Chapter 01 F2016 Review - hyperconjugation.comhyperconjugation.com/3719files/3719Fall2016NoteSlides.pdf• The ground state atomic structure for C does not match CH4 ... Hybridization

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Chemistry 3719

Introduction to Organic Chemistry

Chapter 1

Chapter 1 – A Review of General Chemistry

• Introduction to Organic Chemistry• The Structural Theory of Matter• Electrons, Bonds, and Lewis Structures• Identifying Formal Charges• Induction and Polar Covalent Bonds• Atomic Orbitals• Valence Bond Theory• Molecular Orbital Theory• Hybridized Atomic Orbitals• VSEPR Theory: Predicting Geometry• Dipole Moments and Molecular Polarity• Intermolecular Forces and Physical Properties• Solubility

A Review of General Chemistry Chapter 1 – Energy Relationships

G = H - TS Overall energy within a system relies upon enthalpy (H, e.g.

bond strengths) and entropy (S, e.g. the number of different species present) factors

Energy relates to “stability” and “reactivity” which will help determine which reactions or molecular shapes are viable in Chemistry and Biology

Systems (reactions, individual molecules) will try to become more stable through changes in constitution (chemical change) or shape (physical change)

Understanding the concepts of stability/reactivity will be important in both Organic Chemistry and Biochemistry

2

1.1 – Introduction to Organic Chemistry

1807 Berzelius introduces the term “Organic Chemistry”to describe the study of compounds isolated from nature

Wohler 1828 Movassaghi 2009

1.2 – The Structural Theory of Matter

Wohler 1828

• First synthesis of “Organic” molecule in the laboratory

• Note that these compounds are constitutional isomers

The Structural Theory of Matter

Typical Valencies : Figure 1.1

• Atoms interact in predictable ways to form molecules

• Knowing some basic rules will help you stay organized

Structure of Matter - Valency

• Knowing these simple valence rules will help long term

Skillbuilder Exercise in Klein Text

3

1.3 – Electrons, Bonds, and Lewis Structures Electrons, Bonds, and Lewis Structures

Valences from the Periodic Table

You can always calculate the number of valence electrons

by analyzing the electronic configuration.


Electronic Configurations


4

Types of Bonding

Atoms trying to attain the stable configuration of a

noble (inert) gas - often referred to as the octet rule

Ionic Bonding - Electrons Transferred

Covalent Bonding - Electrons Shared

type of bond that is formed is dictated by the relative

electronegativities of the elements involved

Lewis Structures for X-H Molecules


1.4 – Identifying Formal Charges

or

Formal Charge = group number

- number of bonds

- number of unshared electrons

Formal Charge

O NO

OH Formal Charge =

group number

- number of bonds

- number of unshared electrons


5

1.5 – Induction and Polar Covalent Bonds

H2 HF H2O

CH4 CH3Cl

Polar Covalent Bonds

H H CH

HH C

HH

HNHH

H

C OH

HH Cl H

OH

2.1 2.1

no +/ -

no +/ -

2.12.5

2.13.0

+-

2.1 3.0

+ - +- +

-

+

2.5 3.5 2.1 3.5

Range of Polar Covalent Bonds

+ used to denote electron-deficiency

‐ used to denote electron-excess


Examples of Polar Covalent Bonds

Examples: O

Cl

H N

O

CH3

CH3

+ used to denote electron-deficiency

‐ used to denote electron-excess


6

1.6 – Atomic Orbitals

Wavefunction for an electron may

either be (+), (-), or ZERO (this is not

related to charge)

1.6 – S Orbitals

Probability distribution for an s electron

1s and 2s Orbitals

Boundary surfaces of a 1s and 2s orbital

Structure of p orbitals

Boundary surfaces of the 2p orbitals

P orbitals in the same level are degenerate;

equivalent in size, shape, energy, only differ by direction projected in space

7

Atomic Orbitals

Atomic Orbitals for First Row Elements

• Organic molecules usually deal with 1s, 2s, 2p orbitals

• Knowing the basic electronic structures is essential

Basic Electronic Structures

Atom Atomic No. Electronic Structure

H 1 1s1

He 2 1s2

Li 3 1s2 2s1

Be 4 1s2 2s2

B 5 1s2 2s2 2px1

C 6 1s2 2s2 2px1 2py1

N 7 1s2 2s2 2px1 2py1 2pz1

O 8 1s2 2s2 2px2 2py1 2pz1

Representation of Electronic Structures

• Orbitals fill up with electrons singly before they double up

• Any one atomic orbital may only contain 2 electrons max.


1.7 – Valence Bond Theory

• Constructive interference results in a bonding orbital (s or p)

• Destructive interference results in an antibonding orbital

8

Representations of a Bond

• Constructive interference results in a bonding orbital (s or p)

• Electrons (“glue”) spend most time between the two nuclei

1.8 – Molecular Orbital Theory

• Electrons will populate the lower energy bonding orbital

• Higher energy antibonding orbital available to occupy later

Molecular Orbitals of CH3Br

CH3Br

• Lower energy bonding molecular orbital shown above in (a)

• Higher energy antibonding molecular orbital shown in (b)

1.9 – Hybridized Atomic Orbitals

Are the atomic orbitals of C adequate?

• The ground state atomic structure for C does not match CH4

• The orbital model must be reworked to explain the structure


9

1.9 – Hybridized Atomic Orbitals – sp3

Does 2s to 2p promotion solve the problem?

• We would now have 4 orbitals with 4 single electrons to bond

• The electrons would not contribute to 4 identical single bonds

Hybridization Model for Carbon

Does mixing the orbitals solve the problem?

• We would now have electrons in 4 equivalent atomic orbitals

• The electrons would now contribute to 4 identical single bonds

Sp3 Orbitals for Carbon

What do these sp3 orbitals look like?

Application of Hybrid Orbitals to CH4

The sp3 orbitals overlap with 1s from H to give CH4

10

3-D Representations for CH4

CH4 is tetrahedral about the central C atom

1.9 – Hybridized Atomic Orbitals : sp3

tetrahedral about the central C atoms

Hybridized Atomic Orbitals : sp2

C CH

H

H

HQuite a different bonding pattern requiring a pi bond

Sp2 orbitals

Hybridize to make sp2 orbitals

Pi bond required so one p orbital left untouched

Hybridization involves mixing 1 x 2s and 2 x 2p

11

Bonding in Ethene

sp2 orbitals form sigma bonds

p orbitals overlap to form pi bond

Hybrid Orbitals : sp

Quite a different bonding pattern requiring 2 pi bonds

Hybrid orbitals for sp C

Hybridize to make sp orbitals

Pi bond required so one p orbital left untouched

Hybridization involves mixing 1 x 2s and 2 x 2p

Orbital projections for sp C

sp orbital forms sigma bond

p orbitals overlap to form pi bonds

12

Examples of hybrid orbital diagrams

Examples

1.9 – Bond length and bond strength

1.10 – VSEPR and predicting geometry

Tetrahedral Trigonal pyramidal Bent

Predicting Geometry


13

Bonding and Shape so far… 1.11 – Dipole Moments and Molecular Polarity

Dipole present No dipole

Dipole Moments and Molecular Polarity


Dipole-dipoleinteractions

1.12 – Intermolecular Forces and Physical Properties

14

Intermolecular Forces and Physical Properties Intermolecular forces in alkanes

London dispersion forces

Branched alkanes

Branching decreases intermolecular attractions


1.13 – Solubility

“Like dissolves like”

15

Solubility

Cholesterol

Sucrose

“Like dissolves like”

1

Chapter 2 – Molecular Representations

TaxolMorphine

Brevetoxin B

2.1 – Molecular Representations

Structural isomers


2.2 – Bond-Line Structures Bond-Line Structures


2

Bond-line structures for complex molecules 2.3 – Identifying Functional Groups

Identifying Functional Groups Polyfunctional molecules

3

Alkyl halides (haloalkanes)

Br

ClF

I

Alkyl Halides

Alkenes (olefins)

OH

OHOHO

O

HO

Alkenes

Alkynes

Alkynes

Alcohols

OHOH

OH

Alcohols

4

Ethers

Ethers

Thiols

Thiols

Sulfides

S

SS

Sulfides

Aromatics (Arenes)

Aromatic (or Arene)

