Chem 634 Spring 2015
Introduction and Background
Prof. Mary Watson
Assistant Professor
Adapted from Prof. Don Watson’s Notes
Announcements
Syllabus
Chemistry 634: Advanced Organic Chemistry – Synthesis and Reactivity
Fall 2015, University of Delaware
Lecture: Tuesday and Thursday, 2–3:15p, 228 ALS
Office hour: Wednesdays, 10:30am–12noon, 237 BRL
Website: http://www.udel.edu/chem/mpwatson/mpwatson/Chem_634.html
Course Capture: All lectures will be recorded.
Link: https://udcapture.udel.edu/2015f/chem634-010/
Required Texts:
Strategic Applications of Names Reactions in Organic Synthesis. Kurti, L.; Czako, B.
Advanced Organic Chemistry, Part B: Reactions and Synthesis. Carey, F. A.; Sundberg, R. J.
Classics in Stereoselective Synthesis. Erick M. Carreira, Lisbet Kvaerno
The Art of Writing Reasonable Organic Reaction Mechanisms. Robert Grossman
Recommend Texts (Optional):
Advanced Organic Chemistry · Part A: Structure and Mechanisms Carey, F. A.; Sundberg, R. J.
March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Edition Smith,
M. B.; March, J.
I have requested that all three of these texts be on reserve in the Chemistry Library this
semester.
Additional Text Resources
Comprehensive Organic Transformations: A Guide to Functional Group
Preparations, 3rd Edition Larock, R. C.
Stereochemistry of Organic Compounds Eliel, E.; Wilel, S. H.
Protective Groups in Organic Synthesis, 4th Ed, Greene and Wuts
Transition Metals in the Synthesis if Complex Organic Molecules, 3rd Ed,
Hegedus, L. S.
The Logic of Chemical Synthesis, Corey, E. J.; Cheng, X.
I have requested that all these texts be on reserve in the Chemistry Library this
semester.
Model Kit
REQUIRED!
I do not care what model kit you have.
HGS Models – Nice but expensive
Darling – okay at best, but cheap
Grading
Midterm 1 (10/15)
Midterm 2 (11/17)
Proposal (10/6) OR Presentation (Sat, 12/5)
Problem Sets
Final Exam (TBA)
Total
200 points
200 points
150 points
150 points
300 points
1000 points
All requests for regrades must be submitted in writing at the
beginning of the lecture after the material is returned. Please
note, the entire exam will be regraded – if grading errors are
found the final grades may be higher or lower than original score.
Also note, photocopies may be made prior to returning exams.
Problem Sets/Exams
Five Problems Sets
15% of grade
Will likely only pick one or two problems to grade – see syllabus for details.
You may work with others, but each student must turn in his/her own work.
DO NOT USE DATABASES TO ANSWER
QUESTIONS UNLESS ASKED TO DO SO
Three Exams
2 midterms in class – Oct 15 and Nov 17
each 20% of grade
Final exam – 3 hours, time TBD.
30% of grade
Closed book (but you can use your models)
Proposal or Presentation
You may either write an independent research proposal or give a presentation.
15% of grade
Proposal: You are required to prepare a 2-page proposal for an NSF
Predoctoral Graduate Fellowship (more details coming soon).
Proposals due to Mary on Oct 6!
Proposals due to NSF on Oct 30.
I will get you feedback on your proposals in advance of the NSF deadline, so
you can submit your work for real funding!
Proposal or Presentation
Presentation: You will give a brief presentation to class on a recently
developed organic method (more details coming soon).
Papers must be chosen by Nov 5.
Presentations will be on SATURDAY, Dec 5th from 9am – 3pm (or earlier).
Everyone must attend the presentation (even if you do a proposal).
If you can not attend on Sat, Dec 5, I need to know by the end of this
week.
Topic sign-up list will be by my office door (237 BRL) soon.
First come, first serve.
Computer Lab
On Sept 15th, we will meet in 221 BRL to learn to use
computer databases in computer lab.
Academic Dishonesty
Don’t cheat.
Don’t plagiarize.
Why Organic Synthesis?
•
•
•
•
•
•
•
•
•
Pharmaceuticals and Medicines
Biology and Biological Probes
Electronics
Bioconjugation - for proteomics
Mechanism Questions
Inorganic Chem – ligands
Polymers & Materials
Agrochemicals
Energy Problems
All require complex organic molecules.
What is a complex molecule?
N N
N
N
Me
Me
Me
O
O
Unnatural
OEt
H2N
NH2
(Xanax-Upjohn)
Alprazolam
(anxiety)
Me OH
H
(Tamiflu- Gilead)
Oseltamin
O
H
O
O
H
Me
Natural
HO H
O
HO
H
O
testosterone
O
OH
O
O H
ginkgolide B
(EJ Corey, 1967, 31 steps)
What Defines Complexity?
