The Chemistry of the Alkyl Halides
CHM247H1 Jasmyn Lee Chapter 10: The Chemistry of the Alkyl Halides 10.1 Names and Properties of Alkyl Halides Organic Halides R – X and Ar – X o Where X = F, Cl, Br, I Halogen compounds in human physiology o Table salt is iodized to prevent goite
I HO I
O I
OH NH2
O I
thyroxine
Organo Halides from marine organisms o Almost 100 different organic halides have been isolated from edible red seaweed (asparagopsis taxiformis) o DichloroDiphenulTrichloroethane DDT is a non-specific pesticide Kills insects that spread diseases (eg/ malaria, typhys) Weakly polar, very stable organic molecule Persists in environment, collects in fatty tissue Interferes with egg-shell formation of eagles and hawks Halides are important industrially o Vinyl chloride (CH2 = CHCl) polymerized to give PVC
Cl
Cl
H
CCl3
DichloroDiphenylTrichloroethane
Alkyl, Vinyl and Aryl Halides CCl4 – an alkyl halide, Cl is bonded to an sp3 carbon F2C=CF2 – a vinyl halide, F is bonded to an sp2 hybridized carbon (on an isolated double bond) C6H5-Br – an aryl halide, Br is bonded to an sp2 hybridized carbon of an aromatic ring Spectroscopy IR – the C-X bond stretch appears in the fingerprint region (500-800 cm-1) hard to identify by IR 1H NMR – H – C – X 2.5δ – 4.0δ ; H is deshielded by the influence of the electronegative X downfield
Preparation of Organic Halides Review Methods of Preparation 1. Halogenation of Alkenes 2. Hydrohalogenation of Alkenes 3. Allylic and Benzylic Bromination o (Br placed next to C=C) o Double bond left intact (radical mechanism) o N-bromosuccinamide (NBS) – generates a low concentration of Br2
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CHM247H1 Jasmyn Lee NBS, h Br CCl4 H
H
H + Br 2
Br
h
Br + HBr
NBS h, CCl4
4. Conversion of Alcohols to Alkyl Halides o Most frequently used lab method of alkyl halide preparation o 3° alcohol to halide HCl, 0oC ether
OH
Cl
3° ROH to 3° RX Mechanism H3 C H3 C C
H
H3 C H3 C C
Cl
OH
+
OH 2
H3 C H3C C+
H3 C
H3 C
H3 C
Cl H3 C H3C C
(classic SN1 nechanism)
o
-
Cl
H3C
SOCl
2 1° Halides SN2 2 Type OHDisplacement R by CH R CH2Cl pyridine Need reagents that convert –OH to a better leaving group
R
CH2OH
R
CH2OH
SOCl2 pyridine PBr3 e the r
R
CH2OH
PBr3 e the r
R
CH2Cl
R CH2Br Mechanism of reaction between 1° Alcohol and Thionyl Chloride
R
CH2Br
Advantages of SOCl2 Reagent i. Thionyl chloride (SOCl2) converts OF to chlorosulfite ester, -OSOCl, a better leaving group ii. –OSOCl is pushed out as Cl- is delivered
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CHM247H1 Jasmyn Lee iii.
The byproduct, SO2, is a gas that floats away – irreversible reaction
Summary of Alkyl Halide Reaction Mechanisms
Basicity vs. Nucleophilicity Base reacts with H+ Nucleophile reacts with Cδ+
O _
_
H3C
O
H3C
w. base w. nuc
O
s. base s. nuc
CH3 H3C _
H3C
O
s. base w. nuc
_
I
_
Br
w. base s. nuc
3
CHM247H1 Jasmyn Lee SN2 Summary
1. Inversion of stereochemistry 2. Second order kinetics rate = k [OH] [A] SN1 Summary
1. Racemization 2. First Order Kinetics -
rate = k [A]
E2
1. Stereospecific 2. Second Order Kinetics “Anti Periplanar” E1 1. Non-stereospecific 2. First order kinetics -
rate = k [OH][S]
rate = k [S]
4
CHM247H1 Jasmyn Lee Solvents Protic Solvents – solvents that can H-bond o Stabilize C+ intermediate favor SN1 and E1
Polar Aprotic Solvents – solvents that do not H bond o Do not hinder nucleophile by H-bonding favor SN2 and E2
Trends in Nucleophilicity An anionic (negatively charged nucleophile “has more muscle” than a neutral nucleophile
Eg/ between ROH and RO- – which is better nucleophile? RO- is better than ROH If steric hindrance makes Nu less effective Best to Worst Nu: HO- > CH3O- > (CH3)3 COElectron density is better stabilized when distributed over a larger area – better Nu is lover in the same column of the periodic table Weak Nu for SN1 o Eg/ H2O, ROH, NH3 Strong Nu for SN2 o Eg/ HO-, RO-, NH2In Polar Protic Solvent o Strong nucleophile can’t move freely shielded by H-bonding solvent molecules o Weak nucleophile (preferred in SN1) is less tightly bound by polar protic solvent In Polar Aprotic Aolvent o Strong nucleophile is surrounded by solvent but not solvated – can move freely