5

Ketones and Aldehydes

Ketones & Aldehydes

Carboxylic acids

Nicotinic acid

Citric acid Glutamic acid

Carboxylic Acids

Acid (Acyl) Chlorides

Oxalyl chloride

Benzoyl chloride

Acetyl chloride

Acid (or acyl) Chlorides

(Carboxylic) Anhydrides

Acetic anhydride

Benzoic anhydride

Maleic anhydride

Acid Anhydrides

6

(Carboxylic) Esters

Aspirin

Isoamyl acetate (bananas) Polyester

Esters

(Carbox) Amides

N,N-Dimethylformamide

Glutathione

Amides

Amines

Morphine

AnilineCadaverine

Amines

Complex polyfunctional molecules

7

2.4 – Carbon Atoms with Formal Charges 2.5 – Identifying Lone Pairs


Identifying Lone Pairs


2.6 – 3-Dimensional Bond-Line Structures

8

3-Dimensional Bond-Line Structures 2.7 – Introduction to Resonance

Acetate anionActual structure

Resonance Structures – Examples Introduction to Resonance

Allyl cation Propyl cation

9

Introduction to Resonance… 2.8 – Curved Arrows

Don’t exceed an octet when drawing resonance structures

2.9 – Formal Charges in Resonance Structures 2.10 – Resonance Structures via Pattern Recognition

Allylic lone pair

10

Resonance Structures via Pattern Recognition

Allylic lone pair

Allylic Carbocation

Allylic carbocation

Extended conjugated pi system

Heteroatom-stabilized Carbocations

Lone pair adjacent to a positive charge

Resonance structures for Benzene

Conjugated pi bonds in a cycle

11

2.11 – Assessing Relative Importance of Structures

Minimize charges in structuresElectronegative elements may be positive but must have octet


2.12 – Delocalized and Localized Lone Pairs

1

Chapter 3 – Acids and Bases

Citric acid Phenylalanine

Morphine Strychnine

3.1 – Introduction to Brønsted-Lowry Acids & Bases

Brønsted-Lowry : Acids are proton donors ; Bases are proton acceptors

Introduction to Brønsted-Lowry Acids & Bases

Brønsted-Lowry : Acids are proton donors ; Bases are proton acceptors

Water is amphoteric!

3.2 – Flow of Electron-Density : Curved Arrow Notation

Curved arrows are used to describe mechanisms

2

Flow of Electron-Density : Curved Arrow Notation

Curved arrows are used to describe mechanisms

3.3 – Brønsted-Lowry Acidity : Quantitative Perspective


Brønsted-Lowry Acidity : Quantitative Perspective

Low pKa = strong acid ; High pKa = weak acid


pKa values


3

pKa values..


pKa values…


Need to know these values

Need to know by next class:

• pKa = -log10Ka

• Strong Acid = LOW pKa Weak Acid = HIGH pKa

HI, HCl, HNO3, H3PO4 pKa -10 to -5 Super strong acidsH3O+ pKa – 1.7RCO2H pKa ~ 5 acidsPhOH pKa ~ 10 getH2O, ROH pKa ~ 16 weakerRCCH (alkynes) pKa ~ 25RNH2 pKa ~ 38 Extremely weakRCH3 pKa ~ 50 Not acidic at all

Phenol pKa (PhOH)

4

Amine pKa (RNH2) Alcohol pKa (ROH)

Carboxylic acid pKa (RCO2H)

OOH

Identifying acidic protons

5

Identifying acidic protons… 3.4 – Brønsted-Lowry Acidity : Qualitative Perspective

A separate “basicity constant” Kb is not necessary

Because of the conjugate relationships in the Brønsted-

Lowry approach, we can examine acid-base reactions by

relying exclusively on pKa values

CH

HH

H CH

HH

pKa ~50Not at all acidic

Corresponding baseExtremely strong


Brønsted-Lowry Acidity : Qualitative Perspective

Which side is favoured?

Qualitative perspective

Knowing the stability of the conjugate base

tells you about the strength of the acid

Stable anion

6

Qualitative perspective…

Knowing the stability of the conjugate base

tells you about the strength of the acid

Unstable anion

General acid-base trends

Across the periodic table…

Acids

Conjugatebases

Electronegativity plays a role in anion stability from left-to-right in periodic table

General acid-base trends… General trends

Down the periodic table…

Acids

Conjugatebases

Size of the anion plays a role in anion stability from left-to-right in periodic table

7

Trend down the periodic table

Down the periodic table…

Resonance effects

Why does Acetic Acid have a much more acidic OH group?

Acids

Conjugatebases

Resonancepossible!

Resonance effects…

Conjugate bases differ greatly in stability:

Acetate:

Inductive effects

Inductive effects play a role in anion stability:

Acetic acids:

More stable

8

Hybridization effects

Hybridization effects play a role in anion stability:

More s-character =More stable anion

Overall factors in acidity

Ranking factors that play a role in anion stability:

1. Atom : which atom is the charge on? Electronegativity? Size?

2. Resonance : can the charge be delocalized? Onto which atoms?

3. Induction : are there any electron-withdrawing groups close by?

4. Orbital : what is the hybridization of the orbital bearing the charge?

3.5 – Position of Equilibrium and Choice of Reagents

Conjugate bases

Right-hand side favoured

Position of equilibrium


9

3.6 – Leveling Effect and Choice of Solvent

Water will be useless in many cases since it will react:

Better solvents include alkanes and ethers:

3.7 – Solvating Effects

pKa = 18 pKa = 16

Steric effects mean t-Butoxide is less solvated and less stable

3.8 – Counterions

Cations are usually spectator ions so may be ignored:

3.9 – Lewis Acids and Bases


10

Biological acids and bases

Citric acid Phenylalanine

Morphine Strychnine

Chapter 3 – Acids and Bases : Examples

+ CH3CH2OKa.

b.

c.

CO2H

CC H

+ LiN[CH(CH3)2]

OH

+ CH3ONa

+ CH3CH2OH

CO2K

CC Li

+ HN[CH(CH3)2]

ONa

+ CH3OH

pKa ~ 5 pKa ~ 16products favoured

pKa ~ 26 pKa ~ 26products favoured

pKa ~ 16 pKa ~ 16neither favoured


Example acid-base exam questions

1

Chapter 4 – Alkanes and Cycloalkanes 4.1 – Introduction to Alkanes

Hydrocarbons : Compounds that contain only hydrogen and carbon

Alkanes : Hydrocarbons that only contain single bonds

(completely saturated): General formula = CnH2n+2

4.2 – Nomenclature of Alkanes : See Norris Website

HOH

H

H

(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol

Cholesterol

IUPAC alkane nomenclature

2

Systematic alkane nomenclature

9-(3,3-dimethylhexyl)-16-(4-methylhexyl)-23-(4-methylpentyl)-4-propyltriacontane

Basic nomenclature rules

IUPAC Rules:

Find the longest continuous carbon chain

Identify substituent groups attached to the chain

Number the chain so as to keep numbers small

Write the name in the following format:

Numerical location - [substituent(s)][parent alkane]

e.g. 2,3-dimethylheptane

Rules for naming alkanes

IUPAC Rules:


Parent names for alkanes

IUPAC Rules:


3

Finding the longest chain

IUPAC Rules:

Chains of equal length; choose one with most substituents

Identify substituent groups (branches) attached to the chain

Structures of cycloalkanes

Cycloalkanes

Cyclopropane Cyclobutane Cyclohexane

Cycloalkanes : Hydrocarbons that only contain single bonds (completely saturated): General formula = CnH2n

Identifying substituents

Naming substituents


Substituents on cycles

Naming substituents


4

Cycles as substituents

Naming substituents


Steps for naming alkanes

4-Ethyl-3,7-dimethyl-6-propyldecane


Naming branched substituents

Branched substituents


Butyl substituents



5

Pentyl substituents



Numbering for substituents

Assembling the Systematic Name of an Alkane

Keep the numbers as small as possible


Be careful when numbering




Keep the numbers small




6

Deciding upon the order




Numbering substituents on cycles




Systematic naming

4-Ethyl-2,3-dimethyloctane


Examples of naming alkanes

Examples

4-ethyl-3,6-dimethyloctane

hexane 2-methylhexane

2,4-dimethylheptane

7

Examples of naming cycloalkanes

Examples

1,1,3-trimethylcyclohexane

C(CH3)3

tert-butylcycloheptane

2-ethyl-1,1-dimethyl-cyclopentane

1-(sec-butyl)-3-isopropyl-5,7-dimethylcyclooctane

Bicyclic alkanes

Naming Bicyclic Compounds

Bicyclobutane

Bicyclo[3.2.0]heptane

Bicyclo[2.2.2]octane

Bicyclo[2.1.0]pentane

Bicyclo[4.1.0]heptane

Bicyclo[4.2.2]decane


4.3 – Constitutional Isomers of Alkanes Drawing constitutional isomers

Be careful when drawing isomers!

