Chemistry 20
Weekly Review Lecture: Exam 2
Harvard University
March 25, 2016
2:30 – 4:30 Hall A
Office Hours
this Saturday 3/26
2:30 - 4:30
Science Center
room 102
Modules 4-6
Becoming a Synthesis Tiger: Always Know Your Options for Making C-C Bonds
Synthesis
Tiger
There is a reason there is a column on the reactions spreadsheet that says "new C-C bond?"
Be sure you know your current options for creating new carbon-carbon bonds, but especially make sure you can work
backwards to come up with sensible choices.
From the class reaction spreadsheet: current options for creating new C-C bonds:
3A NaCN + aldehyde/ketone
3A Grignard or organolithium with aldehyde/ketone
3A Grignard or organolithium with ester
3C
3C
3C
3C
1,4 addition to conjugated carbonyl: cyanide at 80° C
1,2 addition to conjugated carbonyl: cyanide at 0° C
1,2 addition to conjugated carbonyl: organolithium
1,4 addition to conjugated carbonyl: lithium dialkyl cuprate
4B SN2 depends on nucleophile (cyanide and acetylide anions)
5C epoxides with carbon nucleophiles (Grignard, acetylide anion, cyanide anion)
6C alkene with HCCl3, KOtBu (the carbene reaction)
6C alkene with CH2I2, Zn(Cu) (the Simmons-Smith reaction)
Propose three different combinations for creating this compound that involve carbon-carbon bond formation.
OH
Chem 20 Weekly Review Lecture: Exam 2
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Becoming a Synthesis Tiger: Acing Ethers - What You Need to Know
Synthesis
Tiger
Ideally students are getting the message that mastery of creating ethers is important. Because we have so many ways to create
ethers, and you really need to know the capabilities and limitations of the different reactions involved, it is a no-brainer to test
students on ether synthesis.
Ethers result when the oxygen of an alcohol links on to a carbon. Techniques used to synthesize ethers include:
o SN2 using alkoxide as the nucleophile - the Williamson ether synthesis
o Alkene + alcohol using the Hg(OAc)2 reagent (oxymercuration/demurcuration reaction) avoids carbocation
o Alkene + alcohol with acid catalyst (the superior carbocation option)
o SN1 using alcohol as the nucleophile (the inferior carbocation option)
o Alkene + Br2 (or Cl2) and alcohol will make a vicinal halo-ether where the ether ends up on whichever half of the alkene would have
been the better carbocation
The key to to synthesizing ether correctly comes down to considering that final connection to form the ether. When deciding how to
make this happen, look at the two carbons sandwiching the oxygen; in most cases (but not all), the best carbon electrophile to
connect to follows this order:
o Allylic or benzylic carbon
o Tertiary
o Methyl
o Primary
o Secondary without resonance - a good choice for using the Hg(OAc)2 reagent.
o *Benzene carbon
*Do NOT try to make a connection to an sp2 carbon UNLESS you are doing nucleophilic aromatic substitution via the addition-elimination pathway (SNAr pathway).
We will deal with that in module 9.
Chem 20 Weekly Review Lecture: Exam 2
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Becoming a Synthesis Tiger: Acing Ethers - Applied Practice
Synthesis
Tiger
Propose reactions that would create these ethers.
O
O
O
Chem 20 Weekly Review Lecture: Exam 2
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Chairs and Stereochemistry: Two Concepts that Like to Piggy-Back
Consider the compound 2,6-dimethylcyclohexanol:
OH
H3C
CH3
(a) Propose all the unique stereoisomers. Points will be lost for repeat compounds.
(b) Indicate which are chiral and which are achiral.
(c) Draw each stereoisomer in their most stable chair conformation.
(d) Rank the chairs in order of stability.
Chem 20 Weekly Review Lecture: Exam 2
2,6-dimethylcyclohexanol
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Cyclohexane - a Treasure Trove of Possibility (part 1)!
Cyclohexane lends itself so well to exam problems that combine many concepts.
(a) The following transformation can be accomplished in two steps. Provided the reagents necessary to make this happen.
Br
O
Br
1.
2.
Br
Compound JL
O
one of the stereoisomers
that will form
(b) Provide a one or two-sentence explanation for why the alkenes react in the order that they do. Your answer should NOT be
discussing sterics.
Chem 20 Weekly Review Lecture: Exam 2
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Cyclohexane - a Treasure Trove of Possibility (part 2)!
(c) Using the Cahn-Ingold-Prelog convention, assign all stereocenters as either (R) or (S) to compound JL. Then draw the enantiomer of
compound JL and indicate if it will form in this reaction.
O
Will the enantiomer of
compound JL be one of
the stereoisomers that
forms in this reaction?
Br
Br
1.
O
2.
Br
from part (a)
YES
Assign (R) or (S) to the
stereocenters of compound JL.
Draw the enantiomer
of compound JL.
NO
Circle one of the above.
(d) Add substituents to the two chair conformations provided. Indicate which chair is lower in energy and why.
Br
Br
O
O
O
Br
compound JL
Chem 20 Weekly Review Lecture: Exam 2
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Cyclohexane - a Treasure Trove of Possibility (part 3)!
(a) Propose a mechanism for the following transformation. Name all the functional groups involved in the starting compound and the
product.
O
OH
HO
O
H+ catalyst
O
(b) When monosaccharides cyclize, they create an equilibrium of two stereoisomers that are known as anomers. Anomers exist in what is
called an form and a form, and this distinction in nomenclature is partially based on the stereochemistry at what is called the
anomeric carbon. The ability to switch between the two stereoisomers is a phenomenon known as mutarotation.
