Chemistry 634: Advanced Organic Chemistry – Synthesis and Reactivity
Fall 2011, University of Delaware
Syllabus
Lecture: Tuesday and Thursday, 7-8:30 PM, Brown Lab (BRL) 207
Discussion Session (Required): Tuesday, 8:30-9:30 PM, Brown Lab (BRL) 207
Professor Donald A. Watson
205 Lammot duPont
302-831-8728
dawatson@udel.edu
Office hour: Friday 9-10am, LDL 205 or by appointment.
Website: http://www.udel.edu/chem/dawatson/classes/Chem634_F11/Chem634_F11-home.html
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.
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.
Classics in Stereoselective Synthesis
Erick M. Carreira, Lisbet Kvaerno
The following texts will also be on reserve in the Chemistry Library (and are good books to consider owning if
you plan to continue in synthetic organic chemistry).
Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition Larock, R. C.
Stereochemistry of Organic Compounds Eliel, E.; Wilel, S. H.
Protective Groups in Organic Synthesis, 4th Ed, Greene and Wuts
rd
Transition Metals in the Synthesis if Complex Organic Molecules, 3 Ed, Hegedus, L. S.
The Logic of Chemical Synthesis, Corey, E. J.; Cheng, X.
Model Kit (required):
I do not care which brand you buy, as long as it is of reasonable quality. If you are looking for recommendations,
here are two (also check with the bookstore, Amazon, or the like):
HGS 4010/Student Set – Expensive but very nice (they are a smaller set of the same models I use – I like them
because they are pretty rigid. Be warned, however, they tend to be fragile).
http://www.maruzen.info/hgs/catalog/product_info.php?cPath=11&products_id=596
Darling Models – Cheaper, but very floppy (which is not great for studying stereochemistry).
http://www.darlingmodels.com/item--KIT-1-ISBN-0-9648837-1-6-Plastic-Box-Organic-Inorganic-Organometallic-kit_1_plastic_student.html
Grading
Breakdown:
Midterm Exam 250 points, 25%
Final Exam 270 points, 27%
Final Project (Written) 150 points: 15%
Final Project (Presentation) 150 points: 15%
Problem Sets 180 points, 18%
Total: 1000 points
Approximate Class Outline (exact dates of topics may vary with class progress):
Week
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Finals
Date
Sept 1
Sept 6
Sept 8
Sept 13
Sept 15
Sept 20
Sept 22
Sept 27
Sept 29
Oct 4
Oct 6
Oct 11
Oct 13
Oct 18
Oct 20
Oct 25
Oct 27
Nov 1
Nov 3
Nov 8
Nov 10
Nov 15
Nov 17
Nov 22
Nov 24
Nov 29
Dec 1
Dec 3
Dec 6
TBD
Lecture
Lecture 1
Lecture 2
Lecture 3
Lecture 4
Lecture 5
Lecture 6
Lecture 7
Lecture 8
Lecture 9
Lecture 10
Lecture 11
Lecture 12
Lecture 11
Lecture 12
Topic
Notes
Reading
Introduction, Arrow Pushing, Mechanism
Nuc. Substitution Chemistry
PS 1 Due
CS-B 3.1-3.2
Carboxylate Chemistry
CS-B 3.4
Retrosynthesis, Route Planning
Corey Chs 1-6, handout
Electronic Databases and Searching the Literature
Meet in 221 BRL
Handout
Aromatic Sub. Chemistry
PS 2 Due
CS-B11.1-11.2
Transition Metal Catalyzed Cross Coupling Reactions
Heg Chs 1-2, CS-B 7.1, 8.2-8.3, 11.2-11.3
Alcohol/Ketone Oxidations
CS-B 12.1, 12.5, 12.7
C=X Reductions, Protecting Groups
CS-B 5.3, 5.6, 5.7, 3.5 and handout (CK 2)
Enolate Chemistry
PS 3 Due
CS-B 1 All
Enolate Chemistry
Aldol Reactions
CS-B 2 All; (CK 4)
Aldol Reactions
Addition of other carbon nuc. to carbonyls
(CK 5)
Midterm Exam
Midterm
Lecture 13
Alkene Synthesis and Reactivity
CS-B 2.4, 4, 5.1, 5.6 (CK 7,8,9)
Lecture 14
Alkene Oxidation
Lecture 15
Alkyne Synthesis
PS 4 Due
Lecture 16
C=C Reductions
Outlines Due
Lecture 17
Radical Chemistry
CS-B 10.3, CS-A 11
Lecture 18
