lecture 15 ii eng slides

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ORGANIC HALIDES

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Alkyl Halides in Nature

Synthesized by red algae

Synthesized by sea hare

a sea hare

red algae




Halogen-containing organic compounds are especially frequentlyfound in marine organisms (e.g. in corals). They generally serveas toxic repellents against natural enemies. Red algae, forexample, produces a compound (a) with a putrid smell meant toward off attackers.

However, sea hares are not repulsed by this repellent, on thecontrary even seem to enjoy it, since they live on red algae. Afterconsuming red algae, sea hares convert the initial haloalkane intoa structurally related compound (b) which aids in their self-defence.




What Is an Alkyl Halide• An organic compound containing at least one carbon-

halogen bond (C-X), but also several C-X bonds

– X (F, Cl, Br, I) replaces H• The C-X bond may be at various C-s:

Csp3 - primary, sec, tertCsp2 – vinylic, aromatic

• Properties and some uses – Fire-resistant solvents – Refrigerants – Pharmaceuticals and precursors




In the IUPAC system, an alkyl halide is named by attaching ahalo prefix to the name of the hydrocarbon. All of the other standard rules of chemical nomenclature apply.

Naming Alkyl Halides

Chloroform CHCl 3

Carbon tetrachloride CCl 4

Also common names are widely used




Naming Alkyl Halides• Name is based on longest carbon chain

– (Contains double or triple bond if present) – Number from end nearest any substituent (alkyl or halogen)

– Begin at the end nearer the substituent whose name comes firstin the alphabet




Classification of Alkyl HalidesThe C attached to the halogen is designated as the HEADCARBON.

a) If the head carbon belongs to a methyl group, we have amethyl halide: Methyl

b) If the head carbon is attached to one alkyl group, the alkylhalide is primary (1o),

c) If the head carbon is attached to two alkyl groups, we have

a secondary alkyl halide (2o

),

d) If the head carbon is attached to three alkyl groups,we have a tertiary alkyl halide (3o),




Structure of Alkyl Halides

• C-X bond is weaker as you go down periodic table• C-X bond is polarized with partial charges, positive on

carbon and negative on halogen

• On C sp2 – X bond also +E effects may show

-I effectONLY on bonds

+E effectONLY on

bonds& lone pairs




Preparing Alkyl Halides1. Alkyl halides by addition of HCl, HBr, HI to alkenes to

produce Markovnikov product (see Alkenes chapter)

2. Alkyl dihalides from anti addition of bromine or chlorine

Anti addition leads totrans configuration

(trans )

(anti )




• Alkane + Cl 2 or Br 2, heat or light replaces C-H with C-XDISADVANTAGE: mixtures result, poor synthetic path – Hard to control – polyhalogenation occurs – Via free radical mechanism

Reaction of Alkanes with Halogens is NOT a valuablesynthetic method for obtaining further compounds

3. Alkyl halides from halogen substitution of alkanes




Mechanism




• If there is more than one type of hydrogen in an alkane, reactionsfavor replacing the hydrogen at the most highly substitutedcarbons (regioselective, not –specific)

Bromination is more selective than chlorination.Owing to its lack of selectivity, free radical chlorination is oflimited utility in synthesis .Another problem with free radical halogenation in synthesisis polychlorination / polybromination .




• Br 2 or Cl 2, +light, or N-bromosuccinimide (NBS) selectivelybrominate the allylic positions

Requires light foractivation

NBS is a source ofdilute (small amounts)of Br atoms

4. Alkyl halides from allylic bromination of alkenes(see Alkenes chapter)

Use of allylic halides: toproduce conjugateddienes, when treatedwith a base in order to

abstract HX (HBr)




a) Out of diazonium salts

Ar-N 2+ + CuCl Ar-Cl

Ar-N 2+ + CuBr Ar-Br

Ar-N 2+ + KI Ar-I

Ar-N 2+ + HBF 4

Ar-F

b) Aromatic Halogenation

Ar-H + X 2, Lewis acid Ar-X + HXX2 = Cl 2, Br 2

Lewis acid = FeCl 3, AlCl 3, BF 3, Fe…

5.Preparation of Aryl Halides

Thesereactions will

be further presented, in anext chapter




• Reaction of tertiary C-OH with HX is fast and effective

• Primary and secondary alcohols react very slowly and oftenrearrange, so alternative methods are used - see next slide

