Part IA Student Handout 1 2021-22 Cambridge NatSci Lecture PDF

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Reactions and Mechanisms inOrganic ChemistryPart IAStudent Lecture Notes&Course QuestionsPart 1Deborah A. [email protected] 245The Department of Chemistry endeavours to develop an inclusive, supportive and intellectually stimulating environment for our undergraduate community.Athena S...

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Reactions and Mechanisms in Organic Chemistry Part IA Student Lecture Notes & Course Questions Part 1 Deborah A. Longbottom [email protected] Office 245

The Department of Chemistry endeavours to develop an inclusive, supportive and intellectually stimulating environment for our undergraduate community. Athena SWAN is an ongoing programme to address the underrepresentation of women in the sciences. The Silver Award recognises the progress that the Department has made in recent years, and the actions that benefit not only our female students, but all our undergraduate chemists. For more information see www.ch.cam.ac.uk/athena-swan Your colleagues in previous years suggested that they would like to know a bit more about their lecturers, so this year each lecturer has been asked to provide some biographical notes. We hope that this will illustrate the different backgrounds of our staff and the varied routes that have brought them to the Department.

Because my dad was in the Royal Air Force, our family moved around the world for several years, including Kenya when I was just two, subsequently the rather less exotic Holland and finally the UK. Because of the educational disruption (and probably with enthusiasm due to reading too much Malory Towers and the like), I then went to a boarding school in the North Yorkshire Moors, where I was educated largely by nuns and the odd lay person, one of whom was my Chemistry teacher, Mrs Wright – a force to be reckoned with. Once I got to the point where even she was struggling to answer my questions, I realised that studying Chemistry at University was the only way forward. Winding several years on, I proceeded to undergraduate study at Durham University (a place which I still hold very fondly in my heart) and where I was fortunate enough to be allowed to take an elective year out of study to work at Lilly Pharmaceuticals, where I really found my passion for organic chemistry. The reality of working somewhere that was actively using University level subject matter to make molecules that could help to save people’s lives was just mind-blowing. Following my degree, I was fortunate to experience another year of employment, this time with GlaxoSmithKline, which really sealed my interest in organic chemistry in particular before coming to Cambridge to study the subject at PhD level with Professor Steven V Ley, where I spent just over three wonderful years indulging in my passion for making molecules, as well as discovering the supervision system, which fuelled another lifelong interest and passion – teaching. Throughout my PhD and in postdoctoral work for KC Nicolaou at the Scripps Research Institute (San Diego), as well as back here in Cambridge with Professor Ley again, research and teaching ran alongside one another as much as was practically possible, with the shift from research to an education focus occurring over several years. Indeed, I have gathered in a rich and varied experience from roles as Director of Studies, College Teaching Officer and Tutor, Departmental Teaching Fellow, Head of Graduate Education and latterly in directing education activities in the School of the Physical Sciences here in Cambridge (which includes 8 of our University Departments), all of which have given me the privilege of a most fulfilling and rewarding career to date. A more personal account will follow in Part 2 next term…..

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INDEX: PART I COURSE OVERVIEW AND SUGGESTED READING

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1. ORGANIC CHEMISTRY: BACKGROUND AND RELEVANCE

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1.1 The History of Organic Synthesis

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1.2 More Recent Developments

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1.3 Chemistry in Everyday Life

10

1.4 The Importance of Chirality

12

1.5 Stereochemical Notation

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2. FUNCTIONAL GROUPS IN SYNTHESIS

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2.1 Functional Group Definitions for Compounds Containing s-Bonds

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2.2 Functional Group Definitions for Compounds Containing p-Bonds

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3. SYNTHESIS AND RETROSYNTHETIC ANALYSIS

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(THE DISCONNECTION APPROACH) 3.1 Synthesis

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3.2 Retrosynthetic Analysis

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4. MECHANISM IN ORGANIC CHEMISTRY

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4.1 The Frontier Molecular Orbital (FMO) Approach

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4.2 Curly Arrows

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4.3 Relative Nucleophilicity

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4.4 Relative Electrophilicity