Same name = same compound


8

4.4 – Relative Stability of Isomeric Alkanes

Branched alkanes are generally more stable

4.5 – Sources and Uses of Alkanes

Alkanes also formed by cracking processes

4.6 – Drawing Newman Projections – See Website 4.6 – Drawing Newman Projections

Concentrating on one particular bond axis

9

4.7 – Conformational Analysis of Ethane and Propane

Conformational analysis possible:

Rotation around the central C-C bond axis

Dihedral angle = 60 o

Rotation around C-C bond axis

Ethane through 360° around the central C-C bond axis

4.7 – Torsional Strain – page 158 in Klein

H

H HH

HH

staggered

Conformational Analysis of Ethane and Propane

Propane through 360° around the central C-C bond axis

10

4.8 – Conformational Analysis of Butane

Butane through 360° around the central C-C bond axis

Conformational Analysis of Butane

Analysis of Butane

Anti(staggered)

eclipsed Gauche(staggered)

eclipsed

• In general, staggered conformations will be favoured over eclipsed

• Combination of torsional (angle) and steric (size) strain accounts for relative stabilities of conformations

Application to other molecules

Anti(staggered)

eclipsed Gauche(staggered)

eclipsed

Me = methyl; Et = ethyl ; Pr = propyl ; i-Pr = isopropyl ;

Bu = butyl ; t-Bu = t-butyl, etc….

11

4.8 – Typical Newman Depiction Questions

• Draw Newman depictions that correspond to the following conformations.

• The least stable conformation of 3-methylnonane along the C-4–C-5 bond.

• The most stable conformation of 1,1-dibromo-6-chlorohexane along the C-3–C-4 bond.

• A gauche conformation for 5-methyl-2-heptanol along the C-3–C-4 bond.

Typical Newman Depiction Questions

Branched examples 4.9 – Cycloalkanes

12

Cycloalkanes

Eclipsing inevitable in cyclopropane, on top of angle strain

Cyclobutane

Cyclobutane puckers to avoid eclipsing; still considerable angle strain

Cyclopentane

Cyclopentane is quite conformationally flexible and has less angle strain

4.10 – Conformations of Cyclohexane

Conformationally flexible (without breaking bonds)

Chair Boat Chair

13

Conformations of Cyclohexane

All staggered !

Conformations of Cyclohexane – Website

Cyclohexane ring-flip process

Cyclohexane interconverts through a ring-flip process

YouTube video describing “ring-flip” process

4.11 – Drawing Chair Conformations

Practice!Skillbuilder Exercise in Klein Text

14

Drawing Chair Conformations

Diagrams must reflect the fact that each

carbon in cyclohexane is sp3 hybridized

and therefore tetrahedral

Placing axial and equatorial groups correctly

Each carbon has one valence “up” and one “down”

Axial and equatorial orientations 4.12 – Monosubstituted Cyclohexane

Groups/atoms larger than H will prefer to be equatorial

15

Fluorocyclohexane

G = -0.24 Kcal/molK = 1.5

Methylcyclohexane

G = -7.6 Kcal/molK = 19

Isopropylcyclohexane

G = -9.2 Kcal/molK = 32.3

t-Butylcyclohexane

G = -22.8 Kcal/molK = >9999

16

Equatorial-axial ratios at equilibrium 1,3-Diaxial interactions

1,3-diaxial interactions account for instability

4.13 – Disubstituted Cyclohexane

Right-hand conformer favoured; both groups equatorial

cis-1,3-Disubstituted cyclohexane

Left-hand conformer favoured; both groups equatorial

17

trans-1,3-Disubstituted cyclohexane

Right-hand conformer favoured; larger group equatorial


4.14 – cis-trans Stereoisomerism

Cis-1,2-dimethylcyclohexane is less stable than the trans isomer

Cis-1,3-dimethylcyclohexane is more stable than the trans isomer

Cis-1,4-dimethylcyclohexane is less stable than the trans isomer

In each case both groups may be equatorial in preferred conformation

cis-trans Stereoisomerism

Equilibrium Constant (K) = [Right-Side][Left-Side]

G = - RTlnK

K > 1, RHS favoured; K ~ 1, equal; K < 1, LHS favoured

1,2-Dimethylcyclohexanes

Each conformation has

one CH3 group axial, K = 1

for equilibrium

Right-hand conformation

has both CH3 groups

equatorial, K >> 1

18

Typical cyclohexane exam question

Draw two chair conformations for cis-1-t-butyl-3-methylcyclohexane that are related through aring-flip. Then circle which conformation you expect to be more stable and explain why. Then dothe same for the trans isomer and, finally, indicate whether the cis or trans isomer should be morestable overall and explain your choice.

Typical Cyclohexane Question

4.15 – Polycyclic Systems Decalins

This isomer has to have

one alkyl group axial on

both cyclohexane rings

In this isomer both of the

alkyl substituents are

equatorial, preferred

19

Polycyclic systems Models of polycyclic systems

Polycyclics – Cholesterol

1

Chapter 5 – Stereoisomerism

Morphine

Cholesterol

Strychnine

Taxol

5.1 – Overview of Isomerism

Overview of Isomerism

(More alkene detail in Chapter 8)

5.2 – Introduction to Stereoisomerism

Chirality : isomers related like your hands

2

Introduction to Stereoisomerism

Chirality : isomers related like your hands

Mirror plane relationships

Chirality : isomers related as non-superimposable mirror images

Non-superimposable mirror images

Carbon atom here is asymmetric C is a stereogenic center or chiral center

Examples of stereoisomers

Looking for 4 different atoms or groups

attached to sp3 carbon atom

3

Determining chirality

Looking for 4 different atoms or groups

attached to sp3 carbon atom

Mirror plane from behind molecule

Amphetamine

Enantiomers : non-superimposable

mirror images

Mirror plane from next to molecule

Enantiomers : non-superimposable

mirror images

Examples of enantiomers

• same physical properties except rotation of plane polarized light

• one enantiomer positive rotation (+) other negative rotation (-)

4

5.3 – Designating configuration : Cahn-Ingold-Prelog

Prioritize based on atomic number

Designating configuration : Cahn-Ingold-Prelog

Place 4 at back, pointing away from you

Cahn-Ingold-Prelog – direction of groups

Look for direction of groups :

clockwise = R ;

counterclock-wise = S

Cahn-Ingold-Prelog – prioritization

Both groups are equivalent –Must go further along chains

5

Cahn-Ingold-Prelog – tie-breakers Cahn-Ingold-Prelog – tie-breaks

Cahn-Ingold-Prelog – double bonds

Look for sequence of groups : Counterclockwise

= S configuration

Don’t get confused…

OH

6

Cahn-Ingold-Prelog rules Cahn-Ingold-Prelog rules – examples

Two chiral centers

Numbers at the front must match the specific chiral center

5.4 – Optical activity

Enantiomers have equal but opposite rotations in polarimeter

7

Optical activity

Enantiomers have equal but opposite rotations in polarimeter

Calculating specific rotation

Specific rotation ensures standardized values

Enantiomeric excess

Enantiomeric excess measures optical purity

Example:

Observed [] = 45[] of pure enantiomer = 53

% ee = (45/53) x 100 = 85%

5.5 – Enantiomers and diastereomers

When 2 or more chiral centres are present a new relationship

between some of the stereoisomers is observed since they

cannot all be enantiomers

8

Enantiomers and diastereomers

2 “cis” isomers 2 “trans” isomers

What is the relationship between (1R, 2S) and (1R, 2R)

or (1R, 2S) and (1S, 2S)?

