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HOW TO USE THIS BOOK - 5 -
UNIT 1 STRUCTURE, BONDING AND DRAWING - 7 - 1.1 Lewis Bonding and Formal Charges - 9 -
1.2 Drawing Condensed and Bond-Line Structures - 19 - 1.3 VSEPR Theory and Drawing Molecules in 3 Dimensions - 22 -
1.4 Molecular Orbital Theory: sp3, sp2 and sp Hybridization - 27 - 1.5 Constitutional Isomers and Units of Unsaturation - 39 -
UNIT 2 FUNCTIONAL GROUPS AND PHYSICAL PROPERTIES - 45 - 2.1 Functional Groups and Their Classification (1o, 2o Etc.) - 47 - 2.2 Intermolecular Forces, Boiling Points and Solubilities - 57 -
UNIT 3 NOMENCLATURE - 67 - 3.1 Nomenclature of Alkanes and Cycloalkanes - 69 - 3.2 Nomenclature of Alkenes and Alkynes - 75 - 3.3 Nomenclature of Alkyl Halides, Alcohols and Ethers - 79 -
UNIT 4 CONFORMATIONS - 85 - 4.1 Conformations of Ethane and Butane: Newman Projections - 87 - 4.2 Small Cycloalkanes (C3-C5): Ring Strain and Conformations - 91 - 4.3 Cyclohexane: Chair and Boat Conformations - 93 - 4.4 Substituted Cyclohexane Conformations - 97 -
UNIT 5 STEREOCHEMISTRY - 103 - 5.1 Chirality, Enantiomers and Chirality Centers - 105 - 5.2 R, S Configurations: The Cahn-Ingold-Prelog Rules - 111 - 5.3 Optical Activity and Racemic Mixtures - 115 - 5.4 Two Chirality Centers: Diastereomers and Meso Compounds - 120 - 5.5 3-D Bond-Line Structures and Fischer Projections - 124 - 5.6 Resolution of Enantiomers - 127 - 5.7Alkene Stereochemistry: Assigning E/Z and Cis/Trans - 128 - 5.8 Table of All Isomer Types Including Stereoisomers - 129 -
UNIT 6 HOW MOLECULES REACT: RESONANCE, ENERGETICS, - 131 - ACIDS AND BASES 6.1 Resonance and Electron-Pushing Rules - 133 - 6.2 Energetics: DGo, DG‡, Keq, Rates and Transition States - 140 - 6.3 Organic Acids and Bases: Brønsted-Lowry Theory, pKa and Equilibria - 146 - 6.4 Trends in Acidity: Electronegativity, Resonance and Inductive Effects - 157 - 6.5 Electrophiles, Nucleophiles and Mechanism Defined - 165 -
4
UNIT 7 ALKYL HALIDES: SN2/E2 AND SN1/E1 REACTIONS - 169 - 7.1Overview of All 4 Reactions - 171 - 7.2 The SN2 Reaction - 173 - 7.3 The E2 Reaction: Dehydrohalogenation - 184 - 7.4 The SN1/E1 Pair of Reactions - 196 - 7.5 Deciding Which Substitution or Elimination Happens - 202 - 7.6 List of Essential Alkyl Halide Reactions - 203 - 7.7 List of Reactions to Synthesize Alkyl Halides - 205 -
UNIT 8 ALKENES - 207 - 8.1 Unsymmetrical Additions: HX, H2O and Markovnikov’s Rule - 209 - 8.2 Symmetrical Additions: X2, H2, 1,2-Dihydroxylation and Epoxidation - 220 - 8.3 Oxidative Cleavages with Hot KMnO4 or O3: Carbonyl Products - 227 - 8.4 List of Essential Alkene Reactions - 231 - 8.5 List of Reactions to Synthesize Alkenes - 235 -
UNIT 9 ALKYNES - 237 - 9.1 Reactions of Alkynes - 239 - 9.2 List of Essential Alkyne Reactions - 247 - 9.3 A Synthesis of Alkynes - 251 -
