Chapter 01 F2016 Review -...
Transcript of Chapter 01 F2016 Review -...
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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
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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
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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.
Skillbuilder Exercise in Klein Text
Electronic Configurations
Skillbuilder Exercise in Klein Text
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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
Skillbuilder Exercise in Klein Text
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
Skillbuilder Exercise in Klein Text
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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
Skillbuilder Exercise in Klein Text
Examples of Polar Covalent Bonds
Examples: O
Cl
H N
O
CH3
CH3
+ used to denote electron-deficiency
‐ used to denote electron-excess
Skillbuilder Exercise in Klein Text
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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
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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.
Skillbuilder Exercise in Klein Text
1.7 – Valence Bond Theory
• Constructive interference results in a bonding orbital (s or p)
• Destructive interference results in an antibonding orbital
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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
Skillbuilder Exercise in Klein Text
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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
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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
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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
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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
Skillbuilder Exercise in Klein Text
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Bonding and Shape so far… 1.11 – Dipole Moments and Molecular Polarity
Dipole present No dipole
Dipole Moments and Molecular Polarity
Skillbuilder Exercise in Klein Text
Dipole-dipoleinteractions
1.12 – Intermolecular Forces and Physical Properties
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Intermolecular Forces and Physical Properties Intermolecular forces in alkanes
London dispersion forces
Branched alkanes
Branching decreases intermolecular attractions
Skillbuilder Exercise in Klein Text
1.13 – Solubility
“Like dissolves like”
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Solubility
Cholesterol
Sucrose
“Like dissolves like”
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Chapter 2 – Molecular Representations
TaxolMorphine
Brevetoxin B
2.1 – Molecular Representations
Structural isomers
Skillbuilder Exercise in Klein Text
2.2 – Bond-Line Structures Bond-Line Structures
Skillbuilder Exercise in Klein Text
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Bond-line structures for complex molecules 2.3 – Identifying Functional Groups
Identifying Functional Groups Polyfunctional molecules
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Alkyl halides (haloalkanes)
Br
ClF
I
Alkyl Halides
Alkenes (olefins)
OH
OHOHO
O
HO
Alkenes
Alkynes
Alkynes
Alcohols
OHOH
OH
Alcohols
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Ethers
Ethers
Thiols
Thiols
Sulfides
S
SS
Sulfides
Aromatics (Arenes)
Aromatic (or Arene)
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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
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(Carboxylic) Esters
Aspirin
Isoamyl acetate (bananas) Polyester
Esters
(Carbox) Amides
N,N-Dimethylformamide
Glutathione
Amides
Amines
Morphine
AnilineCadaverine
Amines
Complex polyfunctional molecules
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2.4 – Carbon Atoms with Formal Charges 2.5 – Identifying Lone Pairs
Skillbuilder Exercise in Klein Text
Identifying Lone Pairs
Skillbuilder Exercise in Klein Text
2.6 – 3-Dimensional Bond-Line Structures
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3-Dimensional Bond-Line Structures 2.7 – Introduction to Resonance
Acetate anionActual structure
Resonance Structures – Examples Introduction to Resonance
Allyl cation Propyl cation
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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
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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
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2.11 – Assessing Relative Importance of Structures
Minimize charges in structuresElectronegative elements may be positive but must have octet
Skillbuilder Exercise in Klein Text
2.12 – Delocalized and Localized Lone Pairs
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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
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Flow of Electron-Density : Curved Arrow Notation
Curved arrows are used to describe mechanisms
3.3 – Brønsted-Lowry Acidity : Quantitative Perspective
Skillbuilder Exercise in Klein Text
Brønsted-Lowry Acidity : Quantitative Perspective
Low pKa = strong acid ; High pKa = weak acid
Skillbuilder Exercise in Klein Text
pKa values
Skillbuilder Exercise in Klein Text
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pKa values..
