Gives an introduction to total synthesis and why we do it (which reminds me, I must add a picture of Everest, as I think the fact that 'it is there' is the main reason for most syntheses). Then to introduce the topic with a reasonably simple synthesis, we will look at an example of the synthesis of Tamiflu.
This is the biggy, the one everyone wants to achieve. Here we will be looking at metal-based chiral catalysis. We will concentrate on bisoxazoline-based Lewis acid catalysis and then look at reductions before finishing with the ubiquitous Sharpless epoxidation and dihydroxylation.
Self explanatory really, this lecture looks at chiral auxiliaries. We will concentrate on oxazolidinones in alkylations, aldol reaction and the Diels-Alder reaction. There will be a couple examples of other auxiliaries.
General introduction to the course followed by a basic introduction to asymmetric or stereoselective Synthesis. Then starting the course proper by looking at substrate control.
The big topic of the last few years, the use of small organic molecules to catalyse enantioselective transformations. This lecture will start with proline before moving on to some of MacMillan's contributions to this field and, finally, finish with hydrogen bond catalysts and Brønsted acids.
A look at epothilone A as it includes examples of many different forms of asymmetric synthesis. Also includes a little bit about ring-closing metathesis.
Gives an introduction to total synthesis and why we do it (which reminds me, I must add a picture of Everest, as I think the fact that 'it is there' is the main reason for most syntheses). Then to introduce the topic with a reasonably simple synthesis, we will look at an example of the synthesis of Tamiflu.
This is the biggy, the one everyone wants to achieve. Here we will be looking at metal-based chiral catalysis. We will concentrate on bisoxazoline-based Lewis acid catalysis and then look at reductions before finishing with the ubiquitous Sharpless epoxidation and dihydroxylation.
Self explanatory really, this lecture looks at chiral auxiliaries. We will concentrate on oxazolidinones in alkylations, aldol reaction and the Diels-Alder reaction. There will be a couple examples of other auxiliaries.
General introduction to the course followed by a basic introduction to asymmetric or stereoselective Synthesis. Then starting the course proper by looking at substrate control.
The big topic of the last few years, the use of small organic molecules to catalyse enantioselective transformations. This lecture will start with proline before moving on to some of MacMillan's contributions to this field and, finally, finish with hydrogen bond catalysts and Brønsted acids.
A look at epothilone A as it includes examples of many different forms of asymmetric synthesis. Also includes a little bit about ring-closing metathesis.
Use of stoichiometric amounts of a chiral source. The usual suspects will be discussed, including borane reagents (mostly pinene derivatives) and the Brown allylation.
123.713A/B. Description of the Jacobsen synthesis of muconin. This is an example of total synthesis, retrosynthesis and asymmetric synthesis and shows the kind of information required in the assigment for this course.
More problems covering asymmetric synthesis. This time with examples of substrate control, chiral reagents, and chiral catalysis. Also another example of a synthesis.
An introduction to total synthesis and retrosynthesis. A quick overview of retrosynthesis followed by one of the many syntheses of (–)-stenine. This is just an overview of the fascinating world of organic synthesis, it is not intended to teach retrosynthesis or organic synthesis. For that see some of my other lecture notes.
Chiral catalysis. This is a relatively brief look at some classic examples of chiral catalysis in organic synthesis. It gives a quick overview but does not go into any detail.
Organic chemistry has two main divisions. One division deals with aliphatic (fatty) compounds, the first compounds you encountered in Organic Chemistry I. The second division includes the aromatic (fragrant) compounds, of which benzene is a typical example.
Total synthesis of Sterpurenone New, Total Synthesis of (훽)-Cyperolone, Protecting Group-Free Total Synthesis of (−)-Lannotinidine B, Enantiospecific Total Synthesis of the (−)-Presilphiperfolan-8-ol, Enantioselective Total Synthesis of (−)-Pavidolide B, total synthesis of Eupalinilide E
Organic chemistry has two main divisions. One division deals with aliphatic (fatty) compounds, the first compounds you encountered in Organic Chemistry I. The second division includes the aromatic (fragrant) compounds, of which benzene is a typical example.
This is an experiment. It is NOT a presentation. It is meant to be an interactive pdf for students to work through/revise from at their own pace. For these features to operate I guess it needs to be downloaded first.
It is based on 123.312 lectures on retrosynthesis or the design of chemical syntheses.
Use of stoichiometric amounts of a chiral source. The usual suspects will be discussed, including borane reagents (mostly pinene derivatives) and the Brown allylation.
