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Alkyl Halides (Haloalkanes)
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2
CH3 CH
Cl
CH CH3
CH3
Cl
CCl Cl
Cl
CH3 CH
Br
CH2 CH2
Cl
F
CH2CH3
BrCl
Cl
CCl F
Cl
F
CCl F
Cl
F
CF
F
C
F
H
H
Tetrachloromethaneor carbon tetrachloride
2-Chloro-3-methylbutane 3-Bromo-1-chlorobutane
1-Ethyl-2-fluorocyclohexane1-Bromobutane 2-Chloropropane or
Isopropyl chloride
Trichlorofluoromethane(Freon-11)
Dichlorodifluoromethane (Freon-12) 1,1,1, 2-Tetrafluoroethane
Structure of Alkyl Halides
Chlorofluorocarbons (CFCs) :Refrigerant Gases, Ozone Depletion
3
3Halothane (Fluothane)
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• Most alkyl halides are liquids at room temperature.
• Liquid alkyl halides are insoluble in water and more dense than water.
Physical Properties of Alkyl Halides
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Alkyl Halides: R-X
The carbon center is sp3 hybridized in alkyl halides and the C-X bond is polarized as shown because of the greater electronegativity of the halogen.
Cδ+ δ−
X
Electronegativity is defined as the ability of atoms to attract shared electrons in a covalent bond ------------ leads to nucleophilic substitution in alkyl halides
Reactions of Alkyl halidesReactions of Alkyl halides
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Nucleophilic Substitution Reactions
Nu:- +
nucleophile
::
alkyl halideR-Nu + :
:
: -
substrateproduct halide ion
R-X X: :
A characteristic reaction of alkyl halides is nucleophilic substitutionwhere a nucleophile with an unshared pair of electrons replaces the halogen.
Nu:- ::
::
: -R X X
: :Substitution occurs by bond heterolysis:
+
bond heterolysis
Nu: +
electron pairfrom nucleophile
R:
Examples of Nucleophilic Substitution
::
- +:
:HO: CH3-Cl:
:: +
:::
-CH3-OH Cl:
:::
- :+
::I CH3CH2-Cl: :: +
::
: -CH3CH2-I Cl
::
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Nucleophiles
.A nucleophile has an unshared pair of electrons availablefor bonding to a positive center
Nucleophiles may be negatively charged:
HO , CH3O , I , NH2- - - -:
:
::
::
::::: :
or neutral:H2O , H3N, CH3OH
::
: ::
Nucleophiles attackelectropositive center.
Halide ionis the leavinggroup.
C Xδ+
δ−The polarity of thecarbon-halogen bond determines the reactivity pattern:
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Examples
(1) -+
nucleophile substrate
HOC Cl
H3CH
H
product leaving group
C OH
H3CH
H
+ Cl
(2) +
nucleophile substrate
C Cl
H3CH
H
HO
H
ethyloxonium ion leaving group
C O
H3CH
H
+ Cl
H
H
product
C OH
H3CH
H
+ H3O
H2O
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Leaving Groups
:The halogen is only one of many leaving groups, "L". A more generaldescription of nucleophilic substitution is
Nu: + R-L- R-Nu + L:-
leaving group
.
A good leaving group produces a stable anion or neutral molecule.Generally, the anions (conjugate bases) of strong acids are good leaving groups
A good leaving group in R-A .
+ H2O + A:+ -strong acid anion
very stable
H-A H3O
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Neutral Molecules as Leaving Groups
.
Poor leaving groups canbe turned into good leaving groups by protonation
Hydroxide ion is apoor leaving groupbecause it is the anion of a weak acid, H2O.
CH3-OH
:a nucleophilic substitution reaction occurs
+CH3OH
H+ H2O
leaving groupnucleophile+
good leaving group
CH3OH+
CH3OCH3H
:: +
+ +CH3OH H2SO4 CH3OHH
HSO4
In the presence of a strong acid,
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A Mechanism for the SN2 Reaction
The Hughes-Ingold Mechanism for the SN2 Reaction
In their mechanism, the nucleophile attacks the carbon center on the sideopposite the leaving group. As overlap develops between the orbital with the electron pair of the nucleophile and the antibonding orbital of the substrate, the bond between the carbon and the leaving group weakens.