These are diastereomers

Three stereocenters

Multiple stereocenters

8 stereocenters = 28 possible stereoisomers

Four stereocenters

4 stereocenters = 24 possible stereoisomers

9

5.6 – Symmetry and chirality

Consider these isomers:

For the transisomers:

The trans isomer possesses a rotational axis of symmetry

Symmetry and chirality

Consider these isomers:

For the cisisomer:

The cis isomer possesses a plane of symmetry

Internal symmetry

The cis isomer possesses a plane of symmetry that

results in two of the possible stereoisomers being

identical, i.e meso

Internal symmetry – meso

Internal plane of symmetry in (c) means only 3

stereoisomers and not 4, i.e meso

10

5.7 – Fischer projections

Multiple chiral centres may be represented

quickly for acyclic molecules

Fischer projections

By definition in Fischer depictions:

Horizontal lines = coming out of plane

Vertical lines = going into plane

Use of Fischer projections

Easy to see enantiomeric and diastereomeric

relationships in more complex molecules.

Very useful later with sugars in Biochemistry

5.7 – Drawing Fischer projections

MeMe

Br

BrMe

MeBr

BrMe

MeBr

BrMe

MeBr

Br

(R, R) (S, S) (R, S) (S, R)

MeMe

Br

Br

(R, S)

Me BrBr

Me

(R, S)

HH

staggered eclipsed

Me

Me

Br HBr H

Fischer

(R, S)

11

Drawing Fischer projections

MeMe

Br

BrMe

MeBr

BrMe

MeBr

BrMe

MeBr

Br

(R, R) (S, S) (R, S) (S, R)

Me

Me

Br HBr H

Fischer

(R, S)

Me

Me

Br HH Br

Fischer

(R, R)

Me

Me

H BrBr H

Fischer

(S, S)

Fischer projections – carbohydrates

CH2OHOHC

OH

OHCH2OH

OHCOH

OHCH2OH

OHCOH

OHCH2OH

OHCOH

OH

(S, R) (R, S) (S, S) (R, R)

C

CH2OH

HO HH OH

Fischer

(S, R)

C

CH2OH

H OHHO H

Fischer

(R, S)

C

CH2OH

HO HHO H

Fischer

(S, S)

C

CH2OH

H OHH OH

Fischer

(R, R)

O H O H O H O H

Stereochemical relationshipsFor each of the following pairs of molecules, provide the configuration of each chiral centre andthen indicate whether the two molecules within a pair are enantiomers, diastereomers, or areidentical.

a.

b.

c.

and

and

and

OH

Br

CH3

CH3

H BrH OH

O CH3

CH3 O CH3

CH3

CH3

H OHCH2Cl

FH H3CCH2Cl

OH

F

5.8 – Conformationally mobile systems

These conformations are enantiomeric,

however the molecules are not chiral

12

5.9 – Resolution of enantiomers

Convert to diastereomers, separate, then

convert back to enantiomers

Resolution of enantiomers

Separate diastereomeric salts by crystallization, then add base

to liberate each amine enantiomer

Stereoisomerism concepts

Organic molecules are capable of being CHIRAL

Must have 4 different atoms/groups attached at sp3 carbon

Non-superimposable mirror images are ENANTIOMERS

Other isomers are related as DIASTEREOMERS

Isomers with internal plane of symmetry are MESO

n stereocenters means a maximum of 2n stereoisomers

1

Chapter 6 – Chemical Reactivity & Mechanisms

heterolytic

homolytic

What makes molecules reactive and how do we describe

how bonds form and break on the way to products?

6.1 – Enthalpy

Atoms bond together to become more stable as molecules

6.1 – Enthalpy : types of bond-breaking

To break bonds requires energy : two unique ways of cleavage

6.1 – Enthalpy : bond energies

2

6.1 – Enthalpy : energy changes

Two types of enthalpy change in a system going from starting materials to products:

Exothermic = products more stable

Endothermic = reactants more stable

6.1 – Enthalpy : using bond energies

For example: using bond energies in a radical halogenation reaction:

6.2 – Entropy 6.3 – Gibbs free energy

G = H – TS

3

6.4 – Equilibria

Thermodynamics

Products favoured in exergonic process

6.4 – Equilibrium constant

Thermodynamics

Equilibrium constant related to populations of products and reactants, which are related to their relative stabilities

6.4 – Equilibrium constant and G

Thermodynamics

Equilibrium favours the more stable material, in this case the products (K > 1)

Equilibrium constant and G

Thermodynamics

4

G and equilibrium constant

Thermodynamics

The bigger the difference in free energy, the bigger the equilibrium constant

6.5 – Kinetics : Molecularity

Kinetics

In Chem 3719 and 3720 we will mostly deal with first and second order reactions

Factors Affecting the Rate Constant – 1. Activation Barrier

Kinetics

Activation barrier dictates the rate of a reaction (or a step)

Rate Constant – 1. Activation Barrier

Kinetics

Remember: not all molecules have the same energy at the same time

5

Activation Barrier

Kinetics

More molecules will have enough energy to get over the

lower barrier so this reaction will be faster

Factors Affecting the Rate Constant – 2. Temperature

Kinetics

Raise the reaction temperature to make

it go faster!

At higher temp, even more molecules will now have enough energy

to get over the reaction barrier so the reaction will be faster

Factors Affecting the Rate Constant – 3. Sterics

Kinetics

Crowding at a reaction centre can slow the rate of reaction by

raising the activation barrier for that process

Factors Affecting the Rate Constant – 4. Catalysts

Kinetics

Catalyst will lower activation barrier but will not change

the composition of an equilibrium

6

6.6 – Reading energy diagrams

Kinetics deals with rates, thermodynamics deals with product stabilities

Reading energy diagrams..

Here the kinetic product is also

the thermodynamic product

Here the kinetic product is not

the thermodynamic product

Reading energy diagrams…

Transition states are in flux; intermediates are real, measurable, species

Concerted reaction profile

Everything happening

at once = Concerted

Transition states feature bonds forming and breaking

7

Stepwise reaction profile

Events happening in

steps = Stepwise

In intermediates bonds are completely formed and/or broken

The Hammond postulate

Hammond Postulate: T.S. resembles the closest species

Towards arrow pushing…

aq. H2SO4 (catalyst)

OH

O

O

OHOH OH2

OH

OH

OH

OH

OH

OH

HO

O

HO OH

HO

HO OH2

O

OH

O

OH

O

OH

H+ trans

HOR

6.7 – Nucleophiles and electrophiles

Polarity in bonds often leads to reactivity:

Electron-poor = electrophile ; electron-rich = nucleophile

8

Nucleophiles and electrophiles

Nucleophiles are Lewis bases (electron-rich) with at least one lone pair available

Powerful nucleophile

(unstable like hydroxide)

Weak nucleophile

(stable like water)

Pi bond as nucleophile

Pi bonds may also serve as nucleophiles as they feature an unshared pair of electrons

Pi electrons will be donated to electron-poor species (electrophiles)

Electrophiles

Electron-poor carbon serves as an electrophile in many different organic reactions

Electrophile may be the consequence of a dipole or a carbocation

Electrophiles – carbocations

Electron-poor reactive intermediates known as carbocations are common species

Carbocations feature trivalent sp2 hybrid C – trigonal planar

9

Examples of nucleophiles and electrophiles 6.8 – Mechanisms and arrow pushing

Polar mechanisms require the use of double-headed arrowsto describe the movement of electrons

Lewis base“nucleophile”

Lewis acid“electrophile”

Arrows flow from electron-rich areas to electron-poor

areas; number of arrows depends upon electrophile

Types of arrow – Nuc attack

There are four basic patterns for arrow pushing

1. Nucleophilic attack

Only need one arrow since the electron-deficient

carbocation is a 6-electron species

Nucleophilic attack

Could use one arrow or two here

10

Types of arrow – Leaving group

2. Loss of a leaving group

Types of arrow – Proton transfer

3. Proton transfers

Types of arrow – Rearrangements

4. Rearrangements

Hyperconjugation is the donation of electron density from adjacent sigma bonds to an electron-deficient

species, here the carbocation (empty p orbital)

Rearrangements to more stable carbocations

4. Rearrangements

Carbocations need electron density – -bonds help

through hyperconjugation

11

Hydride migration

4. Rearrangements

Carbocations need electron density – -bonds can

migrate to produce a better carbocation

Alkyl migration

4. Rearrangements

Carbocations need electron density – -bonds can

migrate to produce a better carbocation

6.9 – Combining the Patterns of Arrow Pushing

Nucleophilic substitution – Chapter 7

Combining the Patterns of Arrow Pushing

Saponification – Chapter 21

Nucleophilicattack

Loss of leaving group

Proton transfer

Of the > 100 mechanisms in Chemistry 3719 and 3720

most are polar and those mechanisms break down to

these four essential types of arrow pushing

12

6.10 – Drawing curved arrows

Be precise! The arrows have meaning.

