1321 CHM Assignment #6 - ANSWERS In this assignment: - Nucleophilic addition to carbonyls - Elimination reactions (E1, E2) To be covered the week of March 24th 1) Give the products of the following reactions and give mechanisms to show how they are formed:
O a) H3CO O H H3CO H BH3 H3CO H 1) NaBH4 2) H3O+ O H H H H3CO repeat 3X H O B(OR)3 H H3CO O b) 1) NaBH4 2) H3O+ O H H BH3 repeat 3X OH B(OR)3 H H H O B(OR)3 H H H H O B(OR)3 H O H H H BH3 O BH3 H H H H H3CO R O B(OR)3 H BH3 O BH3 H
OH B(OR)3 H H3CO H
R
c)
1) NaBH4 O 2) H3O+
O H H BH3
O
BH3 H
O BH3
repeat 3X
B(OR)3 OH H
H O B(OR)3 H H
O B(OR)3
R
Assignment 6 - ANSWERS
O d) 1) NaBH4 2) H3O+
OH
O O H BH3
BH3
O BH 3
repeat 3X O B(OR) 3 H H
B(OR)3
OH
O B(OR) 3
R O e) 2) H3O+ O O H BH3 repeat 3X O B(OR) 3 H H BH3 O BH 3 1) NaBH4 OH
OH
O B(OR) 3 R
2
Assignment 6 - ANSWERS
1) MeMgBr f) O 2) H3O
+
OH
Me MgBr MgBr O O MgBr O H
H2O MgBr O H
OH
O g)
OH 1) MeMgBr 2) H3O+ H2O MgBr MgBr O H MgBr O H
Me MgBr O
O
OH
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Assignment 6 - ANSWERS 2) Predict the major products of the following reactions.
Br a) Mg Et2O Mg Cl b) Et2O A OMgBr MgCl CH3OH B H MgBr
Br c)
Mg Et2O A
MgBr
O
B
Mg d) Br Et2O A Mg e) Cl Et2O A MgBr MgCl MgBr
O
OMgBr
B O OMgCl
B
Br f)
Mg Et2O A
O
OMgBr
B
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Assignment 6 - ANSWERS 3) The following reactions would not work as shown. Explain why (look for a more favorable reaction that would occur instead).
Br 1) Mg a) 2) OH 3) H 3O + Mg O H HO OH
H
MgBr
Br
HH
Br
O H acid-base reaction would destroy the nucleophile.
OH
OH BrMg
O
O b) Br
1) Mg 2) O H OH
O
Mg
3) H 3O+ OMgBr
O BrMg Br
O Br
O Grignard reagent would react with another molecule of starting material instead of "waiting" to react with the aldehyde
O c) O 1) CH3 CH 2 MgBr 2) H 3O+ H O MgBr H OMgBr acid/base reaction faster than Grignard reaction OH OH
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Assignment 6 - ANSWERS 4) Give all the different carbonyl starting materials and the Grignard reagent or reducing reagent that could be used to form each of the following compounds.
O a) OH H H MgBr NaBH2 OR O H
b)
OH H
O OR MgBr BrMg
O OR
O
NaBH 4
c)
OH
O OR
O OR
O
BrMg
BrMg CH 3 BrMg
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Assignment 6 - ANSWERS 5) Name the following compounds
a) 6-methylheptene or 6-methylhept-1-ene
b)
2-ethylpentene or 2-ethylpent-1-ene
c)
4-methylhepta-1,6-diene 4-vinylcyclohexene
d)
e)
3(S),4(R)-dimethylcyclopentene *Don't forget to specify the stereochemistry! E-2-methyloct-4-ene
f)
g)
5Z-2,7-dimethylocta-1,5-diene
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Assignment 6 - ANSWERS 6) Predict the products of E1 elimination for the following compounds. Predict the relative amounts of each product.
OH H2SO4 a) heat OH + H
+
OH2 H HSO4
b)
H3PO4 OH heat + OH + H+ OH2 H H minor (least substituted) + H+ H+
c)
Br
HOCH3
major (most substituted) H + H + HOCH3 HOCH3 + HOCH3 + HBr minor (least substituted) + HOCH3 + HBr major (most substituted)
H Br
d)
Br
HOC(CH3)3 H
H Br H
+
HOC(CH3)3
HBr minor (least substituted) HBr Major (most substituted)
+ HOC(CH3)3
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Assignment 6 - ANSWERS
HOCH3 e) Br H + H Br + HOCH3 HOCH3 + HBr minor (least substituted) + HBr major (most substituted) + HBr major (most substituted)
+ HOCH3 H
f)
Br
HOCH3
H Br + HOCH3
+ HBr major (most substituted)
+ HOCH3 H
+ HBr
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Assignment 6 - ANSWERS 7) When 1-bromomethylcylcohexene is heated in ethanol, three products are observed. Give mechanisms to account for each product.
