Table of contents

Subject Page #
Introduction 1
Introductory concepts 2
Acids and bases 5
Alkane conformations 7
Stereochemistry 10
Elimination and substitution 14
Alcohols, ethers, epoxides 18
Alkenes 22
Alkynes 26
Oxidation and reduction 28
Radicals 32
Diers alders and dienes 34
Electrophilic aromatic substitution 37
Organometallic reagents 41
Nucleophilic addition to aldehydes 44
and ketones
Nucleophilic acyl substitution 48
Substitution reactions of carbonyl 51
carbons at the alpha carbon
Carbonyl Condensations 55
Amines 59
 1

How to use my notes:

Before using my notes as a study tool, please watch chad's videos or use other materials to learn
the basic groundwork information.
My notes are intended to cover the harder topics/topics that were not covered in chad's
videos/groundwork courses to help increase your scores to a 30. These are a complete set of
notes for concepts and reactions organic chemistry. I got a perfect score on organic chemistry
and it was the easiest science section for me by a mile.
Chad's videos = http://www.coursesaver.com/videos/DAT/
Sections not included (watch chad's videos on these specific sections he does a fantastic job
here and nothing more needs to be added than what he says):
1.1 Nomenclature
5.1 Lab Techniques Extractions
5.3 TLC, Gas Chromatography
5.4 Distillation
5.5 IR spectroscopy
5.6 NMR
6.1 Proteins and Amino Acids
6.2 Carbohydrates
6.3 Lipids and Nucleic Acids
Learn Chemical lab tests for alkanes, alkenes, alcohols, and alkyl halides in DAT Destroyer
(page 135). If you don't have DAT destroyer, all the information is in a quizlet here:
https://quizlet.com/83340171/dat-orgo-chemical-lab-tests-for-alkanes-alkenes-and-alcohols-
flash-cards/. This shows up on the DAT so definitely learn this!
To get the most out of my notes, study in the following way:
1) Memorize everything in the notes (MOST IMPORTANT). Memorize the mechanisms
that I laid out (understanding the mechanism gives you better understanding of the
reactions). If you don't understand a certain reaction, feel free to message me on SDN or use
the internet or whatever resources you have available.
2) once you have memorized everything in the notes, begin practice problems. I HIGHLY
suggest you buy organic chemistry odyssey and DAT destroyer by orgoman (fantastic
problem sets). Whenever you get something wrong, understand why you got it wrong, write
a general rule on how to solve that specific example, and then add it to my notes.
3) after you have gone through the practice problems, re-memorize areas of my notes that
you slacked on and the new additions you added while doing practice problems.

Quick note on acid/bases memorize the pKa table given in my notes. I know it may be annoying,
but it will make your life 100 times easier when solving problems that ask you for the most acidic
molecule/proton.

Happy studying!
 2
Electronegativity
Electronegativity is a measure of how much atoms want electrons.
Electronegativity differences between two atoms helps tells you which type of bond they
participate in.
Nonpolar bond has electronegativity differences less than 0.5.
Polar, covalent bonds have electronegativity differences between 0.5 and 2.
Ionic bonds generally have electronegativity differences greater than 2.
Trend:

Lewis structures special notes

Elements not part of the transition metal block and are in the 3rd period and below can have
expanded octets.
Boron is electron deficient, only needed 6 electrons to fill its shell.
When adding up the valence electrons in a molecule, if you get an odd number, then it is a radical.
Formal charge
The formal charge is the charge of an atom in a molecule. By adding all the formal charges of all
the atoms in a molecule, you can determine if the overall molecule is positive, negative, or neutral.
Equation:

Resonance structures
A resonance structure is another way to depict the same molecule. Only electrons can move
around, not atoms!
How to determine importance of resonance structure to the overall structure (most important to least
important factors):
1) All atoms have full octets
2) Minimal separation of charge
3) More electronegative atom should have the negative charge whereas the more electropositive
atom should have the positive charge.
In reality, all resonance structures for the same molecule exist at the same time, all the time.
Most important resonance contributor best describes the shape of the molecule whereas the second
most important resonance contributor best describes the reactivity of the molecule.
 3
Bond length
Bond length describes the distance of a bond between two atoms.
How do rank bond lengths:
Bond length follows the atomic radius trend. Larger atoms that bond together will have larger
bond lengths for this reason. (H-Br > H-F)
single bond > double bond > triple bond
higher % s character (sp > sp2 > sp3) of the atoms participating in the bond, the shorter the bond
NOTE: watch for resonance!

This is NO2-, or nitrite. When looking at the N-O bond lengths, one might be tempted in saying
that one N-O bond is strictly a double bond while the other is a single bond.. However, this is not
true! Note that the molecule can resonate! Because of this, the N-O bond length is actually less
than 2, it is around 1.5.
When given a bond length problem, look for resonance because that can affect the way you
answer the question.
Bond strength
Bond strength indicates how much energy is needed to break a bond into two equal atoms.
General rule: the shorter the bond is, the stronger the bond is
How to rank bond strength:
triple bond > double bond > single bond
Higher % s character (sp > sp2 > sp3) of the atoms participating in the bond, the stronger the bond
strength. This is because the atoms participating in the bonds are in lower energy orbitals and are
more tightly bound by the nucleus.
NOTE: watch for resonance (just like bond length)!
Molecular geometry
Determining hybridization:
1) count every single, double, or triple bond around a given atom as 1
2) count every lone pair around the same atom as 1
3) add up the two counts and then use the table to determine hybridization
Count Hybridization
2 sp
3 sp2
4 sp3
5 sp3d
6 sp3d2
NOTE: watch for resonance! The resonance structure with the smallest observed hybridization
best describes the overall hybridization!
sp = ~109o bond angles and a tetrahedral arrangement
3