Drawing curved arrows

Arrows must represent logical processes

6.11 – Carbocation rearrangements

Arrows must represent logical processes

6.12 – Equilibrium arrows

13

Chapter 6 – Summary

• Starting material(s)

• Reagent(s)

• Reaction rate

• Activation barrier

• Transition state

• Concerted

• Products

• Reversible?

• Equilibrium

• Kinetic product

• Thermodynamic

product

Summary

• Stepwise pathway • Reactive intermediate • Rate-determining step

Mechanistic exam questions

(12 pts) Give the major organic product formed under the following reactionconditions and then a detailed mechanism, using curved arrows to show bondsbeing formed and broken, to describe the transformation.

Exam questions

Draw a reaction profile on the axes below for the formation of the organic productabove that includes structures of the reactant, any intermediate(s), and a transitionstate for the rate-determining step only.

1

Chapter 7 – Substitution Reactions 7.1 – Introduction to Substitution Reactions

Introduction to Substitution Reactions

Alkyl halide substrates are polarized

Halides are good at accepting lone pair

7.2 – Alkyl halides (see website for help)

1. Identify and name the parent alkane

2. Identify and name the substituents

3. Number the parent chain and assign numbers

4. Assemble the substituents alphabetically

2

7.2 – Alkyl halides : naming Alkyl halides : naming

Substitutive name Functional class name

Alkyl halides : examples Alkyl halides : naming examples

• Functional class nomenclature

• Substitutive nomenclature

3

Alkyl halides : molecule geography

Functional groups such as halides and OH

groups are at the alpha position

Alkyl halides : classification

7.3 – Possible Mechanisms for Substitutions

Review from Chapter 6 – Arrow-pushing combinations

7.3 – Possible Mechanisms for Substitution Reactions

Concerted

Stepwise

Impossible

4

7.4 – The SN2 mechanism 7.4 – Biological SN2 mechanism

Biological Alkylation of an Amine

H2N

HO HHO

HO

NHCH3

HO HHO

HO

O

OHOH

SN

N N

N

NH2

CH3

NH3

O

O

O

OHOH

SN

N N

N

NH2

NH3

O

O

SN2 examples

Br+ NaI

acetone I+ NaBr

7.4 – Inversion in SN2

Stereospecificity of SN2 Reactions

5

Inversion in SN2


LUMO of electrophile

Inversion in SN2 – stereospecificity


http://www.bluffton.edu/~bergerd/classes/cem221/sn‐e/SN2.gif

Stereospecificity


The SN2 reaction is said to be stereospecific

where the stereochemistry of the product

depends on the stereochemistry of the reactant

Rates of SN2 reactions

Structure of the Substrate

Crowding around the electrophile slows the SN2 reaction

6

SN2 reaction profile

Steric effects felt inthe transition state

SN2 – relative rates of reaction

SN2 rates : CH3 > 1° > 2° >>> 3°

SN2 – steric effects

Even crowding at the beta carbon will slow the SN2 reaction

SN2 – examples

Br N3NaN3

solvent

Br KCN

solvent

I NaSH

solvent

CN

SH

7

7.5 – The SN1 mechanism The SN1 mechanism

The SN1 mechanism in Biology

Glycosyl cation

Important in oligo- and polysaccharide biosynthesis

Example of biological SN1

7.5 – SN1 reaction profile

8

7.5 – SN1 rates of reaction

This is the opposite order to the SN2 reaction;

here the 3o system will react fastest

Structure of Substrate

7.5 – Relative carbocation stability

Structure of Substrate

7.5 – Activation barrier in SN1 reactions

Reaction rates related to carbocation stability

7.5 – Stereochemistry in SN1 reactions

Stereochemical Changes in SN1 Reactions

Reaction produces a racemic mixture

9

Stereochemistry in SN1 reactions Examples of SN1 reactions

Br CH3OH

BrH2O

I CH3CH2OH

O

OCH3

OCH3

+

racemic

OH

O O

HO

+

racemic

chiral

chiral

achiral

OCH2CH3

achiral

7.5 – The SN1 mechanism : comparison with SN2 7.6 – Drawing the complete SN1 mechanism

Alcohol starting material

Reaction requires the acid, will not work with NaCl

Rate-determining step is unimolecular

How does the mechanism differ?

10

The SN1 mechanism – leaving groups

A proton transfer step will be requiredat the beginning of the mechanism

The SN1 mechanism – arrow pushing

The SN1 mechanism – solvolysis

H+ is lost at the end

SN1 solvolysis with alcohols

Ether

H+ is lost at the end

11

7.6 – Rearrangements in SN1 reactions

Rearrangements possible in SN1

Rearrangements in SN1 reactions


H+ picked up in first step

SN1 rearrangement reaction profile


7.7 – Drawing the complete SN2 mechanism

Alcohol starting material

Reaction requires the acid, will not work with NaCl

Rate-determining step is bimolecular

How does the mechanism differ?

12

Drawing the complete SN2 mechanism


SN2 mechanism with alcohol

H+ lost in the Last step

7.7 – SN2 mechanism with epoxide


H+ lost in the last step

7.8 – Determining which mechanism predominates

Four unique factors play a role in determining which mechanism operates

1. Substrate structure

2. Leaving group type

3. Nucleophile type

4. Nature of solvent used

13

Determining which mechanism predominates

These systems may do either SN1 or SN2

1. Substrate Structure

Methyl and simple 1° systems will always do SN2

3° systems will always do SN1

2° systems may do either depending on conditions

Which mechanism predominates – nucleophile

2. Nucleophile Used

Which mechanism predominates – leaving group

3. The Leaving Group

In both SN1 and SN2 the leaving group must accept a lone pair

Ability to do so is directly related to the base strength of the group

Weak bases make good leaving groups

7.8 – Leaving group ability

14

Leaving group ability Solvation in SN2

4. The Solvent

Solvents for SN2

4. The Solvent

Solvent effect on reaction rates for SN2

4. The Solvent

15

Polar solvents stabilize transition states

4. The Solvent – polar solvents stabilize transition states

Polar protic solvents slow down SN2

4. The Solvent – polar protic solvents mask nucleophiles

Which mechanism predominates?

Overall factors in determining most likely mechanistic pathway

7.9 – Selecting Reagents to Accomplish Functional Group Transformation

16

SN1 and SN2 reactions

Br CH3OH

BrNaCN

I KSCH2CH3

O

OCH3

OCH3

+

racemic

O

CN

3o substrate

SCH2CH3

achiral

weak nucleophile(polar protic)

2o substrate

DMFgood nucleophile

(polar aprotic)

2o substrate

DMSOgood nucleophile

(polar aprotic)

inversion

1

Chapter 8 – Alkenes: Structure and Preparation

Arachidonic acid

Vinyl chloride

Vitamin A

8.1 – Introduction to elimination reactions

8.2 – Alkenes in nature and industry Alkenes in nature and industry

2

8.3 – Nomenclature of alkenes

1. Identify the parent compound

2. Identify the substituents

3. Assign a number to each substituent

4. Arrange the substituents alphabetically

Nomenclature of alkenes





Numbering of alkenes





Pi bond gets low number

Correct numbering of alkenes





Both names are acceptable

3

Common names for alkenes and substituents Alkene substitution patterns

Classification of Alkenes based on Substitution Pattern

8.4 – Stereoisomerism in alkenes

Pi bond is rigid –No rotation

Stereoisomerism in alkenes

Trans isomers for small cycloalkenes are impossible

H

HH

H

Cis-cycloheptene and trans-cycloheptene (too strained)

C-12 cis and trans ~ equal in energy

4

Assigning stereochemistry in alkenes

E and Z designations

Cahn-Ingold-Prelog rules in alkenes


Same rules of prioritization as for chirality centers

Cahn-Ingold-Prelog rules

C-I-P rules in alkenes


Examples of application

Cl

Br

F

O

H

F

CH3

CN

CH3

Br

5

8.5 – Alkene stability 8.5 – Alkene stability : proof

8.5 – Alkene stability : substitution patterns 8.5 – Alkene stability : isomer stability

