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Chemistry E-17

Review Lecture, Week 4

Brandon Conley
Harvard Extension School
October 2, 2017

Copyright 2017, President and Fellows of Harvard University


More Course Logistics
Brandon’s Weekly Office Hours:*
(In-person)
Mondays 7:30-8:30 pm (right after review)
Office: Science Center 116D

(Online/Virtual)
Tuesdays 4-5 pm EST (Zoom)

*office hours extended on exam weeks – stay tuned for announcements!

Problem Set 4 due Thursday, 10/5/2017 at 6 pm!


Submission may be hardcopy (TF mailboxes, 2nd floor of Science Center) or
electronic (annotated PDF or legible scan uploaded to Canvas)
Organic Synthesis
chopped onions, chopped ginger,
chopped tomatoes, yogurt, ground
1. 0.125 equiv. dried cardamom, ground coriander, ghee,
red beans, H2O, kosher salt, cayenne pepper
Dried Intermediate A Intermediate B
black lentils
2. 100 °C rt, 2 hrs H2O, reflux, 5 hrs
1. onion-cumin
tadka

2. scant heavy
cream, chopped
cilantro

Dinner
Organic Synthesis
Learning Reactions
• Focus first on a functional group. Can it act as a donor? With what orbitals?
Can it act as an acceptor? With what orbitals? Am I comfortable generalizing
this functional group in the context of larger structures?

H
Learning Reactions
• Focus next on transformations. What other functional groups can we prepare
starting from this functional group? Do we know any relevant oxidation and
reduction chemistry involving this functional group? Which mechanisms are
important for me to understand?
Learning Reactions
The Reaction Spreadsheet/Table/Chart

Starting Conditions/Reagents Product Mechanism Notes


Material
Aldehyde, 1. R’-MgBr, Et2O Secondary Irreversible Same reaction
2. H+ workup alcohol, nucleophilic as for addition
addition of MgC of R’-Li; must
to *CO always have
workup!
Conjugated 1. R-Li, Et2O Alcohol, Irreversible R-MgBr NOT
Carbonyl, 2. H+ workup tertiary or nucleophilic used for this
secondary addition of CLi transformation;
depending to *CO (“1,2- must always
on starting addition”) have workup!
carbonyl
Learning Reactions
The Reaction Web
Hydration of Ketones and
Aldehydes
The “Proof-of-Concept” Reaction
Hemiacetals & Acetals
Your carbonyl mechanism MVP!
O EtO OEt
EtOH

H+ cat.
Draw the starting materials and reagents necessary for preparation of each
of the compounds shown below.

5
O H+ cat. 1 O4 6
2 6
HO OH
4 2 O 7
1 3 5 7 3

Numbering carbons
is essential here!
What relevance do these have to learning how to solve organic synthesis
problems?

IDK
Provide the most appropriate reagent/conditions for accomplishing the
chemical transformation pictured below. No more than two steps will be
necessary. Briefly justify your decision.

O OH

MeO MeO

O O

Main issue: selectivity (which functional group is affected?)


Provide the most appropriate reagent/conditions for accomplishing the
chemical transformation pictured below. No more than two steps will be
necessary. Briefly justify your decision.

OH O

HO H

Main issue: extent of reaction (how far do we want the reaction to go?)
Provide the most appropriate reagent/conditions for accomplishing the
chemical transformation pictured below. No more than four steps will be
necessary. Briefly justify your decision.

O Ph OH

Main issue: order of operations (will earlier reactions influence the course of
subsequent reactions?)
Aside: More Adventures in Selectivity with Conjugated Carbonyls

Reduction:

NaBH4 O NaBH4, CeCl3 OH


HOT MESS
MeOH MeOH

1. LiAlH4, Et2O
2. H+ workup

not
reliable;
just don't

Organometallic Additions:

1. RMgBr, Et2O O 1. R2CuLi, Et2O O


HOT MESS
2. H+ workup 2. H+ workup R

1. RLi, Et2O
2. H+ workup

HO R
Recap: what relevance do these have to learning how to solve organic
synthesis problems?
Benadryl, a much older antihistamine, essentially “carpet-bombs” many types of receptors all over the
body indiscriminately, including in the CNS, which is why it has such a high incidence of side effects like
drowsiness, dry mouth, dry eye, etc. It is very nonselective. On the other hand, Zyrtec was designed to
be much more targeted and selective, which is why we don’t see patients experiencing the stereotypical
antihistamine side-effect profile on newer agents like Zyrtec and Allegra, which are more selective for
their receptor subtype.

The point is that whenever we can, we want to use selective and targeted reagents in preference to
perhaps stronger but nonselective ones!
Solving Organic Synthesis
Problems: Setup
Propose a reasonable synthetic pathway from the indicated starting materials to
the desired product below. You should need no more than seven synthetic steps
to complete this synthesis.
O Br Cl

H
Starting Materials

OH

Desired Product
Solving Organic Synthesis
Problems: Execution
Propose a reasonable synthetic pathway from the indicated starting materials to
the desired product below. You should need no more than seven synthetic steps
to complete this synthesis.
O Br Cl

H
Starting Materials

OH

Desired Product
Solving Organic Synthesis
Problems: Try This at Home!
Propose a reasonable synthetic pathway from the indicated starting materials to
the desired product below. You should need no more than five synthetic steps to
complete this synthesis.

OH
Br

Starting Materials

Mg
Br MgBr
Et2O
(making an organolithium would
also work perfectly well)

Desired Product
Supplement Slide*: Title Slide
Graphic
In case you’re wondering, the 3D molecule pictured on the title slide is a model
of camphor, a natural product with a characteristic fragrance.

Although it has few, if any, recognized medical or pharmaceutical applications,


camphor was one of the first organic compounds synthesized on a mass scale
starting in the early 1900s. Since then, its structural complexity and reliable
reactivity have made it a prototypical example of ketone reactivity and structural
selectivity in organic reactions at the carbonyl carbon.

*Content on Supplement Slides will not be tested explicitly on exams; however, it may help you gain a better
understanding of content that will be tested!