Br ethanol heat + OCH2CH3 + OCH2CH3
Br
resonance hybrid HOCH2CH3 OCH2CH3 + H2OCH2CH3
OCH2CH3 H HOCH2CH3 + H2OCH2CH3
H
HOCH2CH3 HOCH2CH3 OCH2CH3 H HOCH2CH3 + H2OCH2CH3 OCH2CH3
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Assignment 6 - ANSWERS 8) a) Design an alkyl halide that will give only 2, 4-diphenyl-2-pentene upon treatment with potassium tert-butoxide (a strong hindered base).
Note: Cis/trans are still possible, but only one isomer will be obtained depending on the stereochemistry of the starting material (see parts below)
Br
placing the bromine at any other carbon is incorrect as this leads to 3 products
Br
+
+
b) What relative stereochemistry is required in your alkyl halide so that only the following stereoisomer of the product is formed?
H Br
Newman Projection
R H3C
H Ph
to get this projection, add H and Br antiperiplanar
R H Br
R H3C
H Ph
Br
note: Relative stereochemistry is important at all positions. verify by Newman projection
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Assignment 6 - ANSWERS 9) When 2-bromo-3-phenylbutane is treated with sodium methoxide, alkenes result in addition to the substitution product. a) Draw a mechanism for the reaction showing the major and minor products. Clearly indicate the source of each product (mechanism)
Br + OCH3 OCH3
2-bromo-3-phenylbutane Br H + OCH3
Br
H + OCH3 or stereochemistry will depend on the configuration of the starting material
b) When one pure diastereomer of the starting material reacts, one pure isomer of the major product results. Predict which diastereomer will produce the isomer that has the methyl groups cis.
Br H + OCH3
Look at the Newman Projection add H and Br antiperiplanar Ph H CH3 CH3 product
Br Ph H
Br CH3 H CH3 starting material
c) Draw a Newman projection of the transition state to justify your choice in part b. see above d) Draw a Newman projection of the transition state to show the formation of the trans isomer from the other diastereomer.
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Assignment 6 - ANSWERS
Br H + OCH3
Look at the Newman Projection add H and Br antiperiplanar Ph H3C CH3 H product
Br Ph H3C
Br CH3 H H starting material
e) Predict the stereochemistry of the product produced from the enantiomer of part b. The enantiomer of the material in part b will give the same alkene. Remember that enantiomers have identical properties except their interaction with plane polarized light and their reactivity other with chiral compounds.
Br NaOMe
Ph H
Br CH3 H CH3 Ph H CH3 CH3
Br NaOMe
H3C H3C
Br Ph H H H3C H3C Ph H
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Assignment 6 - ANSWERS 10) Some of the following can exist as stereoisomers and some cannot. For the ones that can, draw the isomers and assign names.
a) 2-bromo-3-chloro-2-pentene Br Br Cl E b) 3-ethylhexa-2,4-diene Z Cl
2E-4E c)
2E-4Z
2Z-4Z
2Z-4E
2-bromo-3-methyl-2-butene
Br d) 1,3-pentadiene
e)
E Z 4-tert-butyl-5-methyl-4-octene
Z f) 3, 7-dichloroocta-2,5-diene 2Z-5E-7S Cl Cl 2E-5E-7S Cl only Z possible Cl
E 2Z-5Z-7R Cl 2Z-5E-7R Cl 2E-5E-7R Cl Cl 2Z-5Z-7S Cl
Cl
Cl Cl
Cl g)
Cl
Cl 2E-5Z-7R
Cl 2E-5Z-7S
cyclohexene
h)
Z
E
cyclodecene
i) E, Z E,E Z,Z cyclodeca1,5-diene
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Assignment 6 - ANSWERS 11) Explain why a strong base such as tert-butoxide cannot dehydrate an alcohol through an E2 mechanism. What can be done to the alcohol to dehydrate it (give 2 methods)? The strong base removes the hydrogen from the hydroxyl group making a terrible leaving group. To dehydrate the alcohol, use acidic conditions or convert the alcohol to a sulfonyl ester.
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Assignment 6 - ANSWERS 12) Predict the elimination products that result when the following are heated in alcoholic KOH. When more than one product is possible, predict the relative amounts.
a) Br KOH Br 3 b) Br KOH Br 3 c) Cl 1 = major 3 = minor 1 2 4 1 = major 4 = minor 1 2
Cl Cl + H H H's antiperiplanar to Cl major minor
d) Cl
(Hint: for parts c and d build models)
Cl Cl H H OCH3 this hydrogen is antiperiplanar to the Cl, can get E2 reaction this hydrogen is not antiperiplanar to the Cl, cannot get E2 reaction
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Assignment 6 - ANSWERS 13) Explain the difference in the following reactions.
Br + NaOH CH3CH2OH OH (1)
Br
+
NaSH
CH3CH2OH
S
(2)
sulfur is a much better electron donor than oxygen is (lower in the periodic table). Therefore it is a much better nucleophile. The product of the first displacement in reaction 2 is still a very good nucleophile and can do a second reaction. The product of the first reaction can do a second displacement, but it will happen much slower (ROH now more hindered than OH-).