6

8.6 – Possible mechanisms for elimination Possible mechanisms for elimination

Concerted pathway

Stepwise pathway

8.7 – The E2 mechanism : evidence 8.7 – The E2 reaction : examples

Br

+NaOCH3

+ CH3OH + NaBr

NaOCH3

Br+ CH3OH + NaBr

only alkene formed

only alkenes formed

KOC(CH3)3I

+ (CH3)3COH + KI

only alkene formed

7

8.7 – The SN2 and E2 mechanisms : competition

Br OCH3

NaOCH3

DMF

OCH3

+ NaBr

NaOCH3

DMF

OCH3

+ NaBr

BrNaOCH3

DMF

OCH3

+ NaBr + CH3OH

Br OCH3

+

+

SN2 only

SN2 and E2

E2 only

8.7 – The E2 mechanism : substrate

SN2 and E2 compete but E2 wins with bulky substrates

The E2 mechanism : substrate

T.S. for 3° system will feature a more highly substituted double bond forming

The E2 mechanism : reaction profile

8

The E2 mechanism : relative rates The E2 mechanism : regioselectivity

Notice the change in regioselectivity

8.7 – The E2 mechanism : stereoselectivity 8.7 – The E2 mechanism : stereospecificity

Only product

9

The E2 mechanism : stereospecificity E2 mechanism : stereoselectivity

Two different beta-H may come off to give isomeric products - stereoselective

8.7 – The E2 mechanism : cycles 8.8 – Drawing the Products of E2

10

E2 reactions : examples

Br KOt-Bu

NaOCH2CH3

I NaOCH3

3o substrate

large base

2o substrate

small base

1o substratesmall base

minor major

+

Br

major

only product

CH3 CH3

minor

CH3

+

8.9 – The E1 mechanism

The E1 mechanism 8.9 – The E1 mechanism : substrate

11

The E1 mechanism : substrate The E1 : substrate

E1 and SN1 both feature carbocation intermediates

In reality, both mechanisms actually compete

The E1 mechanism : example

OH+ H2O

H2SO4

heat

OH2H

protonation

dissociation

deprotonation

Excellent leaving group

8.9 – The E1 mechanism : regioselectivity

CH3HO CH3 CH2

+H+

OHH+

+

12

The E1 mechanism : regioselectivity

Trans favoured

OH2

protonate

lose leaving group

deprotonate

8.10 – Drawing the complete E1 mechanism

Here a proton transfer is required at the beginning to create a leaving group

8.10 – Complete E1 mechanism with rearrangement

A good leaving group is already present so no protonation needed

Complete E1 mechanism with rearrangement

Here a proton transfer is required at the beginning to create a leaving group

13

E1 mechanism with rearrangement E1 mechanism with rearrangement : example

OH

H3PO4

heat

OH2

H

H

H

3% 33% 64%

Secondary cation rearranges to tertiary

8.11 – Drawing the complete E2 mechanism 8.12 – Substitution vs. Elimination : identifying reagents

If you only want the alkene then choose E2

14

Substitution vs. Elimination : identifying reagents 8.13 – Substitution vs. Elimination : identifying mechanisms

E1 and E2 do not compete effectively with these nucleophiles

Substitution vs. Elimination : identifying mechanisms

SN1 and SN2 do not compete effectively with these bases

Substitution vs. Elimination : identifying mechanisms…

Change in mechanism related to accessibility of alpha carbon

15

Substitution vs. Elimination : practicality

Some reactions are too slow and some give too many products

Substitution vs. Elimination : practicality..

Substitution vs. Elimination : prediction Substitution vs. Elimination : examples

Examples

1

Chapter 9 – Addition Reactions of Alkenes

Crixivan® (Indinavir, Merck & Co.) : a protease inhibitor for HIV

9.1 – Introduction to addition reactions

Introduction to addition reactions 9.2 – Addition vs. Elimination : thermodynamics

Chapter 9

Chapter 8

2

Addition vs. Elimination : thermodynamics Thermodynamics

Addition reactions are usually enthalpically favored but entropically disfavoured

9.3 – Hydrohalogenation

Stronger acids react faster :

H-I > H-Br > H-Cl >> H-F

Slow step of reaction is protonation to give

intermediate carbocation

9.3 – Hydrohalogenation – mechanism

3

9.3 – Hydrohalogenation – regiochemistry

Markovnikoff Addition

Hydrohalogenation – regiochemistry


Hydrohalogenation – Markovnikoff


Markovnikoff regioselectivity


4

Anti-Markovnikoff regioselectivity

(Mechanism later in Chapter 11)

9.3 – Hydrohalogenation : stereochemistry

Hydrohalogenation : stereochemistry Hydrohalogenation : examples

ExamplesCH3

HBrCH3

+

HBr, H2O2

H3C Br

Br

Br

+Br

HCl+

Cl

Cl

5

9.3 – Hydrohalogenation : rearrangements

Clue : the nucleophile has added to a carbon that was not part

of the original alkene – must involve rearrangement

Hydrohalogenation : rearrangements

9.4 – Acid-catalyzed hydration 9.4 – Acid-catalyzed hydration - kinetics

6

Acid-catalyzed hydration

Note the Markovnikoff regioselectivity

Acid-catalyzed hydration – controlling equilibrium

Enthalpy favours the right (sigma bonds) but entropy favours the left

(more species) – hydration preferred at low temp., E1 at high temp.

Acid-catalyzed dehydration – the equilibrium Acid-catalyzed hydration – the equilibrium

7

Dehydration – hydration : the equilibrium

HO+ H3O

H2SO4

HOH

H+ transfer

nucleophile attack

H+ transfer

Hleaving group

9.4 – Acid-catalyzed hydration : stereochemistry

prochiral alkeneracemic mixture

prochiralcarbocation

9.4 – Acid-catalyzed hydration : examplesExamples

CH3dil. H2SO4

CH3

+

major minor

dil. H2SO4

H3C OH

OH

(+/-)

OH

+OH

major minor(+/-)

dil. H2SO4+

major minor(+/-)

OH

OH

9.5 – Oxymercuration-demercuration

8

Oxymercuration-demercuration 9.6 – Hydroboration-oxidation

Addition

Oxidation

Hydroboration-oxidation

H.C. Brown

“parachute borane”

Hydroboration-oxidation – boron

Trivalent boron reagents act as Lewis acids

9

9.6 – Hydroboration-oxidation – stereoselective

CH3 1.

2. NaOH, H2O2

H

OH

CH3

H

OH

CH3

+

H

OH

CH3

H

OH

CH3

+

but not

2 new chiral centres formed but only 2 enantiomers produced

The hydroboration/oxidation sequence is both stereoselective and regioselective:

How and why?

(S,S) + (R,R)

(R,S) + (S,R)

BH

9.6 – Stereoselective and regioselective

Addition of H-BR2 is a concerted syn addition – evidence for mechanism :

9.6 – Regioselectivity in addition

Two possible transition states for concerted addition

of H-BR2 to an unsymmetrical alkene

9.6 – Mechanism of addition

CH3 1. H-BR2, THF

2. NaOH, H2O2

H

OH

CH3

HHH

H

Step 1 Syn Addition

HBRR

H

HHH

R2B

H

(+/-)

10

9.6 – Mechanism of oxidation

Step 2 Oxidation

H O O H + NaOH H O O Na-H2O

CH3

HR2B

H O O

CH3

R2BO O H

CH3

HOR2B

CH3

HOHH

OH

CH3

OH-

then hydrolyze

9.6 – Hydroboration : stereopecificity

9.6 – Hydroboration-oxidation : examples

Examples

9.7 – Catalytic Hydrogenation

Catalyst lowers activationbarrier and provides lowerenergy pathway to product

11

Catalytic hydrogenation

H atoms have added to the same face of the alkene - syn addition

Catalytic hydrogenation – catalysts

Organic-soluble

Syn addition only

Catalytic hydrogenation – stereochemistry

Enantiomers formed in both cases

Catalytic hydrogenation – enantioselectivity

Chiral catalyst provides an asymmetric

environment in which complexation to

one face of the alkene is more stable with

a lower energy transition state

12

Catalytic hydrogenation – examples

ExamplesCH3 H3C

only product

H achiral

Honly product

H

H2, PtH

H

H

achiral

racemic

H2, Pt

H2, Pt

9.8 – Halogenation

Induced dipole in the presence of a nucloephile(pi bond)