Mutarotation
CH2OH
HO
anomeric
carbon
O
CH2OH
H2O
OH
O
OH
H2O
HO
HO
anomeric
carbon
O
H
HO
OH
OH
HO
OH
OH
D-glucose (36%)
OH
open-chain D-glucose (0.02%)
D-glucose has a melting point of 146° C. Will the melting point of
Chem 20 Weekly Review Lecture: Exam 2
OH
D-glucose (64%)
D-glucose be the same or different? Explain.
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Cyclohexane - a Treasure Trove of Possibility (part 4)!
(c)
D-glucose and D-idose are shown below. Using the templates provided, draw both of these monosaccharide pyranoses in their
chair conformations.
CH2OH
HO
O
O
HO
CH2OH
OH
O
O
HO
OH
D-glucose
HO
OH
OH
D-glucose chair
D-idose
D-idose chair
(d) When a pyranose is in the chair conformation, the CH2OH group and the anomeric carbon can react as in part (a) to form what is called
the anhydro form of the sugar. (It has lost water.) In an aqueous solution at 100 °C, about 80% of D-idose exists in the anhydro form.
Under the same conditions, only about 0.1% of D-glucose exists in the anhydro form. Draw the structures of the anhydro forms of both
D-glucose and D-idose and explain the percentage disparity between them.
Chem 20 Weekly Review Lecture: Exam 2
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Anomeric Effect Factors (the ALPH*): Going Beyond the Overlap
*ALPH: antiperiplanar lone-pair hypothesis
There is more to the anomeric effect than just drawing orbitals in proper alignment.
For both compounds F and Cl, the favored conformation is on the left. However, compound F has a higher preference for the
conformation on the left. Give two reasons for this observation: one steric, and one electronic.
F
compound F
F
O
O
Cl
compound Cl
Cl
O
Chem 20 Weekly Review Lecture: Exam 2
O
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Anomeric Effect Factors (the ALPH): Going Beyond the Overlap
You have recently learned that peroxides are an unstable functional group; however, the bis-peroxide below is much more stable than
the typical peroxide.
Disregarding interactions with C-H, each oxygen in the bis-peroxide shown below contributes to two different orbital interactions.
On the templates provided, show just one unique orbital interaction on each of the diagrams and indicate which interaction is
stronger. Include a brief explanation for your choice of which interaction is stronger and which is weaker.
O
O
O
O
O
O
O
O
O
O
O
O
a bis-peroxide
Chem 20 Weekly Review Lecture: Exam 2
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E2 and the Chair: Need to Know Your Anti-periplanar Overlap
Circle the major product(s) for the following E2 eliminations. Circle both products if they will be formed in equal amounts or neither if the
reaction will not proceed as shown. Provide a brief explanation for your answer.
H
H
Br
H
Br
t-BuOK
+
(E2)
Br
Br
H
Cl
H
CH3
t-BuOK
Cl
H
CH3
CH3
+
Cl
CD3
Chem 20 Weekly Review Lecture: Exam 2
(E2)
CD3
Cl
CD3
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Anti-Periplanar is Everywhere (part 1)!
When Compound A is subjected to sodium hydride (NaH), a reaction known as the Grob fragmentation occurs.
The Grob Fragmenation
H
OTs
H
NaH
MeO
H
O
MeO
HO
H
O
O
Compound A
Provide a complete curved-arrow mechanism for this transformation.
Chem 20 Weekly Review Lecture: Exam 2
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Anti-Periplanar is Everywhere (part 2)!
A conformationally-accurate depiction of Compound A is provided here for your convenience. Additionally, Compound D is a
diastereomer of Compound A.
H
H
MeO
O
MeO
O
MeO
HO
Compound A
H
H
OTs
H
OTs
H
H
OH
OTs
H
O
HO
Compound D
Compound A
Use the conformationally-accurate structure above to explain why Compound A undergoes the Grob fragmentation but Compound D, a
diastereomer of Compound A, does not undergo a Grob fragmentation.
Chem 20 Weekly Review Lecture: Exam 2
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Solving Elimination Problems: Must Consider the Limitations of the Reactions
Starting with an alcohol, propose a synthesis involving an elimination reaction that could produce this alkene as the major product. And
while we're here, name this alkene!
IUPAC Name of this Alkene:
synthesis involves
An alcohol
doing elimination
Chem 20 Weekly Review Lecture: Exam 2
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Mechanisms 1: Expanding on the General Principles
It is typical for exam mechanisms to involve taking a concept you should know, and doing it one level higher.
Suggest a mechanism for the formation of this cyclopropane.
Cl
Chem 20 Weekly Review Lecture: Exam 2
KOtBu
+
OH
OH
C
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Mechanisms 2: Handling Bicycles and Rearrangements
Provide a complete curved-arrow mechanism for the following carbocation-based transformation. Clearly show the stereochemistry of
all intermediates.
H3O+
HO
O
HO
Chem 20 Weekly Review Lecture: Exam 2
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Mechanisms 3: The Final Product is Always Your Guide
Provide a complete curved-arrow mechanism for the following carbocation-based transformation. Clearly show the stereochemistry of
all intermediates.
Et
O
OH
H3O+
Et
O
OH
Chem 20 Weekly Review Lecture: Exam 2
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Mechanisms 4: Big Picture Understanding is Crucial
It is more important to understand HOW a pi-bond is formed versus just memorizing E1 and E2 mechanisms. A pi-bond forms when the
electrons from one atom move towards the atom next door. In E1, this happens when the beta-hydrogen is removed and the electrons
from that C-H bond move towards the carbocation. In E2, these electrons move towards the C-LG (leaving group) anti-bonding orbital.
But there can be electrons from atoms other than hydrogen.
Provide a curved-arrow mechanism.
O
H3O+
H
O
Chem 20 Weekly Review Lecture: Exam 2
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