UNIT 10 ALCOHOLS - 253 - 10.1 Acid-Base Reactions of Alcohols - 255 - 10.2 Conversion to Good Leaving Groups: Alkyl Halides and Sulfonates - 257 - 10.3 Substitution Reactions: Ether Synthesis and Protecting Groups - 261 - 10.4 Dehydration Reactions: Synthesis of Alkenes - 267 - 10.5 List of Essential Alcohol Reactions - 271 - 10.6 List of Reactions to Synthesize Alcohols - 275 -
UNIT 11 ETHERS AND EPOXIDES - 277 - 11.1 Reactions of Ethers and Epoxides - 279 - 11.2 List of Essential Ether and Epoxide Reactions - 286 - 11.3 List of Reactions to Synthesize Ethers and Epoxides - 288 -
UNIT 12: A SHORT INTRODUCTION TO MULTISTEP SYNTHESIS - 289 -
ANSWERS TO TEST YOUR KNOWLEDGE PROBLEMS - 299 -
ACKNOWLEDGMENTS - 349 -
ABOUT RESCUE EDUCATION AND THE AUTHOR - 350 -
67
UNIT 3 NOMENCLATURE
3.1 Nomenclature of Alkanes and Cycloalkanes - 69 - A. Introduction and Alkane Parent Names - 69 - B. Alkyl Group (Substituent) Names - 69 - C. Alkane Nomenclature - 71 - D. Cycloalkane Nomenclature - 73 - Test Your Knowledge - 74 -
3.2 Nomenclature of Alkenes and Alkynes - 75 - A. Alkene Nomenclature - 75 - B. Alkyne Nomenclature - 76 - C. Phenyl and Benzyl Groups - 77 - Test Your Knowledge - 78 -
3.3 Nomenclature of Alkyl Halides, Alcohols and Ethers - 79 - A. Alkyl Halide Nomenclature - 79 - B. Alcohol Nomenclature - 79 - C. Ether Nomenclature - 81 - Test Your Knowledge - 83 -
75
3.2 NOMENCLATURE OF ALKENES AND ALKYNES
A. Alkene Nomenclature 1. Choose the longest chain containing the double bond as the parent
• change the corresponding alkane ending from -ane to -ene • the parent is not necessarily the longest chain overall but must contain the double bond
2. The alkene has higher numbering priority (it is more important) than any alkyl substituent • the alkene is given the lowest possible number without considering the positions of any
alkyl or other lower priority groups • the lower priority substituents simply take whatever number results from this
assignment • in old IUPAC rules, the alkene position number is put before the entire parent name • in new IUPAC rules, the alkene position number is put directly before the “-ene” • we will use the old IUPAC numbering rule which is still most often used
3. The double bond of a cycloalkene is given position 1 and 2 • the double bond is understood to be at position 1 and the 1 is not included in the name • the double bond is numbered in the direction to give lower priority substituents the
lowest possible combination of numbers 4. Compounds with two double bonds are called dienes and those with three double bonds are
called trienes • the parent alkane name is changed from -ane to -adiene or -atriene • the double bonds are given the lowest possible numbers overall
• finally, lower priority substituents are given numbers
SAMPLE PROBLEMS Name the following molecules using IUPAC nomenclature rules.
ANSWERS
a. b. c. d.
12 3
45
6
123
45
67
8
Old IUPAC: 2-Isobutyl-1-hexene New IUPAC: 2-Isobutylhex-1-ene
a.
b.