123.713A/B. Description of the Jacobsen synthesis of muconin. This is an example of total synthesis, retrosynthesis and asymmetric synthesis and shows the kind of information required in the assigment for this course.
More problems covering asymmetric synthesis. This time with examples of substrate control, chiral reagents, and chiral catalysis. Also another example of a synthesis.
An introduction to total synthesis and retrosynthesis. A quick overview of retrosynthesis followed by one of the many syntheses of (–)-stenine. This is just an overview of the fascinating world of organic synthesis, it is not intended to teach retrosynthesis or organic synthesis. For that see some of my other lecture notes.
Chiral catalysis. This is a relatively brief look at some classic examples of chiral catalysis in organic synthesis. It gives a quick overview but does not go into any detail.
Organic chemistry has two main divisions. One division deals with aliphatic (fatty) compounds, the first compounds you encountered in Organic Chemistry I. The second division includes the aromatic (fragrant) compounds, of which benzene is a typical example.
Total synthesis of Sterpurenone New, Total Synthesis of (훽)-Cyperolone, Protecting Group-Free Total Synthesis of (−)-Lannotinidine B, Enantiospecific Total Synthesis of the (−)-Presilphiperfolan-8-ol, Enantioselective Total Synthesis of (−)-Pavidolide B, total synthesis of Eupalinilide E
Organic chemistry has two main divisions. One division deals with aliphatic (fatty) compounds, the first compounds you encountered in Organic Chemistry I. The second division includes the aromatic (fragrant) compounds, of which benzene is a typical example.
This is an experiment. It is NOT a presentation. It is meant to be an interactive pdf for students to work through/revise from at their own pace. For these features to operate I guess it needs to be downloaded first.
It is based on 123.312 lectures on retrosynthesis or the design of chemical syntheses.
The big topic of the last few years, the use of small organic molecules to catalyse enantioselective transformations. This lecture will start with proline before moving on to some of MacMillan's contributions to this field and, finally, finish with hydrogen bond catalysts and Brønsted acids.
Use of stoichiometric amounts of a chiral source. The usual suspects will be discussed, including borane reagents (mostly pinene derivatives) and the Brown allylation.
This is the biggy, the one everyone wants to achieve. Here we will be looking at metal-based chiral catalysis. We will concentrate on bisoxazoline-based Lewis acid catalysis and then look at reductions before finishing with the ubiquitous Sharpless epoxidation and dihydroxylation.
A look at epothilone A as it includes examples of many different forms of asymmetric synthesis. Also includes a little bit about ring-closing metathesis.
Self explanatory really, this lecture looks at chiral auxiliaries. We will concentrate on oxazolidinones in alkylations, aldol reaction and the Diels-Alder reaction. There will be a couple examples of other auxiliaries.
Gives an introduction to total synthesis and why we do it (which reminds me, I must add a picture of Everest, as I think the fact that 'it is there' is the main reason for most syntheses). Then to introduce the topic with a reasonably simple synthesis, we will look at an example of the synthesis of Tamiflu.
Study Guide Chapter 10-Answers!10.1 Photosythesis_______________.docxhanneloremccaffery
Study Guide Chapter 10-Answers!
10.1 Photosythesis_______________________________________________________
1A. Write the overall reaction (major reactants and major products) for photosysthesis:
sunlight + water + CO2 ( O2 and glucose
B. Where is each reactant used (light reactions or Calvin cycle?)
Sunlight= light reactions
Water= light reactions (when it is “split” the electrons in the bonds of water are used to replace the electrons lost from the P680 reaction center)
CO2= Calvin cycle
C. Where is each product produced (light reactions or Calvin cycle?)
O2= light reactions (when water is “split”)
Glucose= Calvin cycle
2. Compare and contrast Autotrophs and Heterotrophs.
Auto- make their own food
Hetero- rely on autotrophs for food
3. A. Where would you most likely find mesophyll cells in a tree?
Any photosynthetic part of the tree. Leaves are the main photosynthetic organs in the tree.
B. How many chloroplasts does a typical mesophyll cell hold? 30-40
C. What pigment gives a leaf its green color? chlorophyll
D. Where exactly is this pigment located? Within chloroplasts
E. How does carbon dioxide enter the leaf? Through stomata in the leaves
4. Chloroplast structure: Name all components of the chloroplast and describe their orientation relative to one another. Start at the outer membrane and end inside a thylakoid.
Outer membrane
Intermembrane space
Inner membrane
Stroma
Thylakoid membrane
Thylakoid space
5. Identify the two main stages of photosynthesis and where these stages occur respectively. Also describe how the two stages are dependent on one another.