Skillbuilder Exercise in Klein Text
pKa values…
Skillbuilder Exercise in Klein Text
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)
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Amine pKa (RNH2) Alcohol pKa (ROH)
Carboxylic acid pKa (RCO2H)
OOH
Identifying acidic protons
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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
Skillbuilder Exercise in Klein Text
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
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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
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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
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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
Skillbuilder Exercise in Klein Text
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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
Skillbuilder Exercise in Klein Text
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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
Skillbuilder Exercise in Klein Text
Example acid-base exam questions
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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
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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:
Find the longest continuous carbon chain
Parent names for alkanes
IUPAC Rules:
Find the longest continuous carbon chain
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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
Skillbuilder Exercise in Klein Text
Substituents on cycles
Naming substituents
Skillbuilder Exercise in Klein Text
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Cycles as substituents
Naming substituents
Skillbuilder Exercise in Klein Text
Steps for naming alkanes
4-Ethyl-3,7-dimethyl-6-propyldecane
Skillbuilder Exercise in Klein Text
Naming branched substituents
Branched substituents
Skillbuilder Exercise in Klein Text
Butyl substituents
Branched substituents
Skillbuilder Exercise in Klein Text
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Pentyl substituents
Branched substituents
Skillbuilder Exercise in Klein Text
Numbering for substituents
Assembling the Systematic Name of an Alkane
Keep the numbers as small as possible
Skillbuilder Exercise in Klein Text
Be careful when numbering
Assembling the Systematic Name of an Alkane
Keep the numbers as small as possible
Skillbuilder Exercise in Klein Text
Keep the numbers small
Assembling the Systematic Name of an Alkane
Keep the numbers as small as possible
Skillbuilder Exercise in Klein Text
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Deciding upon the order
Assembling the Systematic Name of an Alkane
Keep the numbers as small as possible
Skillbuilder Exercise in Klein Text
Numbering substituents on cycles
Assembling the Systematic Name of an Alkane
Keep the numbers as small as possible
Skillbuilder Exercise in Klein Text
Systematic naming
4-Ethyl-2,3-dimethyloctane
Skillbuilder Exercise in Klein Text
Examples of naming alkanes
Examples
4-ethyl-3,6-dimethyloctane
hexane 2-methylhexane
2,4-dimethylheptane
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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
Skillbuilder Exercise in Klein Text
4.3 – Constitutional Isomers of Alkanes Drawing constitutional isomers
Be careful when drawing isomers!
Same name = same compound
Skillbuilder Exercise in Klein Text
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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
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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
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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….
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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
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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
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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
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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
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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
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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
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trans-1,3-Disubstituted cyclohexane
Right-hand conformer favoured; larger group equatorial
Skillbuilder Exercise in Klein Text
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
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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
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Polycyclic systems Models of polycyclic systems
Polycyclics – Cholesterol
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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
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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
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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 (-)
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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
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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
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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
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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
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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
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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
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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)
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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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
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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
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Inversion in SN2
Stereospecificity of SN2 Reactions
LUMO of electrophile
Inversion in SN2 – stereospecificity
Stereospecificity of SN2 Reactions
http://www.bluffton.edu/~bergerd/classes/cem221/sn‐e/SN2.gif
Stereospecificity
Stereospecificity of SN2 Reactions
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
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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
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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
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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
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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?
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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
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7.6 – Rearrangements in SN1 reactions
Rearrangements possible in SN1
Rearrangements in SN1 reactions
Rearrangements possible in SN1
H+ picked up in first step
SN1 rearrangement reaction profile
Rearrangements possible in SN1
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?
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Drawing the complete SN2 mechanism
H+ picked up in first step
SN2 mechanism with alcohol
H+ lost in the Last step
7.7 – SN2 mechanism with epoxide
H+ picked up in first step
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
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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
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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
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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
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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
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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
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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
1. Identify the parent compound
2. Identify the substituents
3. Assign a number to each substituent
4. Arrange the substituents alphabetically
Numbering of alkenes
1. Identify the parent compound
2. Identify the substituents
3. Assign a number to each substituent
4. Arrange the substituents alphabetically
Pi bond gets low number
Correct numbering of alkenes
1. Identify the parent compound
2. Identify the substituents
3. Assign a number to each substituent
4. Arrange the substituents alphabetically
Both names are acceptable
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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
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Assigning stereochemistry in alkenes
E and Z designations
Cahn-Ingold-Prelog rules in alkenes
E and Z designations
Same rules of prioritization as for chirality centers
Cahn-Ingold-Prelog rules
C-I-P rules in alkenes
E and Z designations
Examples of application
Cl
Br
F
O
H
F
CH3
CN
CH3
Br
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8.5 – Alkene stability 8.5 – Alkene stability : proof