Old IUPAC: 7,7-Dimethyl-3-octene New IUPAC: 7,7-Dimethyloct-3-ene
The longest chain (8 carbons) is not the parentThe parent MUST contain the alkene (6 carbons)
ALWAYS number the alkene even when its in position 1We will use the old IUPAC number position
Only the alkene position is considered in numberingAfter the alkene is given the lowest possiblenumber, the methyl positions are assigned
76
5. The following common names are recognized by IUPAC
6. There are two important double bond-containing substituents • the vinyl group is derived by removing a hydrogen from ethylene • the allyl group is derived by removing a hydrogen from the sp3 carbon of propylene • these names are used as descriptors or in non-systematic (common) nomenclature
7. The informal cis/trans designation of alkene stereochemistry was discussed in 1.3 and 1.4
• the IUPAC sanctioned (and much less ambiguous) E/Z system is discussed in 5.7 B. Alkyne Nomenclature
• The IUPAC nomenclature rules for alkynes are very similar to those for alkenes 1. Choose the longest chain containing the triple bond as the parent
• the corresponding alkane ending is changed from -ane to -yne • like alkenes, the parent is not necessarily the longest chain overall
2. In analogy to alkene nomenclature, the triple bond has higher priority than alkyl substituents and is given the lowest possible number
3. Compounds with both double and triple bonds are called eneynes
1 2
3
45
1
2
3 4
5
5-Ethyl-3-methylcyclohexene
5,5-Dimethyl-1,3-cyclohexadiene
c.
d.
The double bond must be in position 1 and 2 of the ring Choose the direction (3,5 vs. 4,6)
to pick the lowest number (3 beats 4) at the 1st point of difference
Number the double bonds to give the lowest possible numbers (1,3)Choose the direction to give the methyls the lowest numbers
(5,5 and not 6,6)
2 1
46
H2C CH2 H2C CH CH3
Ethylene* Propylene*
H2C CH H H2C CH H2C CH CH2 H H2C CH CH2
OH
Remove sp3 H
Ethylene Vinyl Propylene Allyl
Vinyl bromide Vinyl cyclohexane Allyl alcohol Allylcyclobutane
Remove H
Br
77
• numbering occurs to give the lowest combination of numbers to the unsaturations • if the competing numbering systems are identical, the double bond has slightly higher
priority and wins 4. The common name acetylene is recognized by IUPAC nomenclature
SAMPLE PROBLEMS Name the following molecules using IUPAC nomenclature rules.
ANSWERS
C. Phenyl and Benzyl Groups
• Aromatic nomenclature is covered in 2nd semester but there are two aromatic-derived groups in frequent use
• The phenyl (Ph) group is derived by removing a hydrogen from benzene • phenyl can be a substituent on a chain that is longer than itself (longer than 6 carbons)
• The benzyl (Bn) group is derived by removing a methyl hydrogen from toluene
C C HH
Acetylene*
a. b. c.
1234
56
789
8,8-Dimethyl-3-nonyne
1 23 4
56
4-Hexen-1-yne
12
345
6
1-Hexen-5-yne
a.
b.
c.
The alkyne is higher in priority than the methylsand must get the lowest possible number
The eneyne is numbered (1,4 vs. 2,5) to give the lowest number at the 1st point of difference
(1 wins over 2)
When the two possibilities are the same (1,5) then the alkene wins and gets the lowest number
H CH2 H CH2
Benzene Phenyl (Ph) Toluene Benzyl (Bn)
Remove H Remove sp3 H
78
SAMPLE PROBLEMS Name the following molecules.
ANSWERS
TEST YOUR KNOWLEDGE 3.3 Name the following compounds using IUPAC nomenclature rules. Ignore cis/trans
designations.
3.4 Draw the correct structures for the following names. a. Vinyl chloride b. Ethylene c. 1-Allylcyclohexene d. Benzyl chloride
e. 2-Phenylheptane f. Propylene g. Acetylene
a. b. c.Br
1-Phenyloctane
a.
b.