Stage 1= Light reactions- in thylakoid membranes and thylakoid space, the main products of this stage are some the main reactants of the next stage
Stage 2= Calvin cycle- in stroma, some of the products of this stage are some of the main reactants for stage 1.
10.2 Light Rxns. Chemical Energy of Sun ( ATP and NADPH____________________
6. Green light is _____reflected______________ (reflected/absorbed) by a chloroplast, giving it its green color.
7. What wavelengths of light are most effective in driving photosynthesis?
Violet and red
Briefly describe the experiment (discussed in the chapter and powerpoint for this chapter) that identified these wavelengths of light.
The plants produced high levels of oxygen (one of the major products of photosynthesis) when exposed to violet and red light and produced little to no oxygen when exposed to other wavelengths of light. This makes sense. Think about the photosystem reaction centers in the thylakoid membranes of the chloroplast. P680 and P700, the letter “P” represents “photosystem” and the numbers refer to the wavelengths of light the photosystems absorb. Wavelengths 680 and 700 are both in the red range!
8. Describe what happens when chlorophyll absorbs light?
Electrons in chlorophyll absorb energy and are “jumped” to higher energy level.
9. Photosystems: What are they and where are they located?
Light harvesting comp.
This PowerPoint presentation focuses on capturing the energy in light and the Calvin Cycle. Colorful diagrams and illustrations appear throughout the presentation and the following topics are addressed:
* Plant Cell Structure
* Photosynthesis Equations
* Biochemical Pathways
* 5 Steps of the Electron Transport System
* 3 Steps of the Calvin Cycle
This presentation was created by Stacey Odum in Richmond County, GA.
This presentation discusses the way energy flows and is distributed all throughout the ecosystem, from one member to another. This details how one organism becomes an essential necessity for another and how abiotic components play their role as supportive elements for life.
CHE235L4Spring2017.pdf
FW
(g/mol)
mp (
o
C) bp (
o
C) mmol mass (g)
density
(g/mL)
volume
(mL)
N/A
N/A
bismuth(III) nitrate pentahydrate N/A N/A N/A N/A
sodium chloride, saturated (brine) N/A N/A N/A N/A N/A
ethyl acetate N/A N/A
cis -1,2-cyclohexanediol N/A N/A N/A
trans -1,2-cyclohexanediol, (±) N/A N/A N/A
Prelab 4: Green Lewis Acid-Catalyzed Hydrolysis of Cyclohexene Oxide
Name:
Reaction equation:
Note: For those reagents that are in solution, the FW, mmol, and mass columns refer to the solute in the
solution.
Limiting reagent:
Reagent Table
water
Theoretical yield:
Chemical
cyclohexene oxide
EXPERIMENT #4
GREEN LEWIS ACID-CATALYZED HYDROLYSIS OF CYCLOHEXENE OXIDE
Introduction:
Epoxides are three-membered ethers. They are special because unlike most ethers, they can react
with nucleophiles to form a new bond between carbon and the nucleophile and break a bond
between that carbon and oxygen. This ring-opening reaction makes epoxides versatile functional
groups for organic synthesis. (In fact epoxide is the functional group that makes epoxy resins
possible.)
Scheme 1. Ring opening of an epoxide in the presence of a nucleophile.
Ring-opening of the epoxide can occur under basic or acidic conditions. Under basic conditions,
the reaction is similar to an SN2 reaction so that the nucleophile attacks the less substituted carbon
of an unsymmetrical epoxide by backside attack. Sodium ethoxide reacts with this epoxide in the
following reaction.
Scheme 2. Ring opening of an unsymmetrical epoxide under basic conditions.
Under acidic conditions, the reaction is more complicated. It is similar to an SN2 reaction because
the nucleophile reacts by backside attack. However, because there is partial positive charge on the
Reference Material:
MAHHS Chapter 1: Safety in the Laboratory
MAHHS Chapter 2: Protecting the Environment
MAHHS Chapter 3: Laboratory Notebooks and Prelaboratory Information
MAHHS Chapter 4: Laboratory Glassware
MAHHS Chapter 5: Measurements and Transferring Reagents
MAHHS Chapter 10: Filtration
MAHHS Chapter 11: Extraction
MAHHS Chapter 12: Drying Organic Liquids and Recovering Reaction Products
MAHHS Chapter 17: Thin-Layer Chromatography, especially section 17.8
MAHHS Chapter 20: Infrared Spectroscopy
Klein Chapter 14: Ethers and Epoxides; Thiols and Sulfides
three atoms of the epoxide ring, the nucleophile attacks where the partial positive charge is more
stabilized, the more substituted carbon of an unsymmetrical epoxide. Ethanol in the presence of
sulfuric acid reacts with this epoxide in the following reaction.