8.5 – Alkene stability : substitution patterns 8.5 – Alkene stability : isomer stability
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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
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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
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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
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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
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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
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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+
+
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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
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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
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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
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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
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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
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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
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9.3 – Hydrohalogenation – regiochemistry
Markovnikoff Addition
Hydrohalogenation – regiochemistry
Markovnikoff Addition
Hydrohalogenation – Markovnikoff
Markovnikoff Addition
Markovnikoff regioselectivity
Markovnikoff Addition
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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
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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
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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
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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
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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
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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
(+/-)
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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
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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
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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
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9.8 – Addition of Br2 : stereospecificity Addition of Br2 : stereospecificity
9.8 – Halohydrin formation 9.8 – Halohydrin formation : regioselectivity
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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
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9.9 – Anti dihydroxylation Anti dihydroxylation
9.9 – Epoxides as reactive species 9.10 – Syn dihydroxylation
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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
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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
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Synthesis : The Toolbox
Move a leaving group
9.13 – Synthesis : The Toolbox
Move a leaving group
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
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Chapter 10 – Alkynes
Histrionicotoxin
Chapter 10 – Alkynes : examples
Cicutoxin
Alkynes : examples
Calicheamicin
Alkynes : divalent
Tetrahedral
(4 valent)
Trigonal planar
(4 valent)
Linear
(2 valent)
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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
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10.1 – Introduction to Alkynes Alkynes – the triple bond
Alkynes – biologically active 10.2 – Numbering of alkynes
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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
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Acidity of acetylene and terminal alkynes pKa values for terminal alkynes
10.4 – Preparation of alkynes Preparation of alkynes
(Vicinal)
(Geminal)
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10.5 – Reduction of alkynes Reduction of alkynes
Reduction of alkynes – catalysis Reduction of alkynes – Birch
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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
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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
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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
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10.8 – Halogenation of alkynes 10.8 – Ozonolysis of alkynes
10.10 – Alkylation of terminal alkynes Alkylation of terminal alkynes
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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
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Chapter 11 – Radical Reactions 11.1 – Radicals
11.1 – Radicals : reactive intermediates 11.1 – Radical structure
Experimental evidence for either structure
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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
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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
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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
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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
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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?
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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
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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
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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:
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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
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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
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Autooxidation and antioxidants : triglycerides Antioxidants : examples
Antioxidants : naturally occurring
Resveratrol (grapes, raspberries)Quercitin (fruits, vegetables)
11.10 – Radical addition of HBr
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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
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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
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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:
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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
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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
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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
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Additions
Chapter 9 – Additions
Additions : stereochemistry
Chapter 9 – Additions
Additions : hydrations
Chapter 9 – Additions
Additions : hydroboration
Chapter 9 – Additions
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Additions : syn and anti outcomes
Chapter 9 – Additions
Additions : epoxides
Chapter 9 – Additions
Additions : diols
Chapter 9 – Additions
Additions : ozonolysis
Chapter 9 – Additions
H3CCH3
1. O3
2. Zn, H2O
CH3H
CH3
H3C OO
CH3
H
H3C
H3C OO
OOOO
CH3
H3Cmalozonide ozonide
CH3 H3C
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Eliminations
Chapter 10 – Alkynes
Additions : alkyne reduction
Chapter 10 – Alkynes
Additions : alkyne hydration
opposite regiochemistry
Chapter 10 – Alkynes
Alkyne alkylation
Chapter 10 – Alkynes
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Radical halogenation
Chapter 10 – Alkynes
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
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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
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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
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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
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Retrosynthetic Analysis Retrosynthetic Analysis : alkynes
Precursors to alkynes 12.5 – Precursors to alkynes
Keep in mind:
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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.
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Synthesis problems : 2
?
Br
Br
H
Br2, CCl4
1. xs NaNH2
2. H2O
NaNH2
Br
2.
Synthesis problems : 3
3. ? OH
OH
Br
(+/-)
O
OH
OHBr2, heat
NaOCH3 CH3CO3H
H+, H2O
Synthesis problems : 4
?
HBr, H2O2
KOtBu
Br2, CCl4
Br
Br
Br
Br
Br
Synthesis problems : 5
5.?
OH(all C from same S.M.)
LG
Br OH
H
Br
Br
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Synthesis problems : 5 – synthesis
5.
OHPot 1 HBr
Br
BrPot 2
1. NaOCH32. Br2, CCl4
3. xs NaNH24. H2O5. NaNH2
Br
xs H2, Pd
Synthesis problems : 6
6.? O
Br
O1. Br2, heat2. NaOCH3
3. O34. Zn, H2O
Synthesis problems : 7
7. HBrCH3 CH3
O
(+/-)
CH3CH3Br
CH3H3C Br
CH3 CH3
O
(+/-)
1. Br2, heat2. NaOCH3
3. HBr, H2O24. KOtBu5. CH3CO3H