Ethylbenzene
c.Br
Benzyl bromide
The benzene ring becomes the phenyl substitutent onchains longer than 6 carbons
Remember to include the number 1
The short ethyl chain is a substitutent on benzene
The name benzyl bromide is used almost exclusively instead of a strictly systematic (IUPAC) name
a. b. c. d.
e. f. g. h.
i. j.OH
309
UNIT 3 NOMENCLATURE 3.1 a. 2,2,5,6-Tetramethylheptane h. 1-Ethyl-3-methylcyclohexane b. 3-Isopropyl-2,4-Dimethylpentane i. 3-Ethyl-1,1-dimethylcyclohexane c. 3,7-Diethyl-3,7-dimethylnonane j. 1-sec-Butyl-3-ethylcylcohexane d. 5-sec-Butyl-3,3,7-trimethylnonane k. 2,4-Diethyl-1-methylcyclohexane e. 5-Isobutyl-4-isopropyldecane l. 3-Ethyl-2-isopropyl-1,1-dimethylcyclohexane f. 3,4-Diethyl-2-methylheptane m. 1,5-Dicyclopropylpentane g. tert-Butylcyclopentane n. Cyclopentylcyclopentane 3.2
3.3 a. 6,7,7-Trimethyl-2-octene f. 6,6-Dimethyl-3-heptyne b. 2-Butyl-1-hexene g. 5-Methyl-4-hexen-1-yne c. 2-Ethyl-4-methyl-1-hexene h. 2-Methyl-1-hexen-5-yne d. 4-Ethyl-1-methylcyclopentene i. Benzyl alcohol e. 3,3-Dimethyl-1,4-cyclohexadiene j. 2-Methyl-2-phenyloctane 3.4
3.5 a. 2-Butyl-1-hexanol h. 7-Chloro-7-methyl-2-octyne b. 5-Butyl-6-ethyl-6-hepten-2-ol i. 3,3-Difluorocyclopentanol c. 5-Methyl-6-heptyn-3-ol j. 6-Chloro-2-cyclohexenol d. 3-Methyl-2-cyclohexenol k. 2-Methyl-2-propoxyoctane e. 2-Methyl-1,3-propanediol l. 2-Ethoxyethanol f. 2-Bromo-6-ethyloctane m. 1,3-Dimethoxycyclohexene g. 3-Chloro-1,1-diethylcyclopentane n. sec-Butoxybenzene 3.6
a. b. c.
a. b. c. d. e.
f. g.
ClCl
OH
OH OH
O O O OO
O O OH
a. b. c. d. e. f.
g. h. i. j.Br
277
UNIT 11 ETHERS AND EPOXIDES
11.1Reactions of Ethers and Epoxides - 279 - A. HX: Ether Cleavage with Strong Acids - 279 - B. Epoxide Opening with Strong Nucleophiles - 280 - C. Epoxide Opening with Weak Nucleophiles and Catalytic Acid - 281 - D. Complementary Syntheses of 1,2-Diols - 283 - Test Your Knowledge - 285 -
11.2 List of Essential Ether and Epoxide Reactions - 286 - Test Your Knowledge - 287 -
11.3 List of Reactions to Synthesize Ethers and Epoxides - 288 -
279
11.1 REACTIONS OF ETHERS AND EPOXIDES
A. HX: Ether Cleavage with Strong Acids • Acyclic (non-cyclic) and most cyclic ethers are almost totally inert (i.e. unreactive)
• diethyl ether and tetrahydrofuran (THF) are very common solvents partially because they are so unreactive
• epoxides (3-membered ring ethers) are much more reactive and synthetically useful
• The only general reaction of ethers we will cover is their cleavage with strong mineral acids • both halves of the ether are converted into alkyl halides by either SN1 or SN2 reactions
• Ethyl t-butyl ether is cleaved with 2 eq. HBr in a combination of SN1 and SN2 reactions (7)
• First the ether oxygen is protonated • then ethanol acts as a great leaving group in the 1st step of an SN1 reaction • finally, the relatively stable 3o carbocation reacts with Br– nucleophile
• Next, the ethanol hydroxyl is also protonated and turned into a great leaving group (H2O) • this is displaced by Br– in an SN2 reaction
OO
Diethyl ether Tetrahydrofuran Epoxides
O
SolventsAlmost entirely chemically inert
Much morereactive
R O 2 eq. HXHBr or HI best
R X