Scheme 3. Ring opening of an unsymmetrical epoxide under acidic conditions.
While sulfuric acid is an inexpensive acid catalyst, it is difficult to handle. It is very corrosive and
can cause severe burns. In addition, it is viscous, which makes it difficult to handle on the scale of
the reactions perfor ...
Organic I Review Workbook – The Toolbox ALL STAR MOLECU.docxjacksnathalie
Organic I Review Workbook – The Toolbox
ALL “STAR MOLECULES” () SHOULD BE ORGANIZED AND EMPHASIZED AS THEY CAN
BE CALLED UPON AT ANY MOMENT THROUGHOUT THE COURSE. THEY SHOULD BE
KNOWN BY THEIR STAR/COMMON NAME, IUPAC NOMENCLATURE, LINE ANGLE
STRUCTURE, ACRONYM, SHORTHAND NOTATION, FAVORITE FLAVOR OF ICE CREAM,
FAVORITE ONE REPUBLIC SONG, ETC.
1. Review Basic Geometries/Hybridization/Bonding
Questions:
a) Does the electronegativity of a carbon atom increase or decrease with increasing p-
character? Use acetylene and ethylene as examples to help explain your
reasoning. Still stuck? Table 4.1 may provide even more assistance.
b) What is more nucleophilic, a carbon-carbon bond or bond?
c) What is lower in energy, the * orbital or * orbital of a C=C bond?
d) Are the orbitals described in part c) representative of electrophiles or nucleophiles?
e) A lone pair must be in what kind of orbital(s) in order to participate in
resonance/conjugation? s, p, sp, sp2 or sp3. Choose all that apply.
2. Functional Group Recognition / Functional Group Transformation (A+B = C)
Alkene Aldehyde Glycol
Alkyl halide Carboxylic Acid Ketone
Alcohol (alkyl vs aryl) Ether Nitrile
Amine (1°, 2°, 3°) Ester Sulfide
Alkyne Epoxide Thiol
Amide (1°, 2°, 3°) Enol
Questions:
a) Which functional groups above contain the carbonyl/acyl group?
b) Is the carbonyl/acyl carbon of a ketone electrophilic or nucleophilic?
c) All things being equal, which functional group is the most Bronsted acidic (not
including the carboxylic acid)?
d) The transformation of a functional group can be described as a single functional group
starting material (A) being added to a selective environment (B) to generate a new
functional group (C). Basically, A+B = C. With this in mind, which functional
group(s) was (were) NOT synthesized in the first semester (as described in the text)?
e) Which functional group has the most electron rich sp2 oxygen? Provide a structure
to support your answer. Resonance comes in handy here….
f) Is a Bronsted acid a nucleophile or electrophile? A Bronsted base?
g) How many atoms are sp2 hybridized in acetic acid?
h) How many atoms are sp2 hybridized in phenol?
i) How many atoms are sp2 hybridized in heroin?
3. Structural Relationships and Language - Review all terms and definitions for the following:
Constitutional isomers vs Conformation isomers vs Configurational Isomers
Stereoisomers (Diastereomers, Enantiomers)
Optical Activity, Racemic, Meso
Determination of Absolute Configuration
Questions:
a) What term can be used to describe the isomeric relationship above?
b) Each molecule above can be described as a vicinal diol. What is a more common and
more utilized term for describing a vicinal diol (Hint: It is often used in common
nomenclature and can be found on the Functional Group List on page .
These slides are part of a talk to school teachers. They were designed to showcase some of the applications of organic chemistry, the range of natural and synthetic products. I'm not sure how much use it is without my commentary but, as always, it seems a waste to leave it on my hard drive. The second half gave a overview of chirality and stereoisomers as this topic often causes problems with students. This second half owes a lot to an excellent paper by Robert Gawley (J. Chem. Ed. 2005, 82, 1009) and just has prettier papers. This version of the talk includes a section I removed when presenting (due to time) on artificial sweeteners.
Safalta Digital marketing institute in Noida, provide complete applications that encompass a huge range of virtual advertising and marketing additives, which includes search engine optimization, virtual communication advertising, pay-per-click on marketing, content material advertising, internet analytics, and greater. These university courses are designed for students who possess a comprehensive understanding of virtual marketing strategies and attributes.Safalta Digital Marketing Institute in Noida is a first choice for young individuals or students who are looking to start their careers in the field of digital advertising. The institute gives specialized courses designed and certification.
for beginners, providing thorough training in areas such as SEO, digital communication marketing, and PPC training in Noida. After finishing the program, students receive the certifications recognised by top different universitie, setting a strong foundation for a successful career in digital marketing.