9.8 – Addition of Br2 9.8 – Addition of Br2 : the bromonium ion

13

9.8 – Addition of Br2 : stereospecificity Addition of Br2 : stereospecificity

9.8 – Halohydrin formation 9.8 – Halohydrin formation : regioselectivity

14

9.8 – Halohydrin formation : rationale

Regiochemical outcome is a consequence of stabilized transition state

9.8 – Halohydrin formation : examples

Examples CH3 H3C

only anti products

Br racemic

Br

Br

Br2, CCl4Br

HO

Br

racemic

racemic

Br2, H2O

only anti products

only anti products

Br2, CCl4

9.8 – Syn additions

H H

OH

NaOH/H2O2BH

B

9.8 – Anti additions

15

9.9 – Anti dihydroxylation Anti dihydroxylation

9.9 – Epoxides as reactive species 9.10 – Syn dihydroxylation

16

Syn dihydroxylation Dihydroxylation : examples

ExamplesCH3 H3C

only anti products

OH racemic

OH

OH

1. CH3CO3HOH

HO

OH

racemic

racemic

only anti products

only syn products

KMnO4, NaOH

2. H3O+

1. CH3CO3H

2. H3O+

9.11 – Oxidative Cleavage : Ozonolysis

H3CCH3

1. O3

2. Zn, H2O

CH3H

CH3

H3C OO

CH3

H

H3C

H3C OO

OOOO

CH3

H3Cmalozonide ozonide

CH3 H3C

Oxidative Cleavage : Ozonolysis

17

Ozonolysis examples

ExamplesCH3 H3C

only product

O

OH

1. O3, CH2Cl2 O

O

OH

racemic

only products

only syn products

KMnO4, NaOH

2. Zn, H2O

1. O3, CH2Cl2

2. Zn, H2O

H

O+

9.12 – Predicting the Products of Addition

Factors:

1. What groups are being added across the double bond?

2. Expected regioselectivity (Markovnikoff or anti-Markovnikoff)?

3. What is the expected stereospecificity (syn or anti addition)?

Solving Problems:

1. Know what the products will be for each of the reagents studied

2. Understand mechanism in order to understand regioselectivity

3. Stereochemical outcome is a clue to which mechanism operates

9.13 – Synthesis Strategies : The Toolbox

Substitution

Elimination

Addition

Synthesis Strategies : The Toolbox

Move a leaving group

18

Synthesis : The Toolbox


9.13 – Synthesis : The Toolbox


9.13 – Synthesis : moving a pi bond

Move a pi bond

1. Addition is anti-Markovnikoff (HBr, peroxides)

2. Elimination is Hoffmann (requires large base)

9.13 – Synthesis

1

Chapter 10 – Alkynes

Histrionicotoxin

Chapter 10 – Alkynes : examples

Cicutoxin

Alkynes : examples

Calicheamicin

Alkynes : divalent

Tetrahedral

(4 valent)

Trigonal planar

(4 valent)

Linear

(2 valent)

2

Click chemistry : Bioorganic applications Click chemistry : YSU

OO OO

O

H

N3

(PPh3)3.CuBr, DBUPhMe, reflux O

OO

O O

O

OO

O

O

NN N

H

O

O

O

O

O

NN

N

H

OO O

OO

60%

O

OO

O

O

OMe

N NN

NN

N

NN

N

N

NN

OAcO

AcOAcO

OAc

O

OAcAcO

AcO

OAc

O

AcO

OAcOAc

AcO

O OAc

OAcAcO

AcO

O

OO

O

O

OMe

O

OAcAcO

AcO

OAc

N3

(PPh3)3.CuBr, DBUPhMe, reflux

65%

Penny Miner, Ricerca

David Temelkoff, GSK

Click chemistry : cell engineering R = methyl, ethyl, propyl, phenyl, animal

R = animal

Bertozzi et. al. U.C. Berkeleyand Stanford

3

10.1 – Introduction to Alkynes Alkynes – the triple bond

Alkynes – biologically active 10.2 – Numbering of alkynes

4

Numbering of alkynes Naming of alkynes

10.2 – Nomenclature of alkynes

2-methylnon-4-yne

H

Br

(1R,3R)-1-bromo-3-ethynylcyclohexane

H(Z)-6-fluorohept-5-en-1-yne

F

10.3 – Acidity of acetylene and terminal alkynes

5

Acidity of acetylene and terminal alkynes pKa values for terminal alkynes

10.4 – Preparation of alkynes Preparation of alkynes

(Vicinal)

(Geminal)

6

10.5 – Reduction of alkynes Reduction of alkynes

Reduction of alkynes – catalysis Reduction of alkynes – Birch

7

10.6 – Hydrohalogenation of alkynes Hydrohalogenation of alkynes

Ch. 9

Ch. 10

Hydrohalogenation of alkynes : rate equation Hydrohalogenation of alkynes : anti-Markovnikoff

Ch. 9

“Anti-Markovnikoff” addition via radicals

Addition through secondary vinylic radical preferred

8

10.7 – Hydration of alkynes

Ch. 10

10.7 – Tautomerism

10.7 – Enol tautomerism 10.7 – Hydration mechanism

CH3 C C CH3H+, H2O

CH3 C CH2CH3

O

HO

H

H

CH3 C C CH3

H

CH3 C C CH3

H

OH H

OH

H

CH3 C C CH3

H

OH

HO

H

H

CH3 C CH2CH3

OH

CH3 C CH2CH3

OH

OH

H

OH

H

9

10.7 – Hydration mechanism : terminal alkyne 10.7 – Hydration of alkynes : examples

Examples

H

Br

HF

dil. H2SO4

dil. H2SO4

dil. H2SO4

Br

F

O

O

+

O

CH3

O

CH3

10.7 – Hydration of alkynes : hydroboration

opposite regiochemistry

10.7 – Hydration of alkynes : regioselectivity

10

10.8 – Halogenation of alkynes 10.8 – Ozonolysis of alkynes

10.10 – Alkylation of terminal alkynes Alkylation of terminal alkynes

11

Alkylation of terminal alkynes : examples

Examples

H

H

CH3

HF

1. n-BuLi, THF CH3

CH3

F

2. CH3Br

1. NaNH2, DMF

2. CH3CH2CH2I

1. LiN(iPr)2, THF

2. (CH3)2CHCH2CH2Br

10.11 – Synthesis strategies

Alkynes are versatile reagents for chain-elongation (by alkylation)

Provide access to aldehydes/ketones (by hydration)

Easily converted to cis or trans alkenes by reduction

Synthesis strategies

Examples

H ?

H 1. NaNH2, THF

Na dissolved in NH3

chain elongation

2. CH3CH2Br

Functional grouptransformation

1

Chapter 11 – Radical Reactions 11.1 – Radicals

11.1 – Radicals : reactive intermediates 11.1 – Radical structure

Experimental evidence for either structure

2

11.1 – Radical stability 11.1 – Resonance-stabilized radicals

Allylic radical

Benzylic radical

11.1 – Bond-dissociation energies 11.1 – Comparison of allylic and vinylic

3

11.2 – Common Patterns in Radical Mechanisms

Although radicals are similar to carbocations in terms of

their relative stability, their chemistry is quite different

Common Patterns in Radical Mechanisms

1. Homolytic cleavage

2. Addition to a pi bond

11.2 – Patterns in Radical Mechanisms

3. Hydrogen abstraction

4. Halogen abstraction

11.2 – Patterns in Radical Mechanisms..

5. Elimination

6. Coupling

4

11.2 – Patterns in Radical Mechanisms…

Types of steps in radical mechanisms

11.3 – Chlorination of Methane

Chlorination of Methane 11.3 – Radical Reactions : Free Radical Initiators

All are weak bonds and easy to break

5

11.3 – Radical Reactions : Free Radical Inhibitors 11.4 – Thermodynamic Considerations for Halogenation

Thermodynamic Considerations for Halogenation 11.4 – Enthalpy changes in halogenations

Fluorination is explosive, Iodination is unfavourable

Chlorination and bromination are synthetically useful

6

Enthalpy changes in halogenations

Both chlorination and bromination are exothermic,

however first step in bromination is endothermic

11.4 – Selectivity in halogenations

Bromination is a much slower process and the

endothermic first step leads to selectivity

11.5 – Regioselectivity in halogenations

Statistically the primary product might be expected to predominate

Which product is major?

Regioselectivity in halogenations

In reality the secondary product is actually major

There isn’t much difference in the stability of the products so the

selectivity must be based on the mechanism…

Which product is major?