a. Tertiary halides

6.Preparation of Alkyl Halides out of Alcohols




Specific reagents avoid acid and rearrangements of carbon skeleton

• SOCl 2 (Thionyl chloride) ROH RCl• PBr 3 (Phosphorus tribromide) ROH RBr

• P + I 2 ROH RI

b. Primary and Secondary halides




Haloalkanes are not flammableALL liquid haloalkanes are more dense than water

Physical properties of Alkyl Halides




18

The functional group of alkyl halides is a carbon-halogen bond

With the exception of iodine, halogens have electronegativitiessignificantly greater than carbon.

The electronegative halogen atom creates a polar C—X bond,

making the carbon atom electron deficient.

Consequently, this functional group is polarized so that the carbon iselectrophilic being attacked by nucleophiles (Nu -: or Nu: )

Reactivity of organic halides




Two characteristics other than electronegativity also have animportant influence on the chemical behavior of these halo-compounds:

• The first characteristic is the C ̶ X covalent bond strength.The weakest C ̶X covalent bond is C – IThe strongest C ̶ X covalent bonds is C – F (alkyl fluorides

and fluorocarbons in general are chemically andthermodynamically quite stable)

• The second characteristic to be considered is the relativestability of the corresponding halide anions X -, which is likely

the form in the substitution reactions of RX:X- stability: I - > Br - > Cl - based on the argument that

the strongest acid HX releases the most stable conjugate base ( X-)HI > HBr > HCl




Alkyl Halides Reactivity Classes

There are THREE categories of organic halides in respect with theirshown reaction celerity and reaction parameters:

Halides with “ normal reactivity ”: ALL aliphatic halides, nomatter (1o), (2 o), or (3 o); sp 3 hybridized HEAD CARBON

Halides with “ enhanced reactivity ”: allylic and benzylichalides, with an allylic/benzylic HEAD CARBON

Halides with “ reduced reactivity ”: ALL aromatic & vinylhalides; sp 2 hybridized HEAD CARBON

!!!




The high reactivity of benzyl and allyl halides is explained by thestability of the cation resulted after the halogen cleavage:

The cations’ stability is supported by conjugation

The reduced reactivity of phenyl and vinyl hali des is explained bythe +E effect of the halogen, effect responsible for a partially double

C-X bond:

!!!




Reactions of ALL Alkyl Halides:Grignard Reagents

• Reaction of ALL TYPES of RX with Mg in ether or THF• Product is RMgX – an organometallic compound (alkyl-metal

bond) – R is alkyl 1°, 2°, 3°, aryl, alkenyl – X = Cl, Br, I (Reactivity of HX: HI > HBr > HCl)




Grignard Reagents: A Valuable

Solution for SynthesesBehaves as a RCH 2- reagent,

according to its internal polarity:

?

?Can you discuss this reaction in termsof strong/weak acids (or bases)?

!!! R-Mg-X cannot be prepared in the presence of any material thatis slightly acidic, including compounds with H attached to O or N.

A major reason for making Grignard reagents is to synthesizealcohols




Oxidation and Reduction in OrganicChemistry

• In organic chemistry, we say that oxidation occurs when acarbon or hydrogen that is connected to a carbon atom in astructure is replaced by oxygen, nitrogen, or halogen

– Not defined as loss of electrons by an atom as ininorganic chemistry

• Oxidation is a reaction that results in loss of electrondensity at carbon (as more electronegative atoms replacehydrogen or carbon)

Oxidation: break C-H (or C-C) and form C-O, C-N, C-X




Reduction Reactions

• Organic reduction is the opposite of oxidation – Results in gain of electron density at carbon (replacementof electronegative atoms by hydrogen or carbon)