Radical Chemistry
Lecture 19
Pericyclic Reactions
PS 5 Due
CS-B 6 (CK 16, 17, 18)
Lecture 20
Pericyclic Reactions
Lecture 21
Pericyclic Reactions
Term Paper Due
No Class
Thanksgiving
Lecture 22
Introduction to Organocatalysis
PS 6 Due
Lecture 23
Strained Rings
CS-B 12.2.1, 10.2 (CK 15)
Saturday
Student Presentations, 9a-2p
Presentations
Lecture 24
C–H and C–C Bond Activation, time allowing
(CK 15)
FINAL EXAM
Final
CS = Carey and Sundburg; CK = Carreira and Kvaerno; Heg = Hegedus and Soderberg; () = optional reading
Problem Sets:
There will be six problem sets assigned over this semester. They will total 30 points each. Problem sets will be
graded. In most cases, only representative problems, and not the entire problem set, will be graded. A key will be
posted each week and we will discuss the solutions after class on Tuesdays. You are responsible for making sure
that you understand the correct answers once the key is posted. You are free to work in study groups when working
on the problem sets, but each student must turn in their own work.
Do not use Beilstein, Scifinder or other search engines to look up answers on the homework unless specifically
asked. You will not have these tools when you take the exams (nor on interviews when you look for a job in a few
years), so you are best served by actually learning the material.
Problem sets will be due at the beginning of class on the day that is assigned. Late problem sets will not be
accepted as we may discuss the answers in class after it is due.
For problem sets, you will occasionally be asked to design synthetic routes to target compounds starting with
commercially available materials. For the purpose of this class, please limit these to chemicals that are listed in the
catalogs of Acros, Aldrich, Fisher, Strem, Alfa-Asear, or TCI. (These are the most common suppliers for academic
chemist).
Exams:
Exams will be closed book, closed note, and model set are not allowed. Exams will cover lecture material, problem
sets, assigned reading, as well as current literature discussed in class.
Final Project:
For the final project, students will be asked to review a method or topic from the current organic chemical literature.
A list of possible topics will be distributed early in the semester and students will be allowed to choose topics shortly
thereafter. The project will consist of two parts.
First, each student will write a 3-page review article covering the most important aspects and references from the
assigned topic. This should be a fairly broad summary of the area pertaining to the assigned paper, and not simply
a summary of the paper itself. This should be formatted as a JACS communication article. The reviews will be due
rd
in class on Nov. 22 . Please submit both a paper and electronic copy (via email). The reviews will be compiled and
disturbed to the class at the end of the semester.
th
Second, at the end of the semester, we will hold a mini-symposium on Saturday, Dec 3 from 9am-2pm. Each
student will present a 10-minute PowerPoint lecture in which they will teach the assigned topic to the class.
Regrades:
All requests for regrades must be submitted in writing within 24 hours of the material being 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. If answers are altered, it will be obvious and
provable (see below).
Learning Objectives:
After successful completion of this class, students should:*
1) Understand principles of retrosynthesis and be able to plan synthetic routes to complex organic molecules.
