 or S N 2) b -elimination (E1 or E2)

Nucleophilic Substitution

• Substitution takes place on an sp 3 hybridized (tetrahedral) carbon.

• Nucleophile attacks carbon making a new bond.

• Functional group that is being replaced is called the

leaving group

.

Examples of Nucleophiles and their Products

Nucleophilic Substitution Mechanisms S

N

2 Mechanism

• Chemists propose two limiting mechanisms for nucleophilic substitutions.

• A fundamental difference between them is the timing of bond breaking and bond forming steps.

• At one extreme, the bond making and bond breaking take place simultaneously • Such a reaction is designated

S N 2

.

• S = substitution • N = nucleophilic • 2 = bimolecular (two species are involved in the rate determining step) • rate = k[haloalkane][nucleophile]

• Both reactants are involved in the creation of the transition state of the rate-determining step.

• The nucleophile attacks the reactive center from the side opposite the leaving group. The key step is

reaction of a nucleophile and an electrophile to form a new covalent bond

.

• The product of an SN2 reaction at a stereocenter maintains a specific chirality.

http://www.bluffton.edu/~bergerd/classes/CEM221/sn-e/SN2_alternate.html

The Energy Diagram for the S N 2 Reaction • Note the transition state has a carbon with 5 bonds (high energy, indeed!).

• No intermediate is formed.

S

N

1 Mechanism

• In the other limiting mechanism, bond breaking between carbon and the leaving group is entirely completed before bond forming with the nucleophile begins.

• This mechanism is designated

S N 1

• S = substitution where • N = nucleophilic • 1 = unimolecular (only one species is involved in the rate-determining step) • rate = k[haloalkane]

• S N 1 is illustrated by the solvolysis of

tert

-butyl bromide.

•

Step 1: Break a bond to form a stable ion or molecule

. Ionization of the C-X bond gives a carbocation.

•

Step 2

: Reaction of a nucleophile and an electrophile to form a new covalent bond.

•

Step 3

: Take a proton away (deprotonation). Proton transfer to methanol completes the reaction.

The Energy Diagram for the S N 1 Reaction

• Note the formation of two transition states.

• Note especially the formation of a carbocation intermediate.

• The formation of the carbocation in an S N 1 reaction is the key distinction between it and an S N 2 reaction.

• For an S N 1 reaction at a stereocenter, the product is a racemic mixture.

• The carbocation is planar so that the nucleophile can attack either side of the intermediate.

Determination of Reaction Path in S

N

Reactions

• Whether an alkyl halide substrate reacts with a nucleophile according to an S N 1 or S N 2 mechanism depends on several factors.

1. Structure of the nucleophile 2. Structure of the haloalkane 3. Structure of the leaving group 4. Polarity of the solvent

1. The Nucleophile

•

Nucleophilicity

: a kinetic property measured by the rate at which a Nu: attacks a reference compound under a standard set of experimental conditions.

• For example, nucleophilicity could be measured by examining the rate at which a set of Lewis bases displaces bromide ion from bromoethane in ethanol at 25 °C.

• Those Lewis bases that yield faster reaction rates are better nucleophiles.

• OH OH will react with CH 3 CH 2 Br faster than NH 3 . Therefore, is better nucleophile than NH 3 .

• Judging good nucleophiles from poor • A species with a negative charge is a stronger nucleophile than a neutral molecule.

• RS is better than RSH.

• Nucleophilicity usually increases going down a column on the periodic table because of increasing size and polarizability.

• RO < RS < RSe < RTe • Nucleophilicity vs. basicity. Strong bases are strong nucleophiles, but not all strong nucleophiles are basic.

• I is an excellent nucleophile, but a very weak base.

• A bulkier nucleophile is a weaker nucleophile.

• (C 2 H 5 ) 3 N is a weaker nucleophile than NH 3 .

• Good vs. poor nucleophiles (An S N 2 reaction needs a good nucleophile; whereas an S N 1 reaction does not.)

• Common nucleophiles and their nucleophilicity

2. The Haloalkane Substrate

• S N 1 reactions • Governed by

electronic factors

, namely the relative stabilities of carbocation intermediates.

• Relative rates: 3° > 2° > 1° > methyl • Tertiary and secondary alkyl halides get substituted via this mechanism • S N 2 reactions • Governed by

steric factors

, namely the relative ease of approach of the nucleophile to the site of reaction.