Reduction: form C-H (or C-C) and break C-O, C-N, C-X




26

Main Reactions of Alkyl Halides

leavinggroup

Substitution reactions are named Nucleophilic Substitutions and,according to the mechanism, may be unimolecular (SN1) or

bimolecular (SN2)




LG in Alkyl Nucleophilic Substitution

Recall that the leaving group (LG) is the negatively charged ion thatseparates from the carbon atom during S NIn comparing two LG-s, the better LG is the weaker (more stable)baseCon u ate bases of stron acids are ood LG-s




because in the acidity scale

HF < HCl < HBr < HI




30

• Although nucleophilicity and basicity are interrelated, they arefundamentally different.

Basicity is a measure of how readily an atom donates itselectron pair to a proton . It is characterized by an equilibriumconstant, K a in an acid-base reaction, making it athermodynamic property .

Nucleophilicity is a measure of how readily an atom donatesits electron pair to other atoms . It is characterized by a rateconstant, k , making it a kinetic property .




H

CH 2 CH

Br

CH 3

SN2

HO -/H2O

H

CH2

CH

OH

CH3

H2C CH CH 3Base -/ROH

E2

H

C C

X

NuAff inity for H +

produces EliminationAff inity for C produces Substitution

H

H2C CH

Br

CH 3

Nuacting as a base, -NuHwhen its basic character prevailssolvent alcohol

H

H2C CH

Br

Nu

acting as a nucleophile,when its nucleophilic character prevailssolvent water,

CH 3

-Br -

+Br -

+Br -




Charged Nucleophile

Nucleophiles may be neutral or negatively charged:




SN2 Substitution Reaction with Halides

If concentration of (1) isdoubled, the rate of thereaction is doubled.

bromomethane

(1) (2)

If concentration of (2) isdoubled, the rate of the

reaction is doubled.

methanol

Rate law:rate = k [bromoethane][OH -]this reaction is an example of a SN2 reaction.

S stands for substitutionN stands for nucleophilic

2 stands for bimolecular




Transition state

Increasing the concentration of either of the reactant makes theircollision more probable.

Mechanism of SN2 Reactions≠

Inversion ofconfiguration (Walden)

(S)-2-bromobutane (R)-2-butanol

Slow,rate determining

step




Mechanism of SN2 Reactions

activationenergy: D G1

activationenergy: D G2

Steric effect

E n e r g y

reaction coordinate reaction coordinate

The more “crowded” the raection center, the greater the activatonenergy, and thus the slower the reaction. SN2 is preferred byrather primary unhindered halides than by tertiary ones




Factors Affecting SN2 reaction

Two factors affect the rate of a SN2 reaction:• The ease with which the leaving group dissociates from the carbon• The stability of the carbocation

The less substituted thehaloderivative is, the more

easily it is attacked by behindCH3-X>>CH3CH2-X>>(CH3)2CH-X

The weaker base is the leavinggroup, the less tightly it isbonded to the carbon, the

easier it is to break the bond

The reactivity of the nucleophile: Stronger :Nu - are needed foran SN2 reaction (preferably negatively charged!)




SN2 Reactions With Alkyl Halides

an alcohol

a thiol

an ether

a thioether

an amine

an alkyne

a nitrile




SN1 Substitution Reactions With Halides

1-bromo-1,1-dimethylethane 1,1-dimethylethanol

If concentration of (1) isdoubled, the rate of thereaction is doubled.

(1) (2)

If concentration of (2) isdoubled, the rate of thereaction is not doubled.

Rate law:rate = k [1-bromo-1,1-dimethylethane]this reaction is an example of a SN1 reaction.

S stands for substitutionN stands for nucleophilic

1 stands for unimolecular





C-Br bond breaks

nucleophile attacks the

carbocation

Protondissociation

slow

fast





Same configuration

as the alkyl halide

Inverted configurationrelative the alkyl halide

Trigonal planarcarbocation allows attackon both sides of the plane

Overall RACEMIZATION




Factors Affecting SN1 reaction

Two factors affect the rate of a SN1 reaction:• The ease with which the leaving group dissociates from the carbon• The stability of the carbocation

The more the substitutedthe carbocation is, the morestable it is and therefore the

easier it is to form.