4 bond sand 0 lone pairs = tetrahedral

3 bonds and 1 lone pair = trigonal pyramidal
2 bonds and 2 lone pairs = bent
1 bond and 3 lone pairs = linear
sp2 = ~120o bond angles and trigonal planar arrangement
 4
3 bonds and 0 lone pairs = trigonal planar
2 bonds and 1 lone pair = bent
1 bond and 2 lone pairs = linear
sp = ~180o bond angles and linear arrangement
lone pair electrons take up extra space and crunches the bond angles. The more lone pairs that exist
around an atom, the smaller the bond angles are.
Intermolecular forces
Intermolecular forces are forces that occur between neighboring particles. They have big effects on
physical properties.
In terms of strength: Ion-dipole > hydrogen-bonding > dipole-dipole > van-der-waals
Ion-dipole is an interaction between an ion and an oppositely charged dipole.
Hydrogen bond is the interaction between a lone pair on fluorine, oxygen, or nitrogen and a
hydrogen on another molecule that is directly bound to fluorine, oxygen, or nitrogen.
NOTE: hydrogen bonding can occur between atoms within the same molecule. Intramolecular
H-bonds prevent intermolecular H-bonds from forming and thus weakens its effect on physical
properties.
Dipole-dipole occurs from polar covalent bonds.
NOTE: dipoles within the same molecule can cancel each other out if the dipoles are in the
opposite directions and are of the same magnitude. Factor in the NET molecule dipole.
Van-der-waals occurs between all atoms. It is the brief attraction between neighboring molecules
due to the random movement of electrons.
The larger the molecular weight, the stronger the VDW forces.
The bigger the molecule is (more surface area), the stronger the VDW forces.
The more branched the molecule is, the weaker the VDW forces.
Melting points, boiling points, and solubility
Boiling point ranking:
1) The stronger the IMFs, the higher the boiling point
Note that for hydrogen bonding, oxygen > nitrogen (you will probably never see a fluorine
molecule).
2) The larger the surface area of the molecule, the higher the BP
3) The more polarizable the atom is, the higher the BP
Polarizability is described as the ease of distortion of the electron cloud of a molecule by an
electric field. Polarizability increases down the column of the periodic table. (I > Br > Cl)
NOTE: HF > HI > HBr > HCl for boiling point (note that HF can do hydrogen bonding
whereas the other 3 acids cannot)
Melting point ranking:
1) The stronger the IMFs, the higher the melting point
2) The more branched the molecule is, the higher the melting point
Solubility ranking:
1) similar IMFs between solvent and solute
2) the larger the surface area of the solute is, the less dissolving there is
 5

Acid and base definitions

Bronsted-lowry acid is a proton (H+) donor
Bronsted-lowry base is a proton (H+) acceptor
Lewis acid is an electron acceptor
Lewis base is an electron donor
Acid strength
MAJOR TIP: memorize pKa values as it will make ranking acids much easier. I put a
terrific table on the very last page of this chapter: memorize the values.
General factors that determines acidity (most important to least important):
1) Acidity of H-A increases left to right across a row and down the periodic table (polar
and polarizeable). The opposite trend applies to base strength.

2) Acidity of H-A increases if the conjugate base can resonate

NOTE: if a ring, when deprotonated, becomes an aromatic ring, then acidity greatly
increases.
3) Acidity of H-A increases with the presence of electronegative atoms in A (inductive
stabilization)
NOTE: distance matters! When an electronegative atom is closer to the proton, the
effect is stronger and acidity increases.
4) Acidity of H-A increases as the % s character of the conjugate base increases (sp > sp2
> sp3).
NOTE: intramolecular H-bonding decreases acidity as the hydrogens are less likely to be
deprotonated.
Basicity of amines and aromatics
Alkyl amines are more basic than NH3 because of electron donating R-groups.
Alkyl amines are more basic than aryl amines.
Electron donating groups (refer to EAS chapter) increase basicity/decrease acidity on aryl
amines.
Electron withdrawing groups (refer to EAS chapter) decrease basicity/increase acidity on
aryl amines.
In heterocylic aromatic compounds, if the heteroatom's (nitrogen, oxygen, etc.) electrons do
not contribute to aromaticity, then it is more basic.
Higher % s character (sp > sp2 > sp3) of the orbital containing the lone pair, the less
basic/more acidic the compound is.
Determining Keq
Keq = 10pKa conjugate acid pKa acid
6
 7

Newman Projections
Newman projections allow us to see the relationship of substituents between the front and
back carbons.
Staggered conformation is when the substituents are not overlapping with each other.
Eclipsed conformation is when the substituents are overlapping with each other.
A given molecule will rotate between the two conformation many times per minute.
Staggered is more stable than eclipsed.