A Strategic Approach: GenAI in EducationPeter Windle
Artificial Intelligence (AI) technologies such as Generative AI, Image Generators and Large Language Models have had a dramatic impact on teaching, learning and assessment over the past 18 months. The most immediate threat AI posed was to Academic Integrity with Higher Education Institutes (HEIs) focusing their efforts on combating the use of GenAI in assessment. Guidelines were developed for staff and students, policies put in place too. Innovative educators have forged paths in the use of Generative AI for teaching, learning and assessments leading to pockets of transformation springing up across HEIs, often with little or no top-down guidance, support or direction.
This Gasta posits a strategic approach to integrating AI into HEIs to prepare staff, students and the curriculum for an evolving world and workplace. We will highlight the advantages of working with these technologies beyond the realm of teaching, learning and assessment by considering prompt engineering skills, industry impact, curriculum changes, and the need for staff upskilling. In contrast, not engaging strategically with Generative AI poses risks, including falling behind peers, missed opportunities and failing to ensure our graduates remain employable. The rapid evolution of AI technologies necessitates a proactive and strategic approach if we are to remain relevant.
Unit 8 - Information and Communication Technology (Paper I).pdfThiyagu K
This slides describes the basic concepts of ICT, basics of Email, Emerging Technology and Digital Initiatives in Education. This presentations aligns with the UGC Paper I syllabus.
Thinking of getting a dog? Be aware that breeds like Pit Bulls, Rottweilers, and German Shepherds can be loyal and dangerous. Proper training and socialization are crucial to preventing aggressive behaviors. Ensure safety by understanding their needs and always supervising interactions. Stay safe, and enjoy your furry friends!
MATATAG CURRICULUM: ASSESSING THE READINESS OF ELEM. PUBLIC SCHOOL TEACHERS I...NelTorrente
In this research, it concludes that while the readiness of teachers in Caloocan City to implement the MATATAG Curriculum is generally positive, targeted efforts in professional development, resource distribution, support networks, and comprehensive preparation can address the existing gaps and ensure successful curriculum implementation.
How to Build a Module in Odoo 17 Using the Scaffold MethodCeline George
Odoo provides an option for creating a module by using a single line command. By using this command the user can make a whole structure of a module. It is very easy for a beginner to make a module. There is no need to make each file manually. This slide will show how to create a module using the scaffold method.
Executive Directors Chat Leveraging AI for Diversity, Equity, and InclusionTechSoup
Let’s explore the intersection of technology and equity in the final session of our DEI series. Discover how AI tools, like ChatGPT, can be used to support and enhance your nonprofit's DEI initiatives. Participants will gain insights into practical AI applications and get tips for leveraging technology to advance their DEI goals.
Exploiting Artificial Intelligence for Empowering Researchers and Faculty, In...Dr. Vinod Kumar Kanvaria
Exploiting Artificial Intelligence for Empowering Researchers and Faculty,
International FDP on Fundamentals of Research in Social Sciences
at Integral University, Lucknow, 06.06.2024
By Dr. Vinod Kumar Kanvaria
Read| The latest issue of The Challenger is here! We are thrilled to announce that our school paper has qualified for the NATIONAL SCHOOLS PRESS CONFERENCE (NSPC) 2024. Thank you for your unwavering support and trust. Dive into the stories that made us stand out!
1. These are the old slides that made up the
‘traditional’ version of these two units
(asymmetric synthesis & total synthesis).
I will annotate these slides and see if they
work as the reading material for the
course ... bear with me, it is a bit of an
experiment.
Some of my colleagues would go as far as
saying “we don’t”. They would, of course
be wrong. There are two quick answers:
1) We need organic compounds so we need
to learn how to make organic molecules.
2) Research and Education. The problems
encountered in total synthesis push
forward the development of new
methodology and teach us the application
of chemistry.
1
2. It is made by Roche and at least one of
their published routes is based on the
conversion of shikimic acid (isolated from
star anise) to the final drug.
The entire pharmaceutical industry and
much of the agrichemical industry (and
many other industries) is build on the
chemists’ ability to synthesize molecules
with specific properties.
On this slide we see the molecule
oseltamivir or Tamiflu, an antiviral
medication used in the prevention and
treatment of flu.
2
3. The reported route takes 12 steps to
convert shikimic acid to the final product.