Example
R’ X R’+
CCH3
H3CCH3
O CH2CH3 2 eq. HBr
CCH3
H3CCH3
CH2CH3Br Br+
Can occur viaSN1 or SN2 reactions
CCH3
H3CCH3
O CH2CH3
H Br
CCH3
H3CCH3
O CH2CH3H
CCH3
H3CCH3
SN1Br
CCH3
H3CCH3
Br
H O CH2CH3
H Br
O CH2CH3
HH
Br
SN2CH2CH3Br
+ HO CH2CH3Great LG
Great LG
280
B. Epoxide Opening with Strong Nucleophiles • 3-Membered ring epoxides are unusually reactive due to ring strain (4.2)
• To understand the reactivity of epoxides it is important to realize that the carbons of an epoxide ring have partial positive charge due to electron withdrawal by the oxygen
• A strong nucleophile (i.e. one with a negative charge) can react at one of the d+ carbons and pop open the strained ring in an SN2 reaction
• the reaction proceeds with backside attack • note that the leaving group is an alkoxide (RO–) with R being the rest of the molecule
• You would expect that this RO– (like HO–) would be a poor leaving group in an SN2 reaction • this problem is more than mitigated by the positive outcome of opening the 3-
membered ring and relieving its ring strain
• After opening the epoxide, the alkoxide oxygen must be protonated • this can be accomplished with a protic solvent such as H2O
• In the example above, the unsymmetrical epoxide will be attacked by the strong nucleophile Br– at the least hindered carbon
• this is an SN2 reaction in which nucleophiles must attack a sterically undemanding carbon
• An important variation of this reaction is to use only a catalytic amount of RO– nucleophile in a corresponding alcohol solvent to produce a 1,2-hydroxyether
• CH3O– nucleophile attacks the epoxide at the least hindered carbon in an SN2 reaction
• The resulting alkoxide is then protonated by a molecule of CH3OH solvent • this generates more CH3O– which can attack another molecule of epoxide • only a catalytic amount of alkoxide needs to be added to start the cycle
O
Nuc
δ+ δ+ Nuc–
SN2
O
Nuc
H O H HO
Nuc
ExampleO
H3CH3C
KBrH2O
HO
H3CH3C
Br
Strong nucleophilesdo backside attack
at least hindered carbon(Solvent)
O
H3CH3C
CH3O
O
H3CH3C
OCH3
OCH3HHO
H3CH3C
OCH3+ CH3O
Regenerated
cat. NaOCH3CH3OH
SN2
281
• alternatively, you can use an entire equivalent (i.e. a stoichiometric amount) of alkoxide
• The analogous reaction with catalytic HO– in H2O will yield the 1,2-diol
• In the case of cyclic epoxides, the trans product is obtained exclusively • this derives from the SN2 backside attack of HO– on the epoxide
SAMPLE PROBLEMS For the following problems, supply the correct reagent(s) or product (whichever is indicated by the box). If a particular stereochemistry is obtained, show it clearly.
ANSWERS Strong nucleophiles attack the epoxide via an SN2 reaction so attack is backside and at the least hindered carbon.
C. Epoxide Opening with Weak Nucleophiles and Catalytic Acid
• Weak (i.e. neutral) nucleophiles such as water and alcohols cannot react directly with epoxides • the epoxide ring is not reactive enough
• If the epoxide oxygen is first protonated with an acid then weak nucleophiles can react
O
H3CH3C
HO
H3CH3C
OH
cat. NaOHH2O
O
H HHO
OH
HO H
Hcat. NaOHH2O
a.
O
CH3NaCNH2O
b.
OH
OHO
c.O cat. NaOCH3
CH3OH
a.
O
CH3NaCNH2O
b.
OH
OHO
c.