Anti vs. gauche vs. partial vs. full eclipse

Anti conformer is a type of staggered conformer where the non-hydrogen substituents are
180o away from each other. This is the most stable.
Gauche conformer is a type of staggered conformer where the non-hydrogen substituents
are 60o away from each other. This is the 2nd most stable.
Partial eclipsed conformation is a type of eclipsed conformation where the non-hydrogen
substituents are 120o away from each other. This is the 3rd most stable.
Fully eclipsed conformation is a type of eclipsed conformation where the non-hydrogen
substituents are 0o away from each other. This is the least stable.
 8

Since a molecule will rotate between staggered and eclipsed conformations, a molecule with
non-hydrogen substituents will rotate between all 4 conformers stated above in a given
minute.
NOTE: if the two substituents bound to the two adjacent carbon atoms can hydrogen bond,
make them gauche. Intramolecular hydrogen bonding increases stability of the molecule!
Types of strain
Torsion strain arises from eclipsed interactions between hydrogen and a non-hydrogen
substituent or between 2 hydrogens.
Steric strain occurs when 2 non-hydrogen substituents are gauche or fully-eclipsed.
Angle strain occurs when atoms participating in a ring have bond angles lower than the
expected amount.
Conformations of cyclohexane
Some rings, such as cyclohexane, will pucker to relieve strain.
How to convert from ring to chair:
1) Number the cyclohexane ring. 1 goes to the top priority substituent (top priority
is defined in the nomenclature chapter) and then number in the direction so that the
nearest substituents is at the lowest number.
2) Number the boat counterclockwise or clockwise as long as you are consistent (in the
picture below, it was numbered clockwise)
3) wedge always points UP, and dashed always points DOWN
4) chair flip: move numbers down one clockwise and flip every axial substituent to
equatorial and every equatorial substituent to axial

Axial vs. equatorial

Axial positions are the ones that are pointing up and down vertically
Equatorial positions are the ones that are pointing horizontally on a slant.
MEMORIZE the axial and equatorial positions for each chair

Determining the most stable chair

Non-hydrogen substituents do not like to be in the axial position. Doing so causes them
to bump into other axial substituents, called 1,3-diaxial interactions.
No such problems exist for equatorial positions!
Therefore, the largest, if not all substituents that are not hydrogen should be equatorial.
 9

A note on cis and trans

If the non-hydrogen substituents are both pointing up or down, it is cis. Look at the cis-
1,2-dimethyl-cyclohexane picture: note that both CH3 groups are always pointing up
If one is pointing up, and the other down, it is trans.
 10

Labeling R and S stereocenters

Please refer to this link to learn how to prioritize substituents.
http://chemwiki.ucdavis.edu/Organic_Chemistry/Chirality/Absolute_Configuration,_R-
S_Sequence_Rules
Given dash, wedge structure:
lowest priority group is dashed:
number substituents using priority system
draw a steering wheel from 1 to 3
if the steering wheel is clockwise, it is R. If the steering wheel is counterclockwise it
is S.
In the picture below, draw a steering wheel from 1 to 2 and to 3. Wen you do
this, you will see that you are going in a clockwise direction. So this stereocenter
is S.

lowest priority group is wedged:

number substituents using priority system
draw a steering wheel from 1 to 3
REVERSE! If the steering wheel is clockwise, it is S. If the steering wheel is
counterclockwise it is R.
In the picture below, NH2 is priority 1, CH2CH3 is priority 2, CH3 is priority 3,
and H is priority 4. When you draw the steering wheel, you will see a clockwise
direction. So the stereocenter is R!

Lowest priority group is neither dashed nor wedged:

rotate molecule (in either direction) so that the lowest priority group is dashed
number substituents using priority system
draw a steering wheel from 1 to 3
REVERSE! If the steering wheel is clockwise, it is S. If the steering wheel is
counterclockwise it is R.
In the picture below, H is priority 4 and is neither dashed nor wedged. So here,
rotate the molecule (do so with least amount of turns needed) to get H in dashed.
Rotating the molecule counterclockwise does the trick (figure on the right). Then
assign priorities, do steering wheel, and REVERSE. The stereocenter here is R.
 11

Given Fischer projection

lowest priority group is horizontal:
number substituents using priority system
draw a steering wheel from 1 to 3
REVERSE! If the steering wheel is clockwise, it is S. If the steering wheel is
counterclockwise it is R.

lowest priority group is vertical:

number substituents using priority system
draw a steering wheel from 1 to 3
if the steering wheel is clockwise, it is R. If the steering wheel is counterclockwise it
is S.
In the figure below, hydrogen is the lowest priority substituent and it is in a
vertical position. Simply number the substituents and steering wheel. The
stereocenter here is R as the steering wheel is clockwise.

If there are 2+ centers of chirality in the fischer projection, consider each center
separately
Newman projections
Watch this youtube video on how to convert a newman projection into a fischer
projection https://www.youtube.com/watch?v=fXPrBMFovIs
Once you converted into the fischer projection, use the fischer projection rules to assign
the stereocenters.
Chair structure
Convert chair back into ring (remember wedge = up and dashed = down)
Find stereocenter with dash, wedge structure you created
Definitions
Chiral molecules have at least one stereocenter and is not a meso compound or a racemic
mixture. Rotates plane-polarized light.
 12

A stereocenter is a tetrahedrally arranged carbon bound to 4 asymmetric substituents.

Total number of stereoisomers = 2n n = number of stereocenters
Enantiomers are non-super imposable images.
The way I view enantiomers is that every stereocenter has oppositely assigned R, S
values. So if molecule A has R configuration at C1 and S configuration at C2, then the
enantiomer would have S configuration at C1 and R configuration at C2.