There are many other reported syntheses in
the literature. Some are longer, some are
shorter. We need to learn how to compare
these routes, to determine the pros and
cons of each route and, ultimately, how to
design similar syntheses so that we can
make our own target molecules.
Atorvastatin or Lipitor was one of the most
successful of the statin drugs used to low
blood cholesterol. From 1996-2012 it was
the world’s best selling pharmaceutical. It
is now off patent.
Yet again, it was initially discovered by
organic chemists ...
3
4. The original synthesis started from
isoascorbic acid, a stereoisomer of vitamin
C. It is a cheap ‘chiral pool’ natural
product.
Again, we need to be able to deduce how
Lipitor can be prepared from this
material ...
I could go on and on ... there are many
examples of small organic molecules used
to treat ailments. This is another bestseller
from the pharmaceutical industry and is
used to both treat and manage asthma.
The synthesis of the top molecule
salmeterol is relatively quick, taking just ...
4
5. ... six steps from this salicylic acid
derivative.
Of course, not all treatments are small
organic molecules. Peptides are becoming
popular targets. Fuzeon or enfuvirtide is a
biomimetic peptide that confuses the HIV
virus. It is hard to make and a tad
expensive ($25,000 US per year) so is a
last resort medicine.
5
6. But chemists are everywhere. To display my
Massey card, the next example is from both
the agrichemical sector and companion
animal health sector. Imidacloprid is
probably the world’s most commonly
employed insecticide.
On the downside, it has been linked to
colony collapse disorder in bees.
Its synthesis is shockingly simple and it
can be prepared in just four steps from 3-
methylpyridine.
6
7. Another example from the companion
animal health sector is the various
components of Drontal ...
... while we use this to keep our pets in
good health, one of the major components,
praziquantel, is found on the WHO Model
List of Essential Medicines needed for
basic health care. It used to treat intestinal
parasites.
New synthetic methodology is needed to
allow a cheaper synthesis to be developed
so there is more access to such useful
drugs.
7
8. Given enough time and resources (money
and students!) it looks like most molecules
can be prepared. One of the most
ambitious syntheses was the preparation of
palytoxin. This is the largest (non-
polymeric, non-peptide) compound I could
find.
It is not entirely clear how many steps are
involved as the synthesis of the starting
materials was not reported.
Interestingly, it is often small molecules
that are hard to prepare. The problem with
such molecules is they lack functionality for
us chemists to play with.
This is octanitrocubane. It was predicted to
be one of the most potent carbon based
explosives but it turns out it is not and that
the heptanitrocubane is more explosive.
This fact shows the importance of shape
and conformation to reactivity (as we shall
see later).
8
9. The next synthesis demonstrates the value
of radical chemistry, an area of chemistry
that is sadly glossed over for the most part
and undergraduate level …
This lecture’s target is hirsutene. It has
some antibacterial activity but nothing
spectacular.
The challenge with this molecule is the
fused tricyclic ring system and lack of
functionality for a chemist to play with
during the synthesis.
But first an (re)introduction to radical
chemistry …
9
10. In this example of a radical reaction three
C–C bonds along with three new rings are
created in a single step. It may not have
been the product the researchers were
looking for (they wanted a different
tetracyclic ring system) but it shows a
remarkable increase in complexity can be
achieved within a single step.
So what happened? I’ll discuss the actual
formation of the radical in a couple of slides
time but here are highlights …
• The iodide is transformed into a highly
reactive primary radical (a carbon with a
radical on it only has 7 valence electrons so is
electron deficient and is stabilised by the
same factors that stabilise a carbocation).
• This reacts with the activated (electron
deficient) alkyne - radicals are both
electrophiles and nucleophiles.
10
11. • After the 13-endo-dig cyclisation the
reactive alkenyl radical attacks the furan
ring in a 6-exo-trig cyclisation.
• One of the resonance forms of the
product has the radical stabilised by two
allylic groups and an oxygen. This acts as
quite a driving force for the cyclisation.
• But the ketyl radical keeps reacting and
formation of a stable ketone with
concomitant ring opening results in the
formation of a tertiary radical that is again
doubly allylic stabilised.
• Finally another cyclisation results in
formation of the tetracyclic product.
11
12. The advantages of radica reactions are listed
above.
• They occur under very mild reactions so are
tolerant of a host of functional groups (ionic
reagents are either strong acids or strong
bases).
• They are highly reactive so can perform
many valuable transformations.
Ignore the comment about salvation it is very
wrong.