Leaving Group Has to accept electron pair stabilize the negative charge Better LG more stable on leaving LG has to accept electron pair, but must be a weak base (pKa is a good indicator) Increased radius stabilized negative charge better leaving groups are found lower in the same group
Other good LG’s Ions
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CHM247H1 Jasmyn Lee O S
O O
RO
O tosylate and other sulfonates
O
S
RO
O
O
P
O
O
sulfate
phosphate
Neutral Molecules H
O
H
R
water
O
R
R H
alcohol
N R amines
R
R P
R phosphines
SN1 and SN2 Rates A good leaving group increases the rate of both SN1 and SN2 reactions Organometallic Reagents 1. Grignard Reagent (RMgX) A C-C Bond Building Reaction Victor Grignard – 1912 Nobel Prize Uses RX and Mg to make an organometallic reagent in which the C next to Mg is δ- this makes it anioic in character excellent nucleophile and very strong base Formation of Grignard Reagent
o
Polarity of bonds in the Gragnard Reagent
Grignard Reagent as a Base o Because of their basic character - Grignard reagents are unstable in water or any medium that contains labile protons R – Mg – X –H2O--> R-H o Grignard reagents must be used under dry conditions and in the absence of –OH, -COOH, -NH2, -SH
2. Gilman Reagent (R2CuLi) Formation of the Gilman Reagent:
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CHM247H1 Jasmyn Lee
Gilman Reagents (like Grignard) are a source of R:-
Organometallic Reagents Contain a Carbon-Metal Bond o R-Li (organolithium), R-Mg-X (organomagnesium), R2-Cu- Li+ (organocopper) Electronegativity Values o C (2.5), Li (1.0), Mg (1.3), Cu (1.8) o Relative polarity of C-Metal bond determines relative reactivity Organolithium and Grignard add twice
Cuprates are less reactive
o o
Only one of the alkyl chains from the cuprate adds The ketone is isolated
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I HO I
O I
OH NH2
O I
thyroxine
Organo Halides from marine organisms o Almost 100 different organic halides have been isolated from edible red seaweed (asparagopsis taxiformis) o DichloroDiphenulTrichloroethane DDT is a non-specific pesticide Kills insects that spread diseases (eg/ malaria, typhys) Weakly polar, very stable organic molecule Persists in environment, collects in fatty tissue Interferes with egg-shell formation of eagles and hawks Halides are important industrially o Vinyl chloride (CH2 = CHCl) polymerized to give PVC
Cl
Cl
H
CCl3
DichloroDiphenylTrichloroethane
Alkyl, Vinyl and Aryl Halides CCl4 – an alkyl halide, Cl is bonded to an sp3 carbon F2C=CF2 – a vinyl halide, F is bonded to an sp2 hybridized carbon (on an isolated double bond) C6H5-Br – an aryl halide, Br is bonded to an sp2 hybridized carbon of an aromatic ring Spectroscopy IR – the C-X bond stretch appears in the fingerprint region (500-800 cm-1) hard to identify by IR 1H NMR – H – C – X 2.5δ – 4.0δ ; H is deshielded by the influence of the electronegative X downfield
Preparation of Organic Halides Review Methods of Preparation 1. Halogenation of Alkenes 2. Hydrohalogenation of Alkenes 3. Allylic and Benzylic Bromination o (Br placed next to C=C) o Double bond left intact (radical mechanism) o N-bromosuccinamide (NBS) – generates a low concentration of Br2
1
CHM247H1 Jasmyn Lee NBS, h Br CCl4 H
H
H + Br 2
Br
h
Br + HBr
NBS h, CCl4
4. Conversion of Alcohols to Alkyl Halides o Most frequently used lab method of alkyl halide preparation o 3° alcohol to halide HCl, 0oC ether
OH
Cl
3° ROH to 3° RX Mechanism H3 C H3 C C
H
H3 C H3 C C
Cl
OH
+
OH 2
H3 C H3C C+
H3 C
H3 C
H3 C
Cl H3 C H3C C
(classic SN1 nechanism)
o
-
Cl
H3C
SOCl
2 1° Halides SN2 2 Type OHDisplacement R by CH R CH2Cl pyridine Need reagents that convert –OH to a better leaving group
R
CH2OH
R
CH2OH
SOCl2 pyridine PBr3 e the r
R
CH2OH
PBr3 e the r
R
CH2Cl
R CH2Br Mechanism of reaction between 1° Alcohol and Thionyl Chloride
R
CH2Br
Advantages of SOCl2 Reagent i. Thionyl chloride (SOCl2) converts OF to chlorosulfite ester, -OSOCl, a better leaving group ii. –OSOCl is pushed out as Cl- is delivered
2
CHM247H1 Jasmyn Lee iii.