In 1937 Edward Hughes and Sir Christopher Ingold proposed amechanism to explain the second order kinetics and other important features of this nucleophilic substitution reaction that were known at that time.
C ClH
HH
OH- δ− δ−CHO Cl
HH
H
+ -ClCHO
H
HH
TS
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SN2 reaction
All SN2 reactions proceed with backside attack of the nucleophile, resulting ininversion of configuration at the stereogenic center.
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Examples of inversion of configuration in the SN2 reaction
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Reaction of t-Butyl Chloride with Hydroxide: SN1 Reaction
:
The reaction of t-butyl chloride with sodium hydroxide in a mixture ofwater and acetone (to help dissolve the RCl) shows the following rate expression
+ HO-acetone
+ Cl-CH3-C-ClCH3
CH3
H2OCH3-C-OH
CH3
CH3
.The reaction rate depends on the concentration of t-butyl chloride, butshows no dependence on the concentration of hydroxide ion
A reaction rate that depends on the concentration of only one reactant (to the first power) is called first-order or unimolecular.
The symbol is SN1.
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SN1 reaction
+ + + +
3o 2o 1o methyl
> > >
most stable least stable
CR
RR
CR
RH
CH
RH
CH
HH
Relative stabilities of carbocations
The key features1. The mechanism has two steps.2. Carbocations are formed as
reactive intermediates.3. Reactions proceed with
racemization at a single stereogenic center.
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Use of the SN2 Reaction in Organic Synthesis
.
The conversion of one compound into another through a chemicalreaction is called synthesis. The SN2 reaction is often used to convert alkyl halides into other functional groups
for R= CH3, 1o, 2o
X = Cl,Br, I
Nucleophiles
R'O-
-
R'C
R'-C-O-=
R'3N:
N3-
R-X
HO-
HS-
:CN
C:-
O
alcohols
R-OR' ethers
thiols
nitriles
RC CR' alkynes
R-O-C-R'
=
esters
R-NR'3ammonium ion
azides
R-OH
R-SH
R-CN
O
R-N3
+
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Stereochemistry of SN2 Synthetic Reactions
.As in all SN2 reactions, these syntheses proceedwith inversion at a stereocenter
N C + CH3C
Br
H3CH2CH
(R)-2-bromobutane
CCH3
CCH2CH3
HN
(S)-2-methylbutanenitrile
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Elimination Reactions of Alkyl Halides
In an elimination reaction, the atoms or groups X and Y are lost fromadjacent carbons forming a multiple bond.
CX
CY
C C(-XY)
The Dehydrohalogenation Reaction
A standard synthesis ofalkenes is the dehydrohalogenationreaction of alkyl halides.
CX
CH
C C(-HX)
alkyl halide alkene
Example: The Dehydrobromination of tert-Butyl Bromide
tert-butyl bromide
+ NaOCH2CH3CH3C-BrCH3
CH3
CH2=C + HOCH2CH3
+ Na+ Br-isobutene
CH3
CH3
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A Beta- or 1,2-Elimination Reaction
C
H
H
H
C
CH3
CH3
Br(-HBr)
β position α position
The α or 1 position is the carbon with the halogen leaving group.
CH2 CCH3
CH3
β αCH2 C
CH3
CH3
2 1or
The Role of Base in Dehydrohalogenation Reactions
This reaction is described as a beta-elimination or 1,2-eliminationindicating the positions of the lost atoms or groups.
A number of different bases may be used in the dehydrohalogenationreaction. Typical bases are potassium hydroxide in ethanol (to solubilize the alkyl halide) or sodium ethoxide in ethanol. Potassium tert-butoxide is another oxygen base that is often used in dehydrohalogenation reactions.
KOBu-t
Some Oxygen Bases
KOH NaOEt
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Mechanism of Dehydrohalogenation: The E2 Reaction
The reaction of isopropyl bromide with sodium ethoxide in ethanol togive propene:
isopropyl bromide+
sodium ethoxide ethanolCH3CHCH3
BrNaOCH2CH3
CH3CH=CH2 +
HOCH2CH3 + Na+Br-propene
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A Mechanism for the E2 Reaction
The alkyl bromide reactsfrom a conformation wherethe leaving groups are anti-coplanar.
CH3CH2O-H
C CBrH
CH3
H
H
++ CH3CH2OHBr C CH H
H CH3
.