7

Regioselectivity : reaction profile

Formation of a secondary radical is the lower energy pathway

Regioselectivity : bromination

Bromination is highly selective:

The Br radical is less reactive than the Cl radical

This leads to selectivity in product formation …

11.5 – Regioselectivity : the Hammond postulate

Remember the Hammond Postulate from earlier

11.5 – Regioselectivity : transition states

Because Br abstraction of H has a much later transition state

(endothermic process) there is significant radical character at

that stage; the Cl abstraction process has little discrimination

8

Regioselectivity : transition states

Early transition state has little radical character so little selectivity

Late T.S. allows for sensing of radical character and selectivity

Regioselectivity : 2-methylpropane

11.6 – Stereochemistry of halogenation Stereochemistry of halogenation

9

11.6 – Radical halogenation : examples

Br2

h

Br Br+

Bronly one isomer

formed

racemic mixture

CH3

racemicmixture

CH3Br

Br2

heat

Br2

11.7 – Allylic bromination

Allylic bromination

Reaction looks straightforward:

Competition from:

11.7 – Allylic bromination : NBS

Use N-Bromosuccinimide instead:

10

Allylic bromination : NBS

Propagation steps:

Termination steps also possible as with other radical chain mechanisms

Allylic bromination : regioisomers

11.8 – Atmospheric chemistry and the ozone layer Atmospheric chemistry and the ozone layer

11

Atmospheric chemistry : freon

Chlrofluorocarbons are ozone depletors; most

have now been banned for general use

Atmospheric chemistry : Freon decomposition

11.9 – Autooxidation and antioxidants Autooxidation and antioxidants

12

Autooxidation and antioxidants : triglycerides Antioxidants : examples

Antioxidants : naturally occurring

Resveratrol (grapes, raspberries)Quercitin (fruits, vegetables)

11.10 – Radical addition of HBr

13

11.10 – Radical addition of HBr : initiation

Peroxides feature a weak O-O bond that will break easily

Once radicals are produced propagation steps follow

11.10 – Radical addition of HBr : propagation

Addition to weak pi bond produces more stable 3° radical

Typical termination steps will also occur

11.10 – Radical addition of HBr : reagents

Overall

In both cases the major product is formed via the most stabilized

intermediate; with HBr alone via carbocations but with HBr and

peroxides the reaction proceeds through radicals

11.10 – Radical addition of HBr : stereochemistry

Racemic mixture

14

11.10 – Radical addition of HBr : examples

HBr

HOOH

BrH

BrH

HBr

HOOH

HBr

HOOH

+

H

Br

4 stereoisomers formed

Racemic mixture

CH3 CH3

Br

H4 stereoisomers

formed

11.11 – Radical polymerization

11.11 – Radical polymerization : initiation 11.11 – Radical polymerization : propagation

The reaction repeats until the monomer is exhausted or termination occurs

The OR group will have a negligible effect on the properties of the polymer

15

11.11 – Radical polymerization : termination 11.11 – Radical polymerization : examples

200oC

ethylene polyethylene

or peroxides

tetrafluoroethylene teflon

F

F

F

F

FF

FF

FF

FF

FF

FF

H

H

H

H

200oC

ethylene plexiglass

or peroxides

CO2CH3

CH3H

H

CH3O2CCO2CH3

CO2CH3

11.12 – Radical processes in the chemical industry 11.13 – Halogenation as a synthetic technique

Bromination is highly selective:

Useful entry to other processes:

16

Halogenation as a synthetic technique

CH3 CH2BrNBS, heat

CH2C CHHC CNa

CCl4 THF

CH2C CLi

CH3Liether

CH3CH2CH2Br

ether

CH2C CCH2CH2CH3

Na, NH3 (l)

H

H

H

H

O

CH2Cl2

CH3CO3H(+ enantiomer)

Chapter 11 – Exam questions

Chapter 11 – Sample exam questions Sample exam questions

17

Chapter 11 – Synthesis questions

a. ?

xs H2, Pd

BrBr2

NaOMe

several routes possible here;this was the best answer given

by a student on Exam 3

1

Chapter 12 – Synthesis

Ciguatoxin

Vitamin B12

Brevetoxin

Chapter 12 – Synthesis : “the toolbox”

Concerted

Stepwise

Chapter 7 – Substitutions

Substitutions : stereochemistry Eliminations : E2 and E1

Chapter 8 – Eliminations

2

Additions

Chapter 9 – Additions

Additions : stereochemistry


Additions : hydrations


Additions : hydroboration


3

Additions : syn and anti outcomes


Additions : epoxides


Additions : diols


Additions : ozonolysis


H3CCH3

1. O3

2. Zn, H2O

CH3H

CH3

H3C OO

CH3

H

H3C

H3C OO

OOOO

CH3

H3Cmalozonide ozonide

CH3 H3C

4

Eliminations


Additions : alkyne reduction


Additions : alkyne hydration

opposite regiochemistry


Alkyne alkylation


5

Radical halogenation


12.1 – One-step syntheses from alkenes

Covered each of these conversions in 3719

One-step syntheses from alkenes

Alkanes, Alkenes, andAlcohols are importantStarting materials

OH

H H

HOH

Br

Br2

H

BrBr

HBr

or hv

base (E2)

HBr (addition)neutral (E1)

H2O (SN1)

H+, H2OH3PO4

or H2SO4heat

HBrperoxides

1. B2H62. NaOH, H2O2

H2, Pd(also BrOH)

Organic synthesis : C-C bond-forming

?

Chain extension

Br

xs H2, Pt

C-C bond formation

Functional group manipulation

6

12.2 – Functional group transformations

Functional groups may be changed or moved in synthesis

Organic synthesis relies on two main processes:

1. Carbon-carbon bond formation

2. Functional group transformation

Functional group transformations

You must know the earlier transformations and the ideas

behind their mechanisms

Moving groups - regiochemistry

ZaitsevMarkovnikoff

HoffmanAnti-Markovnikoff

You must know the earlier transformations and the ideas

behind their mechanisms

Moving groups - alcohols

7

Moving groups - alkenes 12.2 – Swapping functional groups

Move the double bond

Add HBr in anti-Mark’

fashion

Solution 1

Br

Br

HBr

ROOR

t-BuOK

HBr

ROOR

Move double bond

Add HBr in anti-Markovnikoff fashion

Solution 2

Move double bondAdd HBr in anti-Markovnikofffashion

8

12.3 – Reactions That Change the Carbon Skeleton

We can stitch carbon chains together:

And we can break carbon chains apart:

Reactions That Change the Carbon Skeleton

How might the following conversion be carried out?

This involves a carbon chain extension:

12.4 – How to Approach a Synthesis Problem

Alkyne alkylation offers a path to chain elongation

The FGT then completes the synthesis:

12.5 – Retrosynthetic Analysis

2-deoxy-D-ribose D-mannopyranose

9

Retrosynthetic Analysis Retrosynthetic Analysis : alkynes

Precursors to alkynes 12.5 – Precursors to alkynes

Keep in mind:

10

Alcohol precursors to alkynes

Viable Synthesis:

12.5 – Multistep alkyne synthesis

Viable Synthesis:

Multistep alkene synthesis

Multi-Step Synthesis:

Synthesis problems : 1

H

H?

H

H

H

NaNH2, THF

Br

Na, NH3 (l)

1.

11


?

Br

Br

H

Br2, CCl4

1. xs NaNH2

2. H2O

NaNH2

Br

2.


3. ? OH

OH

Br

(+/-)

O

OH

OHBr2, heat

NaOCH3 CH3CO3H

H+, H2O


?

HBr, H2O2

KOtBu

Br2, CCl4

Br

Br

Br

Br

Br


5.?

OH(all C from same S.M.)

LG

Br OH

H

Br

Br

12

Synthesis problems : 5 – synthesis

5.

OHPot 1 HBr

Br

BrPot 2

1. NaOCH32. Br2, CCl4

3. xs NaNH24. H2O5. NaNH2

Br

xs H2, Pd


6.? O

Br

O1. Br2, heat2. NaOCH3

3. O34. Zn, H2O


7. HBrCH3 CH3

O

(+/-)

CH3CH3Br

CH3H3C Br

CH3 CH3

O

(+/-)

1. Br2, heat2. NaOCH3

3. HBr, H2O24. KOtBu5. CH3CO3H

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Chapter 01 F2016 Review - hyperconjugation.comhyperconjugation.com/3719files/3719Fall2016NoteSlides.pdf• The ground state atomic structure for C does not match CH4 ... Hybridization