(1,2)
2) Understand absolute and relative molecular stereochemistry and its importance in synthetic chemistry. (1)
3) Understand the use, installation and removal of protecting groups in organic synthesis. (1)
4) Be familiar with the methods and reactivity associated with alkyl groups, carbonyl groups, enolates, alkene,
alkynes, amines, amides, esters, ethers, aromatic rings, and strained rings. (1)
5) Be familiar with nucleophilic substitution chemistry, radical chemistry, methods for oxidation and reduction,
elementary organometallic chemistry as it pertains to organic synthesis, pericyclic reactivity, asymmetric
catalysis, and functional group interconversion. (1)
6) Be familiar with uses and applications of major electronic databases used in organic chemistry. (3,5)
7) Be familiar with major journals and publications pertaining to synthetic organic chemistry. (3,5)
8) Organize and review chemical literature in a topic area and present in clear and concise written and oral
formats. (3,4,10)
Academic Dishonesty
Academic dishonesty will not be tolerated. Not only is such behavior unethical, but also cheating in this class will
result in you not learning material that will be critical to your chosen career path. Simply put, learn this material; you
will need it to be a functional synthetic chemist. Please review the University of Delaware’s Academic Dishonestly
Policy, which can be found at http://www.udel.edu/stuguide/09-10/code.html#honesty. On assigned problem sets,
study groups are allowed, but each person must turn in their own work.
Plagiarism is as using someone else’s words or ideas without acknowledgment and most often results uncited
quoting or paraphrasing. Plagiarism is a serious form of academic dishonesty. For the written review assignments
in this class, make sure to properly cite any sources. For more information, please see:
http://www.english.udel.edu/wc/student/handouts/plagiarism.html
*Parenthetical numbers correspond to departmental learning goals found at www.udel.edu/chem.goals.html.
Important Online Resources (Please see additional pdf handout).
UDel Chemistry Library Homepage: http://www2.lib.udel.edu/branches/chem.htm
Reaction and Structure Searching:
Scifinder: http://www2.lib.udel.edu/database/scifind.html
Reaxys: https://www.reaxys.com/reaxys/secured/start.do
Citation Searching:
Web of Science: http://apps.isiknowledge.com/
General Chemical Procedures:
Science of Synthesis: http://www.science-of-synthesis.com.proxy.nss.udel.edu/thiemechemistry/sos/prod/user/index.html
Listing of review articles complied by Phillip Kocienski (most useful with Endnote format):
Synthesis Reviews: http://www.thieme-chemistry.com/en/products/journals/supplements/synthesisreviews.html
Chemical Suppliers (maybe useful on problem sets):
Aldrich: http://www.sigmaaldrich.com/united-states.html
Acros: http://www.acros.com/
Mechanism and Synthesis
Understanding a reaction at a mechanistic level is necessary in order to be able to apply it to effect the desired
outcome. If you do not know how it works, you might not understand what can go wrong, or how to fix it when it
does. If you encounter a mechanism that you do not understand – take the time to work out a reasonable
mechanism. It is assumed that you are familiar with elementary arrow pushing and we will not be covering this in
class in any depth. For those that need a refresher, the following approach is very useful.
The 12-step guide to arrow pushing (adapted from Prof. Keith Woerpel, UC Irvine):
1) Electrons flow from sites of high electron density to sites of low electron density (show arrows accordingly).
2) Balance the equation. It helps.
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
5) Draw out all intermediates.
a. It may seem tedious at time, but it will avoid mistakes and often reveal new insights.
b. 3-D depictions may help. Use models if needed.
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).
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.
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.
Basic Guide to Retrosynthetic Analysis
1) Maximize convergence
2) Minimize steps by exploring multiple options before deciding on a plan (avoid FGI and protecting groups, if
possible)
3) Add functional groups if they can lead to a simplifying disconnection
4) Disconnect stereocenters (clear stereocenters) where possible
5) C-C and C-CX bonds usually make good disconnections
6) Minimize medium and large rings formation
7) Disconnect unstable functional groups early in retrosynthesis
8) Recognize embedded symmetry
9) ID embedded complex molecules (particularly chiral pool)
10) Use topology to your advantage (particularly in caged molecules, make a model before starting)