Enantiomers are equal in all of their physical properties except for optical rotation. They
rotate plane-polarized light with the same magnitude but in opposite directions (so
opposite signs).
A racemic mixture is a 1:1 ratio of enantiomers. They are achiral (do not rotate plane-
polarized light) because the equal ratios of enantiomers cancel out the rotations.
A meso compound is a molecule with at least one stereocenter and is symmetrical. Meso
compounds are achrial.
A diastereomer is anything but an enantiomer.
The way I view diastereomers is that at least one of the stereocenters have been
changed, but not all of them. In the molecules below, note that only one stereocenter has
been swapped and the other two remain the same.

Diastereomers are characteristically different in their physical properties and thus can be
easily separated by conventional separation techniques.
 13

Determining cis (Z) and trans (E)

1) Split the alkene in half
2) Determine the highest priority groups bound to each carbon that participates in the double
bond. Priority is determined in the same way when assigning R/S stereocenters.
3) If the highest priority groups are on the same side, use the Z notation (think on ze
zame zide). If the highest priority groups are on the opposite side, use the E notation.

Cis and trans isomers have different physical properties and thus can be easily separated by
conventional separation techniques.
In general, the trans isomer has the higher melting point whereas the cis isomer has the
higher boiling point.
 14
Alkyl halides
An alkyl halide is an alkane with a halogen bonded to a carbon.
Types (X = halogen):
Methyl halide = CH3X
Primary alkyl halide = RCH2X
Seocndary alkyl halide = R2CHX
Tertiary alkyl halide = R3CX

Carbocations
Carbocations are positively charged carbon atoms.
Methyl carbocation = CH3+
Primary carbocation = RCH2+
Seocndary carbocation = R2CH+
Tertiary carbocation = R3CX+
Tertiary > Secondary > Primary > Methyl in terms of stability

Leaving group
A leaving group is the species that leaves in a substitution or elimination reaction.
The better the leaving group, the faster the reaction.
How to determine leaving group strength:
The less basic/more acidic, the better the LG
LG strength follows the periodic trend for acidity
Protic vs. Aprotic solvent
A solvent is a liquid that serves as the medium for a reaction. It can serve two major purposes:
(Non-participatory) to dissolve the reactants. Polar solvents are best for dissolving polar
reactants (such as ions); nonpolar solvents are best for dissolving nonpolar reactants (such as
hydrocarbons).
Participatory: as a source of acid (proton), base (removing protons), or as
a nucleophile (donating a lone pair of electrons). The only class of solvents for which this is
something you generally need to worry about are polar protic solvents (see below).
Protic solvents have O-H or N-H bonds. These bonds serve as sources of protons.
We see that protic solvents favor Sn1 and E1 reactions.
Aprotic solvents may have hydrogens on them somewhere, but lack O-H or N-H bonds.
We see that aprotic solvents favor Sn2 and E2 reactions.
 15
Electrophiles vs. Nucleophiles
Electrophiles accept electrons whereas nucleophiles donate electrons.
For this chapter, the electrophile will always be an alkyl halide.
A stronger nucleophile will lead to a faster elimination or substitution reaction. How to determine
nucleophile strength:
In polar, protic solvents:
Nucleophilicity increases as the attacking atom moves down a group of the periodic table.
Nucleophilicity increases right to left across a row of the periodic table.
In polar, aprotic solvents:
Nucleophilicity increases as the attacking atom moves up a group of the periodic table.
Nucleophilicity increases right to left across a row of the periodic table.
If comparing the same atom species, the more basic molecule = the better nucleophile.
Sn1
rate = k[RX]
Rate law only depends on the alkyl halide concentration, not the nucleophile concentration.
The first step is rate determining step (slow step)
Likes to happen in protic solvents
Favored by weaker nucleophiles
Stereochemistry: get both stereoisomers (retention and inversion), but slightly more retention than
inversion occurs.
Alkyl halide that reacts the fastest forms the most stable carbocation. Tertiary > secondary > primary
> methyl halide
Mechanism shown below:

Sn2
rate = k[RX][nucleophile]
Rate law depends on the concentration of the alkyl halide and the nucleophile
Likes to happen in aprotic solvents
Favored by stronger nucleophiles
 16
Transition state is triagonal bipyramidal. Leaving group has a negative charge and the nucleophile
has a positive charge. The carbon involved changes from an sp3 to an sp2 hybridization.
Stereochemistry: inversion of stereocenter (called this backside attack)
Beta branching (branching at the beta carbon) slows down the reaction
Favored by unhindered alkyl halides: methyl halide > primary > secondary > tertiary
The mechanism occurs in a single, concerted step.

E1
rate = k[RX]
Rate law only depends on the alkyl halide concentration, not the nucleophile concentration.
The first step is rate determining step
Likes to happen in protic solvents
Favored by weaker bases
More substituted alkene is favored (zaitev's rule)

E2
rate = k[RX][nucleophile]
Rate law depends on the concentration of the alkyl halide and the nucleophile
Likes to happen in aprotic solvents
Favored by stronger bases
more substituted alkene is favored (zaitev's rule)
There must be an antiperiplanar arrangement of H and X, meaning they must be 180 degrees
apart.
If H and X are not antiperiplanar, rotate the bond until it is. If you cannot rotate the bond to make
H and X antiperiplanar, no reaction will occur.
How can I tell if H and X are antiperiplanar? Draw a newman projection!
If you are doing an elimination of a cyclohexane ring, draw the chair and see if H and X are 180
degrees apart. Note that you may even need to flip the chair in order to see the antiperiplanar
relationship (as shown below)
Sometimes, you will only see that one anti-periplanar relationship is possible and that may
be the less substituted double bond. For more information, visit
http://www.masterorganicchemistry.com/2012/10/18/the-e2-reaction-and-cyclohexane-rings/
 17
The mechanism occurs in a single, concerted step.