Br
+
SH
CH3CH2OH
SH
SH S Br + S
14) Give the major product of the following reactions. Include a mechanism for each, and name the type of reaction (SN1, SN2, E1 or E2).
a) Br Br + + KOH OH SN2 b) Br Br + + I SN2 Br Br CH3CH2OH H N KI DMF DMF OH
I
c)
+ +
NH3 NH3
H
SN2
NH3
NH2 d) H Br + OC(CH3)3 E2 Br + NaOC(CH3)3 HOC(CH3)3
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Assignment 6 - ANSWERS
Cl HOC(CH3)3
e)
+
NaOC(CH3)3
H Cl + OC(CH3)3 E2
f)
F
+
KI
DMF
no reaction
g)
I
+
NH3
NH3
I
+
NH3
H H2N
NH3
SN2 NH2 NH2
h) Br
+
CH3CH2OH
Br
CH3CH2OH
O H CH3CH2OH SN1
O
OSO2CF3 + NaOCH3
i)
HOCH3
OSO2CF3 OCH3 H major E2
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Assignment 6 - ANSWERS 15) For each of the following reactions, indicate if the reaction will work well, poorly or not at all. Give mechanisms and brief justifications.
Br a) Br + OH DMF + NaOH DMF OH OH
work well - good nucleophile and leaving group, dipolar aprotic solvent CH3OH
b)
Cl
+
O
Cl
+
CH3OH O H
-H O
work poorly. Uncharged nucleophile, no strong base leaving group is not the best CH3OH I c) I + CN + NaCN DMF
CN
CN
work well - good nucleophile and leaving group, dipolar aprotic solvent HOC(CH3)3 d) O CH3 S OO OH O
O
O S H OO work well - intramolecular reaction (nucleophile and alpha carbon on same molecule)
CH3
OH
OH
HOC(CH3)3
e)
Br
+
NaSCH3
HOC(CH3)3
S
Br
+
SCH3
HOC(CH3)3
S
will work - good nucleophile and leaving group however the electrophile is hindered and the solvent is protic.
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Assignment 6 - ANSWERS
f)
O
+
DMF CH3I
O
O
+
H3C I
O
will not work - the nucleophile is poor HOC(CH3)3 g) Cl + KOC(CH3)3
HOC(CH3)3 + Cl H OC(CH3)3 will work well - strong hindered base
16) Propose syntheses of the following molecules from the indicated starting materials. You may use any reagents or solvents needed. Give mechanisms for all transformations. Provide a retrosynthetic analysis for each.
a) O Retrosynthesis O OR OR = good leaving group from OH and HO
O
OH Synthesis
+ ClO2S
OH
+ Cl
base S OO
H O
S OO
base
O
S OO
O
O
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Assignment 6 - ANSWERS
OH b) Retrosynthesis X H Synthesis OH H2SO4 H OH2 H base: (such as solvent or HSO4-) from
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Assignment 6 - ANSWERS
c) S S Retrosynthesis S S Synthesis Br SNa HS Br + Br d) SNa from CH3NH2 S S SH SH Na2S S SH Br From Na2S Br S SH Br Na2S S S Br S S X S S X from 1, 3-dibromopropane X SH S X
X
X SH
NCH3 Retrosynthesis
X NCH3 Synthesis Br NH2CH3 Br Br NHCH3 H NH2CH3 NHCH3 X
X NH2CH3
Br NHCH3 NCH3 H
NH2CH3
NCH3
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Assignment 6 - ANSWERS
CF3 e) Retrosynthesis CF3 CF3 H Synthesis HO CF3 H H2O H H2SO4 CF3 H CF3 H B (such as HSO4- or solvent) f) Retrosynthesis from any non-alkene (the Ph is not considered an alkene) X H CF3 HO CF3 H
from any alcohol
Synthesis Br NaOC(CH3)3 H Br Bonus: The required stereochemistry is:
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Assignment 6 - ANSWERS 17) Draw mechanisms and energy diagrams for the following reactions.
a) (CH 3 )3 CCl + CH3 NH 2
Cl
NH2
-H NH2 H NH 2
NH 2
E
Cl NH3 NH2
reaction co-ordinate
24
Assignment 6 - ANSWERS
b) (CH3)2CHCH2Br + Br KOH
OH
OH
E Br
OH OH
reaction co-ordinate
25
Assignment 6 - ANSWERS
heat B (Such as solvent) O
c)
BrCH2CH2CH2CH2OH
BrCH2CH2CH2CH2OH
H O
E H O
O
BrCH2CH2CH2CH2OH
reaction co-ordinate
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Assignment 6 - ANSWERS 18) Explain the following result:
NaOCH2 CH 3 D Br D
NaOCH2 CH 3 D Br Note: D = deuterium, an isotope of hydrogen Hint: build models Chair inversion is impossible for this molecule (check with a model). The reaction is E2 Br D H Antiperiplanar elimination requires that the H is removed. OCH2CH3 D
Br H D Antiperiplanar elimination requires that the D is removed. OCH3CH4 H
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