The mechanism proposed for the E2 reaction is based on the observedsecond order rate expression, as well as the stereochemical outcome observed in alkyl halides with multiple stereocenters. The E2 like the SN2 is a single step mechanism
HC C
BrH
CH3
H
H
As the base removes the H+,the double bond begins to develop and the Br- begins to depart.
CH3CH2Oδ−
δ−
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The E1 Reaction
The reaction of tert-butyl chloride in the mixed solvent of 80%ethanol-20% water at 25o C yields a product mixture from two competing reaction paths: substitution and elimination.
83%CH3C-OR R = H, CH3CH2
-
17%CH2=C
substitution
elimination
CH3CClCH3
CH3
CH3
CH3CH3
CH3
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A Mechanism for the Competing E1/SN1 Reactions
RDSslow step
+ + Cl-
tert-butyl carbocation
bond heterolysis
CH3CClCH3
CH3
CH3CCH3
CH3
:These two competing reactions have the same rate-determining step:bond heterolysis to produce the tert-butyl carbocation
After the rate-determining step, two competing modes of reactionbetween the tert-butyl carbocation and water/ethanol (acting as nucleophile/base) lead to substitution and elimination products.
+
::+
ethanolor water
fastSN1
E1
CH3CCH3
CH4
R-O-H
CH3C-ORCH3
CH3
CH2=CCH3
CH3
ROH asnucleophile
ROH asbase
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The E1 Path: Deprotonation Step
.
The substitution pathway follows the usual course for an SN1reaction. In a fast step, the carbocation intermediate reacts with a nucleophile (water or ethanol) to yield the substitution product
::+
nucleophile substitution product
fast fastCH3C
CH3
CH3
ROH(-H+)
CH3CORCH3
CH3
Along the elimination pathway, in a fast step, a base (water orethanol) removes a beta proton from the carbocation to produce the alkene product.
R-O
: :
+
β+fastC C
HH
HH
CH3
CH3 ROH2 C CHH
CH3
CH3
In the above conformation, the bonding orbital of the beta-H is aligned with the empty p-orbital. This stereoelectronic requirement allows immediate overlap of the developing p-orbitals of the π bonding molecular orbital.
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Summary of Reactions
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Summary of Reactions
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ALCOHOLS
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AlcoholsAlcohols can be regarded as derivatives of water in which one or two of the H atoms has been replaced by an alkyl group
OH H
104.5o
0.96 AoWater, H2O
OC H
108.5o
0.96 AoMethanol, CH3OH
HHH
1.43 Ao
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Methanol
Electronegativity of oxygen causes an unsymmetrical distribution of charge
OH3C H
- I (net dipole)
δ +δ −
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Ethanol content
Beer, 3-9% Wine, 11-13%
Whisky, 40-45% Vanilla Extracts, 35%
Listerine, 25%
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Classification of Alcohols
HC OHH3CH
CH3
C OHH3CH
CH3
C OHH3CCH3
Primary (1o) Alcohol Secondary (2o) AlcoholTertiary (3o) Alcohol
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Alcohols are very weak Acids
R O HHO H R O +
HO HH
Alcohol Alkoxideδ +δ + δ −
Relative Acidity ; H2O > ROH > C CR H > RH
CH3CH2OH + Na CH3CH2 O Na + H2
Vigorous Reaction
2 2 2
Acidity of Alcohols
sodium ethoxide
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Preparations of Alcohols
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Hydration of AlkenesHydroboration-oxidation
Oxymercuration-reduction
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Prepare 1,2-diols
Hydroxyration
Acid-catalyzed hydrolysis of epoxides
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Reduction of carbonyl compounds
Sodium borohydride, NaBH4, is ususlly chosen because of its safety and ease of handling.
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Reduction of carbonyl compoundsLithiun aluminum hydride, LiAlH4, is more reactive reducing agent than NaBH4. All carbonyl groups, including acids, esters, ketones, and aldehydes, are rapidly reduced by LiAlH4. Note that one hydrogen atom is delivered to the carbonyl carbon atom during ketone and aldehyde reductions but that two hydrogens become bonded to the former carbonyl carbon during carboxylic acid and ester reductions.