Choosing between E1, E2, Sn1, and Sn2

NOTE: bicyclo compounds, halides attached to aromatic rings or to carbon that participates in a
double/triple bond do not react in these schemes.
Step 1: determine if you have primary, secondary, or tertiary alkyl halide.
If I have a primary alkyl halide:
Step 2: determine if the base is bulky
If it is, then do E2
If it is not, then do Sn2
NOTE: if the base is a bad nucleophile, then there will be no reaction
If I have a secondary alkyl halide:
Step 2: determine if the base is bulky
If it is, then do E2
If it is not, proceed to step 3
Step 3: determine if the base is strong
If it is, then E2 and Sn2 will occur, but E2 will be favored
If it is not, proceed to step 4
Step 4: determine if the species is a good nucleophile
If it is, then E2 and Sn2 will occur, but Sn2 will be favored
If it is not, then Sn1 and E1 will be favored
If I have a tertiary alkyl halide:
Step 2: determine if the base is strong
If it is, then do E2
If it is not, then do Sn1 and E1
What does strong base mean?
For our purposes, look for anions (e.g. RO-) that are not sulfur-based.
Weak bases will be protonated (e.g. ROH)
What is a bad base but a good nucleophile?
For DAT, think of sulfur-based nucleophiles and cyanide nucleophiles.
Benzylic and allylic halides do Sn1 and Sn2 depending on the solvent.
Note that if you can create a conjugated double bond system via elimination, do elimination!
A special note on bulky bases:
(CH3)3CO- K+ is hoffman elimination. Form the less substituted double bond!
C2H5O- Na+ is standard E2 elimination (zaitev's rule)
Alcoholic * KOH (1 mol) + heat gives you E2 elimination whereas Aqueous * KOH (1 mol) +
heat gives you Sn2 substitution
 18
The alkoxide nucleophile
An alkoxide anion is RO-
It participates in Sn2 with Ch3X or primary alkyl halides
It participates in Sn2/E2 (more E2) with secondary and tertiary alkyl halides
How to make an aloxide
use NaH to deprotonate alcohols (acid-base mechanism). The byproduct, H2 gas, will bubble out
of the solution.

Williamson ether synthesis

React an alkoxide with an alkyl halide to generate an ether.
Mechanism is Sn2 inversion of stereochemistry and as a result, the alkyl halide cannot be
hindered (the alkoxide can be hindered though). Only use primary or secondary alkyl halides!
The solvent is typically the conjugate acid of the alkoxide.

Using NaH to form expoxides

If the molecule has an OH group and a halogen 1 carbon away (vicinal), use NaH to form the
epoxide.

Heating alcohols
Heat a primary alcohol to 140oC to create the ether.

Heat a primary alcohol to 180oC to create the alkene. The more substituted alkene will be favored
(zaitev's rule).

Elimination of tertiary alcohols using strong acid

Use H2SO4, TsOH, H3O+, etc. on a tertiary alcohol alcohol to generate the alkene.
The acid protonates the -OH group to generate a good leaving group.
Mechanism is E1.
 19
Elimination of secondary alcohols using strong acid
Use H2SO4, TsOH, H3O+, etc. and heat on a secondary alcohol alcohol to generate the alkene.
The heat helps stabilize the secondary carbocation.
The mechanism is E1 (exactly the same as the mechanism for tertiary alcohols)
NOTE: watch out for carbocation shifts!
Elimination of alcohols without carbocation generation
Add POCl3 and pyridine to form the alkene
These reagents are advantageous because there is no carbocation generation.
If you want to eliminate a primary alcohol, you must use these reagents. These reagents also work on
secondary and tertiary alcohols.
Mechanism is E2. Remember that an antiperiplanar arrangement is needed!
Generating tertiary alkyl halides from tertiary alcohols
Use HI, HCl or HBr on a tertiary alcohol to generate the tertiary alkyl halide.
Mechanism is Sn1. Remember that there will be retention and inversion!

Generating secondary alkyl halides from secondary alcohols

Use HI, HCl or HBr on a secondary alcohol to generate the secondary alkyl halide.
Mechanism is Sn1. Remember that there will be retention and inversion!
Watch out for carbocation shifts!
Generating primary alkyl chlorides from primary alcohols
Use ZnCl2 on a primary alcohol to generate the alkyl chloride.
Note that there will be no carbocation shifts!
Mechanism is Sn2. Remember that there will be inversion at the stereocenter!

Make R-Cl from primary or secondary R-OH

Use SOCl2 and pyridine to generate the alkyl chloride.
Note that there will be no carbocation shifts!
Mechanism is Sn2. Remember that there will be inversion at the stereocenter!
 20
Make alkyl bromide from a secondary alcohol
Use PBr3 to generate the secondary alkyl bromide.
Note that there will be no carbocation shifts!
Mechanism is Sn2. Remember that there will be inversion at the stereocenter!

Convert R-OH into R-Ots

Add TsCl + Pyridine to generate the tosylate.
The point of this reaction is to turn the alcohol into a molecule with a good leaving group.
The tosylate is an excellent leaving group (approximately as good as Br-).

Ether cleavages
Add HI, or HBr in excess to cleave an ether into alkyl halides. Do NOT use HCl!
An ether with a primary or secondary alkyl group attached to the oxygen will undergo Sn2.
An ether with a tertiary primary alkyl group attached to the oxygen undergoes Sn1.