HO
CH3
H
CN
CN and OH must be trans
–CN attacks least hindered carbon
HCN
CH3OH
HO– can be addedeither catalytically
or stoichiometrically
cat. NaOH, H2Oor 1 eq. NaOH , H2O
HO
H3C OCH3
O
H3C
SN2
HHcat. NaOCH3
CH3OH
CH3O– attacks least hindered carbon
O
CH3CN
H
282
• the protonation converts the poor alkoxide leaving group (seen in the epoxide openings B) into the much better alcohol leaving group
• The weak nucleophile attacks the most substituted (i.e most hindered) carbon • the result is the opposite selectivity to that seen with strong nucleophiles
• The mechanism for the reaction in the example reveals the reason for this selectivity
• In the 1st step, a protonated methanol is the likely acid which protonates the epoxide • the protonated methanol is made by reaction of CH3OH and H2SO4 catalyst • the oxygen of the epoxide is turned into a much better neutral leaving group
• The protonated epoxide is now much more reactive • it can react with a molecule of weak nucleophile (e.g. neutral methanol)
• The protonated epoxide has a positive charge which partially “leaks” onto the attached carbons
• in an unsymmetrical epoxide, most of this leaking positive charge will reside on the most substituted carbon and form a partial carbocation
• recall that a more substituted carbocation is more stable (7.4B) • the nucleophile will attack the carbon with the most positive charge (i.e. the most
substituted carbon)
O GreatLG
HO
OR
Example
O
H3CH3C
H3CH3C
Weak nucleophilesneed catalytic acidBackside attack on
most substituted carbon
ROH or HOHcat. acid
OH
H O R
CH3OHcat. H2SO4
OH
CH3O
O
H3CH3C
H3CH3C OH
CH3O
H OH
CH3 O
H3CH3C
H
OHH3C
δ+
δ+ Positive charge on epoxide oxygen “leaks” onto
most substituted carbon
Mostsubstituted
OHH3CH3C
O
HH3C
OHH3C
+OHH3C
H
Regenerated
Great neutral LG
283
• This is an SN2-like reaction with backside attack but there is also an SN1 aspect because of the definite carbocation character of the carbon being attacked
• The selectivity of this reaction is determined by which epoxide carbon has the most carbocation character (and not by which is least sterically hindered)
• This reaction can be used to effectively perform an anti 1,2-dihydroxylation • this is an SN2-like opening of the epoxide, so a cyclic epoxide will yield the trans 1,2-diol
D. Complementary Syntheses of 1,2-Diols
• Recall that syn-1,2-diols are made from the alkene by reaction with cold basic KMnO4 or with OsO4 followed by reaction with aqueous NaHSO3 (8.2C)
• The double bond is, in effect, “capped” by the reagents and addition occurs to the same face of the double bond (syn addition)
• The complementary anti-hydroxylation of a double bond (i.e. hydroxyls adding to opposite faces of the double bond) can be accomplished via the epoxide
• first the epoxide must be synthesized using mCPBA (8.2D) • then either acid or base catalyzed reactions will lead to the same product
• It is always useful to think of partial mechanisms to remember these reactions
• in the base-catalyzed reaction, a strong nucleophile (HO– ) attacks the epoxide directly in an SN2 reaction
O
H H
OH
HO H
HTrans diol onlycat. H2SO4
H2O
H
H
OH
OH
Cold KMnO4 H2O, NaOH
1. OsO42. NaHSO3, H2Oor Syn dihydroxylation
Cis product only(8.2D)
H
H
OH
OHor Anti dihydroxylation
Trans product onlycat. H2SO4
H2Ocat. NaOHH2OO
H
H
mCPBA
O
H H
HO
O
H H
OH
HO H
H
cat. H2SO4
H2OO
H H
H
OH H
cat. NaOHH2OSN2
284
• in the acid-catalyzed reaction, an acid activates the epoxide for SN2-like opening with the weak nucleophile water
SAMPLE PROBLEMS React cis- and then trans-2-butene with each of the following sets of reagents. Clearly show stereochemistry of the products. If a set of enantiomers is formed, you only need to draw one of them. Label any meso products.
a. 1. Cold KMnO4, NaOH, H2O c. 1. mCPBA 2. cat. NaOH, H2O b. 1. OsO4 2. NaHSO3, H2O d. 1. mCPBA 2. H2O, cat. H2SO4
ANSWERS Reagents a. and b. both give syn dihydroxylations and reagents c. and d. both give anti dihydroxylations. To get the meso compound (A) you can either syn dihydroxylate the cis isomer or anti dihydroxylate the trans isomer. We have rotated the products of the trans alkene so you can see them in the same orientation as the cis alkene products. For a review of the stereochemistry of molecules with 2 chirality centers go to 5.4A.