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Reaction of carbonyl compounds with Grignard reagents
Alkyl, aryl, and vinylic halides react with magnesium in ether or tetrahydrofuranto generate Grignard reagents, RMgX. These Grignard reagents react with carbonyl compounds to yield alcohols in much the same way that hydride reducing agents do.
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Ester reaction
Carboxylic acid don’t give addition products!
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Reactions of Alcohols
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Dehydration of Alcohol to AlkenesDehydration is a β elimination reaction in which the elements of OH and H areRemoved from the α and β carbon atoms, respectively.
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Dehydration in Acid
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Dehydration using POCl3 and Pyridine
Because some organic compounds decompose in the presence of strong acid. Another method to convert alcohols to alkenes has been developed by using phosphoorus oxychloride and pyridine.
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Conversion of Alcohol to Alkyl Halides with HX
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Mechanism
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Problem
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Solution
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Conversion of Alcohol to Alkyl Halides with SOCl2 and PBr3
Phosphorustribromide
1o and 2o alcohols can be converted to alkyl halides using SOCl2 and PBr3
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Mechanism
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Mechanism
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Oxidation of Alcohols
• Three important oxidation reagents– Potassium permanganate (KMnO4). Deep purple in color, such a solution
is a strong oxidant. In the course of reaction, the purple Mn(VII) is reduced to Mn(IV), which precipitates as brown manganese dioxide (MnO2).
– Chromic acid (H2CrO4). A strong oxidant usually used with alcohols, chromic acid can be produced in solution by two methods: (1) from sodium dichromate (Na2Cr2O7) and sulfuric acid, or (2) by dissolving chromic anhydride (CrO3) in concentrated sulfuric acid and water (this version is called Jones'reagent). During an oxidation reaction, the orange-colored Cr(VI) in this reagent forms greenish-blue Cr(III), which remains in solution.
– Pyridinium chlorochromate (C5H6NCrO3Cl, PCC). A mild oxidizing reagent, PCC is a soluble complex of chromic anhydride (CrO3) and pyridine in dilute HCl.
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• Oxidation of a 1o alcohol with a strong oxidant (KMnO4 or H2CrO4) gives a carboxylic acid.
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• An aldehyde (RCHO) can be obtained from a 1o alcohol if PCC (pyridinium chlorochromate) is used.
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• 2o Alcohols, which have only one hydrogen bonded to the carbon carrying the hydroxyl group, are oxidized by chromic acid or permanganate to ketones. The oxidation can proceed no further because the carbon double-bonded to the oxygen has no more hydrogens.
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Mechanism
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Summary Oxidation of Alcohols• Note that the overall change produced in the oxidation of 1o and 2o
alcohols is removal of a hydrogen from the hydroxyl group and from the carbon to which it is attached:
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Breathalyzer Tests
When the Breathalyzer test is used for suspected drunk drivers, the driver exhales a volume of breath into a solution containing the orange Cr6+ ion. If there is ethyl alcohol present in the exhaled air, the alcohol is oxidized, and the Cr6+ is reduced to give a green solution of Cr3+
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ETHERS
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Acyclic Ethers
OH H
104.5o
0.96 AoWater, H2OO
C C
111.7o
Methyl ether, CH3OCH3
HHH
1.43 Ao
HHH
109.5o1.10 Ao
CH3CH2 O CH2CH3
CH3CH2 O
H3C O
Ethoxy group
Methoxy group
Diethyl Ether
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Acyclic Ethers, R-O-R
1-Propoxypropane
Methoxybenzene “anisole”
Methoxycyclo-hexane
Cyclic Ethers
Non-Flammable Anaesthetics
ClCHF
CF
FO C H
F
FEnflurane
FCFF
CH
ClO C H
F
FIsoflurane
H3CO O
OCH3
Diethyl Ether
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Reaction of EtherWilliamson Ether Synthesis
Alkoxides needed in Williamson reaction are normally prepared by reactionof an alcohol with a strong base such as NaOH or NaH.
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Examples
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Acidic Cleavage of Ethers
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Cyclic Ethers
OTetrahydrofuran (THF) OO
Furan Pyran
Cyclic ethers are one of the main components of epoxy glues. Such a glue is strong,but also lightweight. It is used as a component of the Stealth bomber.
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Preparation of Epoxides
Mechanism
One stepWithout intermediates
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