The disadvantages are getting fewer
everyday.
with the only ones remaining from the list
above being:
• They are highly reactive (good and bad)
• People are scared/don’t understand them
12
13. Above is a simple radical conjugate addition. The
classic reagents for this are:
Tributyltin hydride
AIBN - azobisisobutyronitrile
substrate
radical precursor (bromide)
heat
The real disadvantage of this chemistry is that
tin reagent, which while perfect for radical
reactions is highly toxic and very hard to remove
from the product.
So a classical radical chain reaction occurs
in three stages:
1) initiation
2) propagation
3) termination
lets look at each in turn …
13
14. Initiation forms the first radical.
AIBN is the radical initiator. It is a
thermally unstable molecule that readily
decomposes on heating to give nitrogen
gas and 2 alkyl radicals.
These react with the tributyltin hydride to
form a tin radical. This relies on the Sn–H
bond being readily cleaved.
Note: there are two conventions for depicting
the same thing. In the first (previous slide) we
show the movement of every electron. Each
braking bond will require two fishhooks and
every new bond will be formed from two
fishhooks.
Alternatively, chemists being lazy (and
wanting neat drawings) sometimes draw the
fishhooks like curly arrows just showing the
overall flow of electrons … this is cleaner but
not very accurate or helpful.
14
15. In the propagation step the tin radical
reacts with an alkyl bromide, breaking the
weak C–Br to selectively form the
secondary alkyl radical.
The alkyl radical then adds to the alkene to
give the more stable α-keto radical
(resonance stabilisation like an enolate).
This reacts with tributyltin hydride to give
the product and the tin radical.
And here is the alternative representation.
I prefer the first representation with all
fishhooks. It shows what is happening and
does not rely on readers remembering what
is being represented. I confess I am guilty
of frequently drawing the second version
(as shown on this slide).
Just remember every bond is two electrons
so there needs to be two electrons moving.
15
16. You will notice that the tin radical is at the
start and finish of this slide. It is known as
the radical chain carrier as it propagates
the chain reaction.
In theory we only need one molecule of
initiator to form one molecule of tin radical
and then this will be continuously
regenerated until all the substrate has
reacted.
Of course, chemistry is not that simple …
… and we have the termination steps that
kill the chain reaction. These occur
whenever any two radicals meet.
Ideally we want to avoid any terminations.
To do this the concentration of the radical
needs to be kept low.
This can be achieved by using a very small
amount of initiator and more importantly
adding the tributyltin hydride very slowly
(which is a pain in the neck).
16
17. The big problem with classic radical
reactions is the use of the tin reagent.
There has been considerable research
trying to circumvent the use of these
reagents. There are many good reviews
(including two by me) on radical reagents.
The real break through was mentioned in
lecture 6; photoredox chemistry has the
potential to revolutionise radical chemistry.
The retrosynthesis of hirsutene starts by
two C–C disconnections removing two 5-
membered rings.
Radical reactions tend to favour 5-exo
cyclisations over 6-endo cyclisations so this
is a quite reasonable disconnection.
Removing two rings rapidly simplifies the
synthesis. It leaves an iodide as the radical
precursor, an alkene and an alkyne as
radical acceptors.
17
18. A C–C disconnection then removes the
alkyne.
At first glance this may look like a stupid
disconnection as it leaves two iodides and
the issue of chemoselectivity raises its
ugly head.
Fortunately …
… one of the alkyl iodides is next to a
geminal dimethyl group (or is effectively a
pseudo-neopentyl iodide).
The neopentyl group is very bulky and
prevents SN2 reactions (it blocks approach
of the nucleophile to the σ* anti-bonding
orbital so stops backside attack).
18
19. One iodide is going to be derived from a
carboxylic acid (we shall see later why this
is a good idea).
The other will be derived from an alcohol.
We need to remove the iodides early in a
retrosynthesis (or introduce them late in
the forward synthesis) as they are very
reactive/unstable and can cause
chemoselectivity issues.
All these FGI have been useful (as we shall
see) but they have not simplified the
molecule or got us back towards a simple
starting material.
So the next step is to remove one of the
branches off the ring.
Here we show a possible pair of synthons
for a C–C disconnection. We have decided
to make the carbon chain nucleophilic and
the ring electrophilic.
19
20. The obvious synthetic equivalent for an
electrophilic carbon atom is an alkyl halide.
We could make the halide above but there
are a number of issues. Firstly, how would
we make it? Secondly, as it would be an
allylic halide would it react by an SN1, SN2
or SN’ mechanism and what would the
consequence be to the stereoselectivity?
Alternatively, we could rely on an SN’
reaction and this would take us back to the
bicyclic lactone above.