EJ Corey, Harvard University
1990 Nobel Prize In Chemistry
•  size
•  topology
•  functional groups
•  atom content
•  stereochemistry
•  functional
•  group density
•  stability/reactivity
Principle of Synthesis
Molecules are made from other molecules
(occasionally with the use of elemental reagents)
O
O
H2N
NH2
OEt OEt
O
O
Me Me
heat
HN
NH
O
O
Me Me
C8H12N2O3
Barbital (early drug)
Bayer, 1904
(Emil Fisher)
This means we need to know how molecules react
so we can predict how they will go together.
General Considerations In Synthetic Routes
1)  Yield:
Consider a three step sequence:
A
B
C
If average yield is 90%, what is the overall yield?
0.9 X 0.9 X 0.9 = 0.73
73% overall yield => 1/4 of the material is lost
If 70% (more realistic), you will get 34% overall yield, 2/3 lost.
General Considerations In Synthetic Routes
2) Length
15 steps at 70% = 0.47% overall (999/1000 SM lost)
Means that you need to start with 1000 times
the material you need!
Also, in lab: Each step is 2-4 weeks (minimum)
sometimes years
Longer if new
General Considerations In Synthetic Routes
3) Convergence
Consider:
A
B
D
C
E
F
5 steps @ 70% = 17%
Now Consider:
A
B
C
longest sequence now 3 steps
D
E
G
70% average per step is 34% yield
C+G
F
2X material
then
General Considerations In Synthetic Routes
4) Selectivity (many types)
Chemoselectivity (which group)
O
O
+
Me
Me
vs.
O
Me
Favored
has 2 pi bonds
General Considerations In Synthetic Routes
4) Selectivity (many types)
Regioselectivity (which site)
O
O
O
+
Me
Me
vs. Me
Me
Me
Favored
regioisomers
Me
General Considerations In Synthetic Routes
4) Selectivity (many types)
Diastereoselectivity (which diastereomer)
Me
+
Me
O
Me
O
Me
Me
O
vs.
exo
Me
endo
Favored
diasteromers
General Considerations In Synthetic Routes
4) Selectivity (many types)
Enantioselectivity (which enantiomer)
Me
+
Me
O
Me
Me
O
Me
vs.
enantiomers
O
Me
General Considerations In Synthetic Routes
5) Precedent
What is known in the literature and how close is the
analogy to the reaction you want to do?
1 hour in library = 1 month in lab
Exact precedent vs. Close precedent
If close, consider FG, ring size,
substituents, stereochemistry.
ALL can affect outcome!
General Considerations In Synthetic Routes
5) Other Factors
waste stream, cost, toxicity, contaminates, safety,
scale, starting material availability, intellectual property issues, etc.
Retrosynthetic Analysis
Molecules can be complex. A rational approach is required to prepare them.
Retrosynthetic analysis is used to plan routes to target molecules.
Focus of Chem 635, but we need rudimentary understanding here.
Earliest Example
Me
"disconnection
arrow"
O
N
O
tropinone
CO2H
H
+ MeNH2 +
H
2 CO2
2 H2O
O
O
CO2H
Sir Robert Robinson
"imaginary hydrolysis”
Now called disconnection: means to work backwards
Robinson JACS 1917, 111, 762
References
Robinson JACS 1917, 111, 762
Author Journal, Year, volume, page
JACS = J. Am. Chem. Soc. = Journal of the American Chemical Society
“Retrosynthetic Analysis”
E.J. Corey
Harvard University
Nobel Prize 1990
"Retrosynthetic analysis" - 1960’s
codified strategy to “disconnecting” a target
back to starting materials
work backwards approach
very successful way to think about how to
prepare molecules
Retrosynthesis 101
1) maximize convergence
2) minimize steps
a) look at multiple routes
b) avoid functional group interconversion (FGI) & protecting groups
when possible
3) add FGs if they can help
4) C–X & C–CX bonds are usually good disconnections
5) disconnect stereocenters when possible (clear them)
Retrosynthesis 101
6) minimize medium & large rings (or have a really good plan)
O
Me
Michael
O
O
H
Wieland-Miescher Ketone
H2
or H-
poor: 10 membered ring
Functional Group Addition
(FGA)
O
Me
O
O
Me
aldol
base O
O
Me
O
Me
Robinson Annulation
O
Michael
base
O
Me
+
Me O
Retrosynthesis 101
6) minimize medium & large rings (or have a really good plan)
O
O
O
O
Me
Me
OH
Me
PO
Me
Me
PO
Me
(± periplanone B)
WC Still JACS, 1979, 101, 2493
Retrosynthesis 101
7) disconnect unstable groups early
O
OH
N
O
O
N
H
O
Me3Si
Indolizomycin
unstable at pH 7, rt
FGI
O
H
O
N
TEOC
H
N
H
MeO
Me
Me
Note: the molecule requires medium ring
disconnection! Needed a good plan.