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5. NUCLEOPHILIC ADDITION TO THE CARBONYL GROUP

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(ALDEHYDES AND KETONES) 5.1 Mechanism, Orbitals and Angle of Attack

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5.2 Reactions

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5.2.1 Reaction with Hydride

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5.2.2 Reaction with Organometallic Reagents

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5.2.3 Reaction with Water and Alcohols

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5.3 Summary

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6. ACIDITY, BASICITY AND pKa: LEAVING GROUP ABILITY

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6.1 Importance of Leaving Group Ability

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6.2 Quantifying Acidity and Leaving Group Ability: the pH Scale

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6.3 Quantifying Acidity and Leaving Group Ability: the pKa Scale

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6.4 Examples of pKa Values

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6.5 Using pKa Values to Determine Leaving Group Ability

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6.6 Anion Stability: Key Factors Explained

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6.7 Explaining Relative pKa Values

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6.8 The Effect of Hybridisation on pKa

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7. NUCLEOPHILIC SUBSTITUTION AT THE CARBONYL GROUP: PRINCIPLES

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7.1 Strength of the Incoming Nucleophile

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7.2 Reactivity of the Carbonyl Group

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7.2.1 The inductive effect

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7.2.2 The conjugative effect

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7.2.3 Balance of the inductive and conjugative effects

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7.3 Leaving Group Ability

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7.4 Illustrating the Principles

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7.4.1 Converting an acid chloride to an ester

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7.4.2 Converting an ester to an amide

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7.5 Using this Rationale to Predict Whether a Reaction Will be Successful

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Appendix 1: Summary Of Arrow Types And Meaning

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Appendix 2: Organic Chemistry Mechanisms - Examples from Practical A

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Appendix 3: Reference Table of pKa Values

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PAST PAPER EXAM QUESTIONS

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SUPERVISION PROBLEMS: PART 1

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COURSE OVERVIEW AND SUGGESTED READING 1 Organic chemistry comprises a great diversity of structures and functional groups, which can undergo a wide variety of chemical reactions. The principle aim of this part of the Chemistry course is to develop a good understanding of those reactions, using the concepts of mechanism and ‘curly arrows’. Some unifying concepts will be introduced to provide a rationale that will enable you to explain and predict a variety of reactions that proceed by different mechanisms. Several reaction types will then be covered and finally, a logical approach as to how to plan the synthesis of unfamiliar molecules will be discussed if there is time. More specifically, the topics which will be covered during the Part IA organic chemistry course are: 1. Organic Chemistry: Background and Relevance 2. Functional Groups in Synthesis 3. Synthesis and Retrosynthetic Analysis 4. Mechanism in Organic Chemistry 5. Nucleophilic Addition to the Carbonyl Group (Aldehydes and Ketones) 6. Acidity, Basicity and pKa: Leaving Group Ability 7. Nucleophilic Substitution at the Carbonyl Group: Principles 8. Nucleophilic Substitution at the Carbonyl Group: Reactions 9. Hard and Soft Nucleophiles and Electrophiles 10. Nucleophilic Substitution at Saturated Carbon: SN1 and SN2 Reactions 11. C=C Double Bond Formation: Elimination Mechanisms 12. Reactions of p-Bonds: Electrophilic Attack and Hydrogenation In order to further your understanding of each of these topics, it is a good idea to read additionally around the course. Of the suggested texts in the ‘IA Course Guide’, the book most recommended to support this course (which can be found in most College libraries) is ‘Organic Chemistry’ by Clayden, Greeves, Warren and Wothers. The most useful chapters in each of these are given on the next page:

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This part of the Chemistry course is based on previous versions given by Dr Bill Nolan & Professor Shankar Balasubramanian: it has been rewritten but the content has not been expanded.