The byproduct, SO2, is a gas that floats away – irreversible reaction
Summary of Alkyl Halide Reaction Mechanisms
Basicity vs. Nucleophilicity Base reacts with H+ Nucleophile reacts with Cδ+
O _
_
H3C
O
H3C
w. base w. nuc
O
s. base s. nuc
CH3 H3C _
H3C
O
s. base w. nuc
_
I
_
Br
w. base s. nuc
3
CHM247H1 Jasmyn Lee SN2 Summary
1. Inversion of stereochemistry 2. Second order kinetics rate = k [OH] [A] SN1 Summary
1. Racemization 2. First Order Kinetics -
rate = k [A]
E2
1. Stereospecific 2. Second Order Kinetics “Anti Periplanar” E1 1. Non-stereospecific 2. First order kinetics -
rate = k [OH][S]
rate = k [S]
4
CHM247H1 Jasmyn Lee Solvents Protic Solvents – solvents that can H-bond o Stabilize C+ intermediate favor SN1 and E1
Polar Aprotic Solvents – solvents that do not H bond o Do not hinder nucleophile by H-bonding favor SN2 and E2
Trends in Nucleophilicity An anionic (negatively charged nucleophile “has more muscle” than a neutral nucleophile
Eg/ between ROH and RO- – which is better nucleophile? RO- is better than ROH If steric hindrance makes Nu less effective Best to Worst Nu: HO- > CH3O- > (CH3)3 COElectron density is better stabilized when distributed over a larger area – better Nu is lover in the same column of the periodic table Weak Nu for SN1 o Eg/ H2O, ROH, NH3 Strong Nu for SN2 o Eg/ HO-, RO-, NH2In Polar Protic Solvent o Strong nucleophile can’t move freely shielded by H-bonding solvent molecules o Weak nucleophile (preferred in SN1) is less tightly bound by polar protic solvent In Polar Aprotic Aolvent o Strong nucleophile is surrounded by solvent but not solvated – can move freely
Leaving Group Has to accept electron pair stabilize the negative charge Better LG more stable on leaving LG has to accept electron pair, but must be a weak base (pKa is a good indicator) Increased radius stabilized negative charge better leaving groups are found lower in the same group
Other good LG’s Ions
5
CHM247H1 Jasmyn Lee O S
O O
RO
O tosylate and other sulfonates
O
S
RO
O
O
P
O
O
sulfate
phosphate
Neutral Molecules H
O
H
R
water
O
R
R H
alcohol
N R amines
R
R P
R phosphines
SN1 and SN2 Rates A good leaving group increases the rate of both SN1 and SN2 reactions Organometallic Reagents 1. Grignard Reagent (RMgX) A C-C Bond Building Reaction Victor Grignard – 1912 Nobel Prize Uses RX and Mg to make an organometallic reagent in which the C next to Mg is δ- this makes it anioic in character excellent nucleophile and very strong base Formation of Grignard Reagent
o
Polarity of bonds in the Gragnard Reagent
Grignard Reagent as a Base o Because of their basic character - Grignard reagents are unstable in water or any medium that contains labile protons R – Mg – X –H2O--> R-H o Grignard reagents must be used under dry conditions and in the absence of –OH, -COOH, -NH2, -SH
2. Gilman Reagent (R2CuLi) Formation of the Gilman Reagent:
6
CHM247H1 Jasmyn Lee
Gilman Reagents (like Grignard) are a source of R:-
Organometallic Reagents Contain a Carbon-Metal Bond o R-Li (organolithium), R-Mg-X (organomagnesium), R2-Cu- Li+ (organocopper) Electronegativity Values o C (2.5), Li (1.0), Mg (1.3), Cu (1.8) o Relative polarity of C-Metal bond determines relative reactivity Organolithium and Grignard add twice
Cuprates are less reactive
o o
Only one of the alkyl chains from the cuprate adds The ketone is isolated
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