H3C
H
CH3
H
H3C
CH3
H
HCis Trans
HHCH3H3C
Cis
Cold KMnO4 H2O, NaOH
1. OsO42. NaHSO3, H2O
or
Anti dihydroxylation: c,dSyn dihydroxylation: a,b
HHCH3H3C
H
HCH3
H3C
HO OH HO
OH
B (+ Enantiomer)
CH3HHH3C
Trans
Cold KMnO4 H2O, NaOH
1. OsO42. NaHSO3, H2Oor
Anti dihydroxylation: c,dSyn dihydroxylation: a,b
CH3HHH3C
CH3
HH
H3C
HO OH HO
OHRotate
HHCH3H3C
HO OH
Rotate
H
HCH3
H3C
HO
OH
A (Meso)
H2O, cat. H2SO4
1. mCPBA2. cat. NaOH, H2O
or
H2O, cat. H2SO4
1. mCPBA2. cat. NaOH, H2O
or
A (Meso)
285
TEST YOUR KNOWLEDGE 11.1 For each of the following reactions, give product(s) and complete mechanisms (including
electron-pushing arrows). In the case of b. and c., explain why the nucleophile attacks where it does.
11.2 For each reaction, give the correct starting compound, reagent(s) or product; whichever is indicated by the box. If you expect a certain stereochemistry, be sure to clearly draw it.
a.
OCH2CH3CH3 Excess HCl +
Both products contain Cl
b.
O
H3CH3C
cat. CH3CH2ONaCH3CH2OH
O
H3CH3C
CH3CH2OHcat. H2SO4
c.
H3C
CH3
H
H
1. mCPBA2. H2O, cat. acid
1. mCPBA2. 1 eq. NaOH
meso-2,3-ButanediolN3
OH
OH
OH
OCH3
CH3OHcat. acid
OCH3 CH3
OHCl
Cold KMnO4 H2O, NaOH
Excess HBr
a.
b.
c.
d.
e.
f.
g.
h.
+
CH3
O
286
11.2 LIST OF ESSENTIAL ETHER AND EPOXIDE REACTIONS
1. Cleavage of All Ethers by HX (11.1A)
2. Opening of Epoxides with Strong Nucleophiles (11.1B)
3. Opening of Epoxides with Weak Nucleophiles (11.1C)
4. Complementary 1,2-Diol Syntheses (11.D)
R O 2 eq. HXHBr or HI best
R X
Example
R’ X R’+
CCH3
H3CCH3
O CH2CH3 2 eq. HBr
CCH3
H3CCH3
CH2CH3Br Br+
Can occur viaSN1 or SN2 reactions
O
Nuc
δ+ δ+ Nuc–
SN2
O
Nuc
H O H HO
Nuc
ExampleO
H3CH3C
KBrH2O
HO
H3CH3C
Br
Strong nucleophilesdo backside attack
at least hindered carbon(Solvent)
O GreatLG
HO
OR
Example
O
H3CH3C
H3CH3C
Weak nucleophilesneed catalytic acidBackside attack on
most substituted carbon
ROH or HOHcat. acid
OH
H O R
CH3OHcat. H2SO4
OH
CH3O
H
H
OH
OH
Cold KMnO4 H2O, NaOH
1. OsO42. NaHSO3, H2Oor Syn dihydroxylation
Cis product only
H
H
OH
OHor Anti dihydroxylation
Trans product onlycat. H2SO4
H2Ocat. NaOHH2OO
H
H
mCPBA
(8.2D)
287
TEST YOUR KNOWLEDGE
11.3 Give all necessary reagents to synthesize each product from the starting molecule. More than one set of reagents may be necessary.