Sn1 is faster than Sn2 in this situation. (3o > 2o or 1o)

1o is faster than 2o since both alkyl groups undergo Sn2 but a primary alkyl group is better suited for
Sn2. (1o > 2o)
If the question is an ether cleavage but only one equivalent of reagent is used, the fastest reaction
will occur first! (3o > 1o > 2o)

If the ether is directly attached to an aromatic ring, keep the phenol!

Epoxide opening under basic conditions

Use strong nucleophiles to open an epoxide under basic conditions (RS-, RO-, RCN-)
Mechanism is Sn2. Remember that there will be inversion at the stereocenter!
Nucleophile attacks the least hindered side: 1o > 2o > 3o
 21
Epoxide opening under acidic conditions
Use an acid catalyst (H2SO4, H3O+) and a weak nucleophile (H2O, ROH, HBr, HI)
Mechanism is Sn2. Remember that there will be inversion at the stereocenter!
Nucleophile attacks the most hindered side: 3o > 2o > 1o
 22

General Notes on Alkenes

Alkenes are somewhat nucleophilic due to its pi bond.
Since alkene carbons have sp2 hybridization, they are more acidic than alkanes.
Alkenes tend to undergo electrophilic addition reactions.
Degrees of unsaturation (DOU)
Given a picture of the molecule: DOU = # rings + # pi bonds
Maximum HsActual Hs
Given a molecular formula: DOU =
2
Maximum Hs = 2n + 2
n = # of carbons in the molecule
To calculate number of actual Hs:
Add up every hydrogen in the formula given.
Add 1 to actual Hs for every halogen.
Subtract 1 to actual Hs for every nitrogen.
Ignore oxygen in calculations.
Hydrohalogenation of alkenes
Add HI, HCl, HBr to an alkene to create the corresponding alkyl halide.
Stereochemistry: syn + anti addition
Markovnikov addition: add H to less substituted carbon
Watch out for carbocation shifts!

In general, you get syn and anti addition when you form a carbocation!
Acid-catalyzed addition of H2O or ROH to alkenes
Add a strong acid catalyst (i.e. H2SO4) + H2O or primary alcohol to an alkene to generate
the corresponding ether or alcohol.
Stereochemistry: syn + anti addition
Markovnikov addition: add H to less substituted carbon
Watch out for carbocation shifts!
 23

Halogenation
Add Br2, Cl2 but NOT I2 to generate the vicinal 1,2 dihalide.
stereochemistry = anti addition
In the mechanism, you generate a halonium ion intermediate. Nucleophilic X- attacks the
more hindered side of the halonium ion.

Hydroboration/oxidation of alkenes
Add (1) BH3 (2) H2O2 & NaOH to generate the alcohol.
Stereochemistry = syn addition
anti-markovnikov addition: add OH to the least substituted carbon.

Oxymercuration/deoxymercuration and alkoxymercuration/dealkoxymercuration

Oxymercruation:
1) Hg(OAc)2/H2O 2) NaBH4
no carbocation shifts
no stereochemistry
Markovnikov addition of H and OH to make an alcohol.
 24

Alkoxymercuration:
1) Hg(OAc)2/ROH 2) NaBH4
no carbocation shifts
no stereochemistry
Markovnikov addition of H and ROH to make an ether.

Halohydrin formation
Add Br2 or Cl2 in H2O solvent to an alkene to form a halohydrin.
NBS (N-bromosuccinimide) can be used instead of Br2.
Stereochemistry = anti addition
OH- adds to more substituted carbon and the halogen adds to the less substituted carbon.

Similar to the reaction up above, you can add an alcohol along with X2 instead of water to
generate the ether.

Simmonds-smith reaction
Add CH2I2, Zn [Cu] to an alkene to generate a cyclopropane.
Stereochemistry:
trans in alkene trans on cyclopropane
cis in alkene cis on cyclopropane
 25

Cyclopropane formation with diazomethane

Add CH2N2 and heat or light to alkenes to generate cyclopropanes.
Stereochemistry:
trans in alkene trans on cyclopropane

cis in alkene cis on cyclopropane

 26

General properties of alkynes

Nucleophilic due to pi bonds.
More acidic than alkanes and alkenes due to sp hybridization.
Undergoes electrophilic addition reactions.
Alkyne synthesis
Double E2 elimination of vicinal 1,2 dihalides or geminal 1,1 dihalides.
Add NaNH2 (2 equiv.) or Potassium Tert-butoxide (2 equiv.) and heat.
If two alkynes are possible, you will get a mixture of both.

Addition of HX to alkynes
Add HCl or HBr (1 equiv.) to generate a vinyl halide.
Add HCl or HBr (2 equiv.) to generate a geminal dihalide.
NOTE: Do not use HI!
Halogens add in markovnikov fashion.
Mechanism generates special carbocation intermediates called vinyl cations.
Terminal and symmetrical alkynes give 1 product = GOOD
Internal and asymmetrical alkynes generate 2+ products = BAD

Effect of halogens bound to a carbocation

Halogens are electronegative, so they will pull electron density away. This will destabilize
the carbocation.
Halogens can donate electrons via resonance to generate a full octet. This stabilizes the
carbocation.
Overall, halogens stabilize carbocations.
Addition of Br2, Cl2 to alkynes
This is anti addition so you get the trans alkene (E).
Mechanism goes through a halonium ion intermediate, similar to alkenes.
Adding 1 equivalent of Br2, Cl2 NOT I2 gives vicinal E-dihalides.
 27

Adding 2 equivalent of Br2, Cl2 NOT I2 gives you tetrahalides.