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Topic

2001 Edition

2012 Edition

Introduction to Synthesis: Functional Groups and Oxidation Level

Chapters 1 & 2

Chapters 1 & 2

Mechanism in Organic Chemistry

Chapter 5

Chapter 5

Nucleophilic Addition to the Carbonyl Group Chapters 6, 9 & Chapters 6, 9 & 11 (Aldehydes, Ketones) part of 14 Acidity, Basicity and pKa

Chapter 8

Chapter 8

Nucleophilic Substitution at the Carbonyl Group: Principles and Reactions

Chapter 12

Chapter 10

Nucleophilic Substitution at Saturated Carbon: Chapter 17 SN1 and SN2 Reactions

Chapter 15

C=C Double Bond Formation: Elimination

Chapter 19

Chapter 17

Electrophilic Addition to Alkenes

Chapter 20

Chapter 19

The Disconnection Approach to Organic Synthesis

Chapter 30

Chapter 28

‘Organic Chemistry’ by David Klein is also highly recommended.

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1. ORGANIC CHEMISTRY: BACKGROUND AND RELEVANCE In this section, we will discuss: 1.1 The History of Organic Synthesis 1.2 More Recent Developments 1.3 Chemistry in Everyday Life 1.4 The Importance of Chirality 1.5 Stereochemical Notation 1.1 The History of Organic Synthesis Between 1828 and 1950, some landmark syntheses were carried out, driving organic chemistry forward and truly spectacular for their time: OH O H 2N

O

O NH 2

H 3C

Urea (Wöhler, 1828)

OH

Acetic acid (Kolbe, 1845)

HO HO

OH

O HO

O O

OH

Glucose (Fischer, 1890)

Aspirin (Hoffmann, 1899)

N

N

N Fe

O N

N

O

OH

HO 2C Camphor (Komppa, 1903; Perkin, 1904)

α−Terpineol (Perkin, 1904)

Tropinone (Robinson, 1917)

CO2H Haemin (Fischer, 1929)

H O

OH

OH H H HO

OH H HO

N H Cl

N

H N

R O

S

N O

MeO

H

CO2H

N

Equilenin (Bauchmann, 1939)

Pyridoxine hydrochloride (Folkers, 1939)

Penicillins Quinine (Woodward/Doering, 1944) (1940s, industrial manufacture)

These began with relatively simple targets but rapidly progressed to far more complicated molecules, driving the development of new reactions with which to accomplish the challenges posed. During World War II, the most notable development was then of antibiotics, which drove the development of industrial scale processes and, in effect, saved the allied troops in Normandy. 8

1.2 More Recent Developments After World War II, several further areas were developed: Electronic theory and mechanism of organic reactions Conformational analysis (shape of molecule) Analysis and purification techniques X-ray crystallography and spectroscopy methods

• • • •

Concurrently, the targets became ever more complex: MeSSS

O

N I H

H

N H H

O O

O

O

S

O HO MeO OH

OMe

H O N HO H N MeO

H

OMe

O

O NHCO 2Me O

O

Calicheamicin γ1 (1992): antitumour/antibiotic

Strychnine (1954): rat poison

O O

O

OH

O

HO H O

OH O OH

OH

Ph

NH 2

NH

O

OH O H

O

O

HO O

Taxol (1994): antitumour

Discodermolide (1993): antitumour

Chemists were driven forward in their efforts by the following: • • • •

Structural challenge Biological activity Inability to isolate sufficient quantities from natural source Development of new methods to make bonds

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H

O

H

O O

O

1.3 Chemistry in Everyday Life Chemistry, in particular organic chemistry is relevant now for a whole host of different career paths and applications. Amongst them but by no means definitive: • • • • • • •

Medicinal chemistry Process chemistry Agrochemicals Food chemistry Perfumes Washing powders Make-up ingredients

And the list goes on. For example, organic synthesis is used to make new molecular types for direct treatment of disease, often more simple than natural products themselves:

Treatment of infections:

Male erectile dysfunction: O

H N

Ph

O

HN

H S

O O

CO2H

Penicillin G: antibiotic

HO

NH 2 H 3PO 4 N3

AZT: HIV

Oseltamivir/Tamiflu: influenza

Central nervous system, e.g. anxiety: O

N

O

O

O S O N

Viagra

N

Cardiovascular, e.g. heart failure: O

Cl N

N

HN N

Cl

N N

AcNH

O

N

HN

N

N

O

EtO

CO2Et

O

NH

Ph

N H

Diazepam

Barbituric Acid

CO2H

O

Captopril

SH

Cl

N H Clonidine

Organic chemistry is therefore an excellent training for those who wish to become medicinal chemists but so much more besides: organic molecules are everywhere, from crop sprays to vitamins, dyes to smells and washing powder to recreational drugs and bombs:

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Herbicides:

Vitamins: CF3

NH2 N SEt

O N

O Cl

N

H 2N

O

OH OH

N H

N

N

O

N H N

Vitamin B6

Norfluazone

Amethidone

OH

NH2

N N

N H

O

O

O

Folic Acid (in pregnancy)

Dyes: I

SO3Na

I

HO

O

O

O

H N

NaO 3S I

I CO2Na

N H

HO SO3Na

O

N

N N

N

CO2Na

NaO 3S Etyrosine

Indigo Carmine

Tartrazine

INDIGO

YELLOW

RED

Whiteness:

Aromas: N

N N

4

N

N Roast Meat

N

OMe

Nutty Coffee

OMe

O

Boiled Rice

Cl

Recreational Drugs: O

N N

N

MeOSO 3

O N

N

O

Pepper

Everyday addiction:

O Me 3N O S

N

N

Et 2N

CO2Me

N

N

O

N

H

Ph

LSD

N O

Caffeine

N H

Cocaine

Nicotine

Bomb Making:

O

H 2O 2, H +

O O

O O

O O Acetone (in nail polish remover)

O O O O

Dimer Trimer Acetone Peroxide

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- July 2005 bombings in London - 'Mother of Satan'

1.4 The Importance of Chirality Chirality is important because it imparts different physical, chemical or biological properties. Enantiomers are mirror images of one another but they do not necessarily have the same properties. For example, carvone: Mirror

O

O

(R)-(–)-Carvone

O

(S)-(+)-Carvone

For example, thalidomide: Mirror O

O

O NH

N

O

O

NH

HN O

O

N O

O (S )-thalidomide

O

N

O

O

(R)-thalidomide

1.5 Stereochemical Notation The way in which molecules are represented in this course is as follows: Bonds above the plane of the paper are: Bonds below the plane of the paper are: You should be aware however that you will find alternative stereochemical notation used in a variety of publications, even though some consider it to be ambiguous:

Or better used for a partial bond, to show delocalisation or a hydrogen bond:

A note about drawing charges: throughout this course, charges are simply represented with a + or a – sign. There is no universal directive in this area but you may find it clearer to draw charges with a circle around them to avoid any confusion, i.e.

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2. FUNCTIONAL GROUPS IN SYNTHESIS In this section, we will look at some basic ideas, which many of you may have come across before: 2.1 Functional Group Definitions for Compounds Containing s-Bonds We will consider two major bond types to begin with, C–C/C–H bonds and C–X bonds: • C-H and C-C s-bonds are very strong and not strongly polarised: it is difficult to break them in a chemical reaction d+d– • C–X s -bonds are polarised and reactive towards nucleophilic attack: it is much easier to break them in a chemical reaction A C–X bond is one where X is a heteroatom, i.e. an element other than C or H but usually: N, O, halogen A functional group is how we describe these reactive C-X s-bonds: ‘a group with a function’ In Part IA, we will be concerned with four main types of C–X bonds: alcohols, ethers, amines and halides, each of which is outlined below, where: • R, R1 and R2 etc. are alkyl groups • Ar = aryl group, i.e. aromatic ring system such as phenyl but may have other substituents attached. Alcohols (R–OH): Primary

Secondary

Tertiary

OH OH

Propan-1-ol

HO

Propan-2-ol

tert-Butanol

Ethers (R1–O–R2); R1 and R2 can be different or the same: O

Diethyl ether (R1 = R2)

O

tert-Butyl methyl ether (R1 ≠ R2)

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Amines (R–NH2): Primary (1˚)

Secondary (2˚) N H

N

Diethyl amine

Di-iso-propylethylamine

H 2N

tert-Butyl amine

Tertiary (3˚)

Halides (R–Hal): Linear

Branched Br

I