11.4 For each question, give all necessary reagents to synthesize each alternative product from
the starting material shown. More than one set of reagents may be necessary. Be sure you will produce the indicated stereoisomer as the major or only product.
O
OH
HO
OCH2CH3
HO
OH
H3CO
OH
Br
OH
NCA
B
C
D
E
H3C
CH3
H
HHH
CH3H3C
H
HCH3
H3C
HO OH HO
OH
+ Enantiomer
H3C
H
CH3
H H
HCH3
H3C
HO
OH
+ Enantiomer
HHCH3H3C
HO OH
OH
OH
OH
OH
a.
b.
c.
288
11.3 LIST OF REACTIONS TO SYNTHESIZE ETHERS AND EPOXIDES
A. From Alcohols by Williamson Ether Synthesis (SN2 Reaction) (10.3B)
B. Epoxides From Alkenes Using Peroxyacids (8.2D)
R OH Strong Base(e.g. NaNH2)
R O + R’ XSN2
Methyl or 1o
only
R O R’
Example
CCH3
H3CCH3
OH 1. NaNH2 CCH3
H3CCH3
ONa2. CH3Br
CCH3
H3CCH3
OCH3
WilliamsonEther SynthesisMust be SN2
O
RCO3HA peroxyacid
Syn addition
ExampleH
HO
H
H
mCPBACO
OOH
meta-Chloroperbenzoic acidmCPBA
Cl
An epoxide
342
UNIT 11 ETHERS AND EPOXIDES
11.1
11.2
11.3 A. CH3CH2OH, cat. H2SO4 B. NaBr, H2O C. cat. CH3ONa, CH3OH or you could use 1 eq. CH3ONa, CH3OH D. cat. NaOH, H2O or you could use 1 eq. NaOH, H2O or H2O, cat. acid E. NaCN, H2O
a.
b.
O
H3CH3C
OCH2CH3
c.
OCH2CH3CH3
O
H3CH3C
O
H3CH3C
H Clδ+ δ-
δ+
O
CH3
CH3CH2 H
O
CH3
CH3CH2 H
Cl
H Clδ+ δ-
OCH3CH2H
HClCl CH2CH3
Cl
CH3SN1
SN2
OCH2CH3
SN2
H OCH2CH3HO
H3CH3C
OCH2CH3
H OH
CH2CH3O
H3CH3C
H
δ+
δ+ δ+
H CH2CH3O
Positive charge “ leaks” onto most substituted carbonEtOH attacks there
SN2 reaction so EtO- attacks at
least hindered carbon
OCH2CH3+ Regenerated
H3CH3C
O
OH
H CH2CH3
H CH2CH3O
H3CH3C
CH3CH2O
OH
+ RegeneratedHO
HCH2CH3
OHCH3
a. 1. mCPBA 2. NaN3, H2O
b. cold KMnO4, H2O, NaOH
c.
f.
g.
h.
OCH3
d. KCl, H2O
H3C
H
CH3
HCis
HHCH3H3C
HO OHCH3
e.
OH
OHH
Two –OH groupsare anti
Br + CH3Br
343
11.4
H3C
CH3
H
HHH
CH3H3C
H
HCH3
H3C
HO OH HO
OH
+ Enantiomer
H3C
H
CH3
H H
HCH3
H3C
HO
OH
+ Enantiomer
HHCH3H3C
HO OH
OH
OH
OH
OH
a.
b.
c.
Cold KMnO4, H2O, NaOH or
1. OsO4 2. NaHSO3, H2O
Cold KMnO4, H2O, NaOH or
1. OsO4 2. NaHSO3, H2O
Cold KMnO4, H2O, NaOH or
1. OsO4 2. NaHSO3, H2O
1. mCPBA2. cat. NaOH, H2O or1. mCPBA2. H2O, cat. H2SO4
1. mCPBA2. cat. NaOH, H2O or1. mCPBA2. H2O, cat. H2SO4
1. mCPBA2. cat. NaOH, H2O or1. mCPBA2. H2O, cat. H2SO4