Cl
O
Me3Si
O
Danishefsky (Columbia)
JACS, 1990, 112, 2003
Retrosynthesis 101
8) Recognize embedded symmetry
Me
Me
O
O
O
H
O
O
(±) carpanone
O
[4+2]
Me
Me
O
O
O
O
=
O
O
Me
Me
O
O
2 steps
O
O
O
O
O
O
OH
O.L Chapman
JACS, 1971, 93, 6696
Retrosynthesis 101
9) identify embedded "complex" molecules
H
Me
Me
Me
N
H
N C
Me
Me
H
Me
Me
Me
=
O
O
Me
Me
Ambiguine
O
Me
(S)-carvone
(S)-carvone comes from caraway seeds.
Obtaining chiral centers from readily available natural product starting
materials is often called "chiral pool” strategy.
Baran (Scripps), Nature, 2007, 446, 404
Retrosynthesis 101
10) use topology (shape) of molecule to guide disconnections
HO
OMe
OH
O
NMe
FGI/FGA
O OH
H
=
MeN
O
MeN
H
H
HO
(–) morphine
Heck
Pd
I
tandem
reaction
H
MeO
I
OH
OH
MeN
OH
OMe
OMe
MeN
H
=
NP
Pd-π-allyl
Build Models!!!!!
Overman (Irvine)
Pure & Applied Chem 1994, 66, 1423
Mechanism & Arrow Pushing
Mechanistic understanding is critical for synthesis.
Mechanisms are represented using “arrow pushing.”
Arrow pushing =
•  Accounting for electrons (and keeping track of where they start and
end)
•  Represents our understanding of how Frontier Molecular Orbitals
(FMOs) interact.
HOMO (filled) + LUMO (unfilled) = New Bond
geometrical/spatial
overlap
E
ΔE
EA – EB
ΔE
∝ orbital overlap
EA – EB
If closer in energy,
then more stability
by forming a
covalent bond.
Frontier Molecular Orbitals (FMOs)
=
π∗
antibonding
E
nonbonding level
π
=
H2C CH2
sp2
sp2
bonding
Frontier Molecular Orbitals (FMOs)
=
π∗
=
π∗
E
π
=
π
H2C CH2
sp2
sp2
H2C O
sp2
sp2
•  Ethylene (H2C=CH2) has a higher HOMO => Better Nucleophile
•  Formaldehyde (H2C=O) has a lower LUMO => Better Electrophile
oxygen is more
electronegative
than carbon…
lower 2p orbital
& asymmetric
π orbitals
worse energy
overlap => less
stabilization by
forming a bond (but
still pretty good)
Frontier Molecular Orbitals (FMOs)
H2C CH2
+
Br
Br Br
+
H3CO
σ∗
Br–Br
Br
σ∗Br–Br
O
H
H2C CH2
Br
H3CO
H
O
H
H
π∗
E
H3C O
π
H2C CH2
lpo
H2C O
lpo (sp3)
Frontier Molecular Orbitals (FMOs)
Points to Remember:
(1)  Consider the geometry of the orbitals relative to the molecule.
O
π*C=O is perpendicular to bonds in carbonyls
(2) If 2 atoms are different, the coefficients will not be the same.
(a) In HOMO, larger coefficient on more electronegative atom.
(b) In LUMO, larger coefficient on less electronegative atom.
(3) Substituent effects
(4) Use Huckel MO when considering conjugated systems.
Arrow Pushing
My assumption is that you understand and can efficiently push arrows.
Mechanistic understanding is critical for understanding synthesis.
The 12-step guide to arrow pushing (adapted from Profs. Woerpel, NYU, and
Douglas, UM):
1)  Electrons flow from sites of high electron density (filled orbitals,
HOMOs) to sites of low electron density (unfilled orbitals, LUMOs).
Arrows represent this electron flow.
Remember: Push electrons, not charges!!
2)  Balance the equation. It helps. What are the byproducts?
3)  Don’t violate basic rules of physics.
a.  Converse mass and energy (see rule 2)
b.  Conserve charge
4)  Three Arrow Rule: Don’t push more than 3 arrows at one time
Arrow Pushing
5)  Draw out all intermediates.
a.  It may seem tedious at time, but it will avoid mistakes and often
reveal new insights.
b.  Draw out lone pairs and H’s on reacting atoms.
c.  3-D depictions may help. Use models if needed.
d.  Consider reaction conditions when drawing intermediates. No
carbocations under basic conditions and no anionic leaving groups
under acidic conditions.
6)  Use your lone pairs (often the site of FMO’s).
7)  All steps are, in principle, reversible.
8)  Contemplate your options and carry each to its conclusion before
discarding (this is seriously useful advice).
It can be helpful to star (*) intermediates where you made a choice.
Arrow Pushing
9)  The correct mechanism gives the observed product (should not be
taken to mean that all mechanisms that lead to the product are
necessarily correct).
10)  Use connectivity to tell you how the puzzle fits together… Make/
Break Table
a.  Number atoms logically
b.  “Principle of least action” usually holds.
11)  Always identify the nucleophiles and electrophiles at each step.
a.  At times it may be useful to substitute oxidants and reductants
above.
12)  Work backwards from the product to the likely precursors.