Hydration of alkynes via oxymercuration

Add catalytic HgSO4, catalytic H2SO4 and H2O solvent to generate the ketone.
Markovnikov addition of H2O.
The reason you don't get an alcohol is because the original product is an enol. There will be
a spontaneous tautomerization of enol to keto since keto is more stable.

Hydroboration-oxidation of alkynes
Add (1) BH3 and (2) H2O2, NaOH to generate the ketone.
Anti-markovnikov addition of H2O.
The reason you don't get an alcohol is because the original product is an enol. There will be
a spontaneous tautomerization of enol to keto since keto is more stable.
The tautomierzation mechanism is the same as the picture above.

Generating acetylide nucleophiles

Add NaNH2 to a terminal alkyne to deprotonate it into an acetylide anion.
The acetylide anion is very nucleophilic and basic. It is good for substitution reactions.
 28

What does it mean to oxidize and reduce in terms of organic chemistry?

Reduction = more C-H bonds are created
Oxidation = more C-O or C-C bonds are created
Catalytic hydrogenation
H2 (2 equiv.) + Pd-C catalyst turns alkynes into alkanes.
H2 (1 equiv.) + Pd-C catalyst turns alkenes into alkanes.
H2 + lindlar's catalyst turns alkynes into alkanes.
General mechanism for catalytic hydrogenation:

Stereochemistry = syn addition

Benzene rings do not hydrogenate.
Do not try to hydrogenate if there are carbonyl groups present!

Sodium metal reduction

2 Nao + NH3 reduces an alkyne into a trans alkene.
Does not work on alkenes and benzene rings.
Do not try to use this if there are carbonyl groups present!
 29

Reductive opening of epoxides

Use LiAlH4 with H2O workup to open up an epoxide at the least hindered position.
This is like epoxide openings under basic conditions.
Markovnikov addition of H2O.

mCPBA/RCO3H epoxidation
Add mCBPA or RCO3H to an alkene to create an expoxide.
Stereochemistry:
If the alkene is cis the epoxide will be cis (syn addition).
If the epoxide is trans, the alkene will be trans (anti addition).

Anti vs syn dihydroxylation

Anti dihydroxylation
step 1) mCPBA step 2) NaOH, H2O

H2O
workup

Syn dihydroxylation
Use OsO4 + NMO or KmnO4 + cold NaOH + H2O
 30

Permanganate oxidation of alkenes

Add KMnO4 + heat to alkenes to oxidatively cleave it into a ketone or a catalytic acid or
carbon dioxide.
Will turn into a carboxylic acid if the carbon participating in the double bond has 1
hydrogen bound to it.
Will turn into a ketone if the carbon participating in the double bond has 0 hydrogens
bound to it.
Will turn into a carbon dioxide if the carbon participating in the double bond has 2
hydrogens bound to it.

Note that you will never produce aldehydes using this reagent!
Oxidative cleavage of diols
Add HIO4 or NaIO4 to a vicinal 1,2 diol to generate the aldehyde or ketone.
If the carbon bound to the -OH group is also bound to a hydrogen, it will turn into an
aldehyde.
If the carbon bound to the -OH group is not bound to a hydrogen, it will turn into a
ketone.

Ozonolysis of alkenes and alkynes

O3 + Zn/H2O or (CH3)2S to alkenes cleaves double bond into C=O

O3 + H2O workup to alkynes cleaves triple bond into COOH

 31

In ozonolysis, molecules with multiple alkenes/alkynes are cleaved into fragments. Cyclic
alkenes/alkynes become chains.
Oxidation of alcohols by chromium compounds
There is no oxidation of tertiary alcohols
Secondary alcohols oxidize into ketones. Add any of the following reagents:
(1) CrO3 + H2SO4/H2O
(2) K2Cr2O7 + H2SO4/H2O
(3) PCC + CH2Cl2
(4) CrO3 + Pyridine, CH2Cl2 @ 40o C
Primary alcohols oxidize into aldehydes or carboxylic acids.
If you want an aldehyde, add:
(1) CrO3 + Pyridine, CH2Cl2 @ 40o C
(2) PCC + CH2Cl2
If you want a carboyxlic acid, add:
(1) CrO3 + H2SO4/H2O
(2) K2Cr2O7 + H2SO4/H2O

Reaction of alkyl halides into alkanes

Add (1) LiAlH4 and (2) H2O or ether
Mechanism is Sn2. There will be inversion at the stereocenter. Less substituted alkyl halides
react faster than more substituted ones.
 32

What are radicals and how do they react?

Free radicals are chemical species that contain an orbital with one electron in it. They are
neutrally charged and highly reactive.
Free radical reactions do not involve the donation or acceptance of electrons but instead
operate through homolytic cleavage. This means that bonds break in such a fashion that
equal numbers of electrons are distributed to each atom.
We use fish-hook arrows to represent these cleavages:

Stability of radicals
VERY USEFUL LINKS:
http://www.masterorganicchemistry.com/2013/08/02/3-factors-that-stabilize-free-
radicals/
http://www.masterorganicchemistry.com/2013/08/05/what-factors-destabilize-free-
radicals/
Tertiary radical > secondary > primary > methyl radical

If the radical can do resonance, it is more stable.