As in the case of SN2, theweaker base is the leavinggroup, the less tightly it is

bonded to the carbon and theeasier it is to break the bond

The reactivity of the nucleophile has no effect on therate of a SN1 reaction (even H 2O is enough!)




Alkyl Halides and Nucleophilic SubstitutionPredicting the Likely Mechanism of a Substitution Reaction.• Four factors are relevant in predicting whether a given reaction is likely to proceed by an S N1 or an S N2 reaction—The most important is the identityof the alkyl halide.




Aryl & Vinyl Halides

Organic compounds with a halogen atom attached to an sp2

(aromatic or vinylic) carbon are very different from thosecompounds where the halogen is attached to an aliphatic compound.While the aliphatic compounds readily undergo nucleophilicsubstitution and elimination reactions, the aromatic compounds

resist nucleophilic substitution, only reacting under severeconditions or when strongly electron withdrawing groups are

present ortho/para to the halogen. For the same reason, vinyl halidesare of no practical use, except polymerization

!!!




In aryl & vinyl halides, the carbon to which the halogen is attached issp 2 hybrizided. The bond is stronger and shorter than the C-halogenbond in aliphatic compounds where the carbon is sp 3 hybridized.Hence it is more difficult to break this bond and aryl & vinyl halidesresist the typical nucleophilic substitution reactions




1. Formation of Grignard reagent

Two main types of Aromatic Nucleophilic Substitution :

2. Nucleophilic aromatic substitution (bimolecular displacement)

( Ar must contain strongly electron withdrawing groupsortho and/or para to X)

3. Nucleophilic aromatic substitution (elimination-addition)

(Ring not activated to bimolecular displacement )

In the ring, usual Aromatic Electrophilic Substitution

4. EAS

Aryl Halides (Ar ̶X)Reactions




Behaves according to its internal polarity:

!!! Ar-Mg-X cannot be prepared in the presence of any material thatis slightly acidic, including compounds with H attached to O or N.

A major reason for making Grignard reagents is to synthesizealcohols, or to deuterate hydrocarbons.

1. Grignard reagents

The only reaction occuring to ALL organic halides, no matter

their reactivity

MgBr +- O

D2O

OMgBr OHH

+

D




2) Nucleophilic aromatic substitution (bimolecular displacement)

CONDITION: Ar ring activated by proper substituents

Ar must contain strongly electron withdrawing groups orthoand/or para to the X to make the reaction possible, even easy:

a)




The bimolecular displacement (nucleophilicaromatic substitution) mechanism:

Meisenheimercomplex,similar to the

complex in the EAS

OPTIONALslide




Nucleophilic aromatic substitution

CONDITION: when the Ar ring is not activated;

BUT!!! extremely strongnucleophiles are needed)

Br

+ NaNH 2, NH3

NH2

F

+ H2OC6H5Li

C6H4Li

Cl

*

* 14C

NaNH 2

NH3

NH2

* *+NH2

47% 5 3%

OCH 3

Br H3C NaNH 2

NH3

NR

a

b

c

d

b)

OPTIONALslide





The mechanism is as follows:

The benzyne intermediate has been evidenced by being trappedin a Diels-Alder cycloaddition

OPTIONALslide

* 14

C1) + :NH2

2) + :X

benzyne

3) + :NH2

NH2

4)

eliminationstep

additionstep

X

H :

- NH3

X

:

X

: :

: :

: :

: : : :

: :

:

: :

NH2:

NH2H NH2

H

+ :NH2

:

* *

* *

* *

**

a)

a)for var.

:




4) EAS (Electrophilic Aromatic Substitution)

The –X group is electron-withdrawing anddeactivating (very strong -I effect) in EAS, butis an ortho/para director due to its +E effect.




Benzyl Halides in NucleophilicSubstitution (both SN1 and SN2)


lecture 15 ii eng slides

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