• Relative rates: methyl > 1° > 2° > 3° • Methyl, primary and sometimes secondary alkyl halides get substituted via this mechanism.

•

Steric factors

• Compare access to the reaction center in bromoethane and 2-bromo-2-methylpropane (

tert

butyl chloride).

• Effect of electronic and steric factors in competition between S N 1 and S N 2 reactions of haloalkanes.

3. The Leaving Group

• The best leaving groups are very weak bases, e. g., the halogens I – , Br – , and Cl – are excellent leaving groups • OH – , RO – , and NH 2 – are such poor leaving groups that they are rarely if ever displaced in nucleophilic substitution reactions.

• Hydroxide ion, OH – , is a poor leaving group. • However, the –OH group of an alcohol can be transformed into an excellent leaving group, H 2 O, if the –OH group is first protonated by an acid to form —OH 2 + .

4. The Solvent

•

Protic solvent

: a solvent that contains an –OH group and is a hydrogen bond donor.

•

Polar aprotic solvent

: A solvent that does not contain an –OH group and is not a hydrogen bond donor. • Polar aprotic solvents favor S N 2 reactions.

• Formation of carbocations is more difficult in polar aprotic solvents.

Summary of S

N

1 and S

N

2 Reactions of Haloalkanes

• Example: Predict the product of each reaction, its mechanism, and the stereochemistry of the product.

b

-Elimination

 b

-Elimination

: Removal of atoms or groups of atoms from adjacent carbons to form a carbon carbon double bond.

• We study a type of b -elimination called

dehydrohalogenation

(the elimination of HX).

• The label “ b ” implies that a functional group and a hydrogen atom on the second carbon away from the functional group are being eliminated.

•

Zaitsev’s rule

: The major product of a b elimination is the more stable (the more highly substituted) alkene. When

cis-trans

isomerism is possible, the trans isomer is favored.

• • • There are two limiting mechanisms for b -elimination reactions.

E1 mechanism

: at one extreme, breaking of the C-X bond is completed before reaction with base breaks the C-H bond.

• Only R-X is involved in the rate-determining step.

• Formation of carbocation makes the reaction rate unimolecular.

E2 mechanism

: at the other extreme, breaking of the C-X and C-H bonds is concerted.

• Both R-X and base are involved in the rate-determining step.

• Since both substances are involved in the creation of the transition state, the reaction is bimolecular.

Elimination Reaction Mechanisms

E1 Mechanism •

Step 1: Break a bond to give a stable molecule or ion.

Rate-determining ionization of C-X gives a carbocation intermediate and halide ion.

•

Step 2: Take a proton away.

Proton transfer from the carbocation to a base (in this case, the solvent) gives the alkene.

E2 Mechanism • A one-step mechanism; all bond-breaking and bond forming steps are concerted. Simultaneously (1) take a proton away and (2) break a bond to form a stable ion or molecule.

Summary of Elimination Reactions

Substitution versus Elimination

• Because many nucleophiles are also strong bases (OH – and RO – ), S N and E reactions often compete.

• The ratio of S N /E products depends on the relative rates of the two reactions.

S

N

1 versus E1

• Reactions of 2° and 3° haloalkanes in polar protic solvents give mixtures of substitution and elimination products. Product ratios are difficult to predict.

S

N

2 versus E2

• It is a little bit easier to predict the ratio of S N 2 to E2 products.

• Stronger bases (such as NH 2 ), lead to E2.

• Bulky bases (such as (CH 3 ) 3 CO ), lead to E2 • More branching near the a and b carbons leads to E2.

• Yuck! We used a instead of a and b instead of b in previous overheads.

Summary of S

N

versus E for Haloalkanes

• For Methyl and Primary Haloalkanes

• For Secondary and Tertiary Haloalkanes

S N 2

3º << 2º < 1º

Substitution – Elimination matrix

S N 1

3º > 2º >> 1º

E2

3º < 2º < 1º

E1

3º > 2º >> 1º Strong nucleophile Polar aprotic solvent Rate =

k

[halide][Nuc] Weak nucleophile Strong or bulky base required Polar protic solvent Solvent polarity not important Rate =

k

[halide] 1 step, concerted, inversion of configuration 2 steps, C+, racemization Rate =

k

[halide][base] 1 step, concerted Weak base Good ionizing solvent Rate =

k

[halide] 2 steps, C+

Substitution – Elimination flowchart

Summary of S

N

versus E for Haloalkanes

•

Examples

: Predict the major product and the mechanism for each reaction.