This would guarantee the stereochemistry
as the nucleophile would attack anti to the
leaving group and from the outside (convex
face) of a v-shaped molecule.
20
21. Lets now go through this elegant synthesis.
The first stage is to prepare the bicyclic
lactone. This synthesis makes racemic
hirsutene but it would not be hard to
convert it to an enantioselective synthesis.
The starting material is 2-
methylcyclopent-2-enone.
1) A Luche reduction guarantees a 1,2-
reduction that will not be contaminated
with either the 1,4-addition or the over
reduction.
2) Acetylation gives the ester
Finally, silyl ketene acetal formation
furnishes the rearrangement precursor
above.
21
22. There are a number of potential explanations for
the effectiveness of the Luche reduction.
It appears that cerium catalyses the formation of
various alkoxyborohydrides. These reagents are
‘harder’ than NaBH4 so are more selective for
the reaction at the hard 1,2-position rather than
the soft 1,4-position. It is also thought that the
cerium coordinates to methanol making the
protons more acidic and capable of hydrogen
bond activation of the carbonyl (although it is
possible that the cerium does this directly itself).
How might we make the reduction
enantioselective?
Think about some of the earlier lectures
and either the CBS reduction (which would
be perfect for this) or asymmetric
hydrogenation.
22
23. Heating the silly ketene acetal to reflux
initiates an Ireland-Claisen rearrangement.
This is a pericyclic reaction, specifically a
concerted [3,3]-sigmatropic
rearrangement. Such reactions are
stereospecific.
You can recognise the possibility of such
rearrangements just by looking for two
multiple bonds whose terminals are 6
atoms apart.
Normally, such rearrangements occur
through a chair-like transition state and you
can use this to rationalise the
stereochemical communication.
This is shown above.
More information can be found about such
rearrangements here:
Stereoselective Synthesis - lecture 11 or
Advanced Organic Synthesis - lecture 8
23
24. The silyl ester can be cyclised to produce
the lactone by treatment with phenylselenyl
chloride.
This reaction is analogous to bromination
or the reaction of alkenes with ‘bromine
water’. So you know the mechanism …
… if you remember the bromination reaction,
it proceeds through the formation of a
bromonium ion.
This cyclisation occurs through the formation
of a selenonium ion, which is then attacked
by the carboxylic acid. The selenonium ion
forms reversibly but will only be attacked
when it is anti to the acid (SN2-like attack). We
could also argue that as selenium is very big
it forms on the least hindered face.
24
25. To install the required alkene the selenide
is oxidised with hydrogen peroxide to form
the selenoxide.
Such species spontaneously undergo syn-
elimination at room temperature
(analogous to the sulfoxide syn-elimination
we saw in the synthesis of hirsutene).
The SN’ reaction is achieved by forming an
organocuprate. A ‘soft’ nucleophile is
required to insure attack occurs on the ‘soft’
alkene and not at the ‘hard’ carbonyl carbon.
(if you do not know what Pearson’s Hard Soft
Acid Base (HSAB) concept then you should
start reading now … it’s very useful).
The cuprate is formed by reductive halogen-
metal exchange with Li-naphthalenide
followed by transmetallation to the copper
reagent.
25
26. After this, the conversion to the radical precursor, is
straightforward.
1) Acetal hydrolysis cleaves the THP-protecting
group (ppts = pyridinium para-toluenesulfonate)
2) Reduction of the carboxylic acid to an alcohol
gives the diol
3) Treatment with Tf2O forms the triflate. Triflates
are very good leaving groups (consider the pKa of
triflic acid)
4) The iodide displaces the triflate to give the
diiodide
5) Nucleophilic displacement of the accessible
iodide with TMS-acetylene is followed by:
6) Deprotection of the acetylene is achieved with
CsF.
Finally, the radical bicyclisation …
Treatment of the iodide with tributyltin
hydride and AIBN results initiates the
radical chain reaction. First the unstable
primary alkyl radical is formed. This
undergoes 5-exo-trig cyclisation to give the
cis fused 5,5-bicyclic tertiary radical.
Formation of the trans fused bicyclic
compound is disfavoured due the ring
strain.
26
27. The tertiary radical then cyclises onto the
alkyne (5-exo-dig cyclisation) to give an
alkenyl radical.
Reduction with tributyltin hydride gives the
product and regenerates the radical chain
carrier.
As we can see the bicyclisation occurs with
an excellent yield.
Hopefully this synthesis demonstrates the
power of radicals in synthesis and the fact
they can form multiple C–C bonds in one
step.
27