As %s character increases, stability decreases (alkanes > alkenes > alkynes)
Stability increases as electronegativity decreases.
Stability increases going from right to left across a row periodic table and from top to
bottom down a column of the periodic table.
If the radical is adjacent to an electron withdrawing group, stability decreases. This only
applies to electron withdrawing groups that cannot donate electrons.
Adding Br or Cl to alkanes
Add Br2 or Cl2 and light (hv) or heat to a tertiary carbon to turn it into an alkyl halide. This
rarely is done on secondary alkanes and never to primary alkanes.
Stereochemistry: retention and inversion of stereocenter (similar to Sn1)
Chloronation is exothermic whereas bromination is endothermic.
Radical chain mechanism (done with methane, although unrealistic in reality):
Step 1: initiation Heat or uv light cause the weak halogen bond to undergo
homolytic cleavage to generate two bromine radicals and starting the chain process.
There is a NET INCREASE in free radicals!

Step 2: propogation A bromine radical abstracts a hydrogen to form HBr and a

methyl radical. There is NO NET CHANGE in the number of free radicals!

Step 3: propogation The methyl radical abstracts a bromine atom from another
 33

molecule of Br2 to form the methyl bromide product and another bromine radical,
which can then itself undergo step 2 creating a cycle that can repeat. There is NO NET
CHANGE in the number of free radicals!

Step 4: termination Various reactions between the possible pairs of radicals allow
for the formation of ethane, Br2 or the product, methyl bromide. These reactions remove
radicals and do not perpetuate the cycle. There is a NET DECREASE in the number of
free radicals!

Adding Br to an allylic carbon

Add NBS and light, heat, or ROOR to replace an allylic hydrogen with bromine.
The problem with this reaction is that unsymmetrical substrates gives mixtures of products.

Anti-markovnikov addition of HBr to alkenes

Add HBr and ROOR, hv, or heat to add bromine in anti-markovniknov fashion to alkenes.
Stereochemistry: syn + anti addition
 34

Conjugated dienes and allylic carbocations

A conjugated diene has 2 double bonds separated by 1 carbon-carbon bond.
A unique property of conjugation is the ability to absorb light energy at certain
wavelengths. The more conjugation, the more absorbing power.
An allylic carbocation is stable due to resonance:

HBr, HCl addition to a conjugated diene

Add Hbr or Hcl to a conjugated diene to generate 1,2 and 1,4 addition products
The 1,2 addition forms faster (it is the kinetic product)
The 1,4 addition is the more stable (it is the thermodynamic product)
Add heat to favor the 1,4 product.
Keeping the reaction cool (under 0 degrees Celsius) will favor the 12 product.
Below is a table showing the effect on temperature and product ratios (don't need to learn
this table. More for general understanding):

Mechanism:
 35

Diels-Alder Reaction
Diene + dienophile + heat ring

The diene must be conjugated and in the s-cis conformation. The diene also cannot be
sterically hindered. 4 possible situations in diels-alder problems:

Situation 1

The diene above is a diene in the s-cis conformation. Note that there is a wide gap for
the dienophile to attack the diene (it is unhindered). As a result, this diene is a good
molecule for diels-alder.

Situation 2

The diene above is a diene in the s-trans conformation. In this current conformation, this
molecule cannot participate in diels-alder. However, this molecule can rotate around its
single bonds and thus attain a conformation similar to the diene in situation 1. Note that
there is also a wide gap for the dienophile to attack the diene (it is unhindered). As a
result, this molecule is also good for diels-alder.
S-cis
s-trans
Situation 3

The diene above is a diene in the s-trans conformation (left picture). Like situation 2,
this diene can rotate around its single bonds to attain a s-cis conformation (right picture).
When this molecule is in the s-cis conformation, the methyl groups close the opening.
This molecule is hindered and the dienophile will not be able to attack the diene.
Therefore, this molecule is BAD for diels-alder.

Situation 4

The diene above is a diene in the s-trans conformation. This diene cannot rotate around
its single bonds to attain a s-cis conformation because it is part of a ring (rings cannot
rotate around bonds). Therefore, this molecule is BAD for diels-alder as it will never
attain an s-cis conformation.
 36

Stereochemistry:
trans subsituents on the dienophile lead to anti addition
cis substituents on the dienophile lead to syn addition

Cis dienophile leads to syn

addition of R groups

Trans dienophile leads to anti

addition of R groups

You can use alkyne dienophiles instead of alkene dienophiles. Make sure to include the
extra double bond directly across from the double bond formed in the diels-alder reaction!

The diene can be a ring. If the diene is a ring, you will generate a bicyclo compound. In
bicyclo compounds, the endo product is favored. In the endo product, the R groups are
pointing downward, not horizontally outward (exo).
 37

Huckel's rules for aromaticity

For aromatic compounds:
4n+2 pi electrons (2,6,10...)
planar, cyclic array
overlapping pi bonds and/or on orbitals
no sp3 carbons present in the ring unless it is a carbanion
For anti-aromatic compounds
4n electrons (4,8,12...)
planar, cyclic array
overlapping pi bonds and/or on orbitals
no sp3 carbons present in the ring unless it is a carbanion
Count lone pairs (maximum of 1 lone pair per atom) if the heteroatom is not connected to a
double bond. If the heteroatom is connected to a double bond, do not count them!
Fused aromatic rings can be cyclic. If 2 neighboring rings share a double bond, it counts to
both rings.
Count triple bonds as 2 electrons, not 4 electrons!
Note: if the lone pair of electrons on the heteroatom contribute to aromaticity, they are
unreactive.
EAS regiochemical considerations
Memorize this table:

Activating groups (aka. Electron donating groups) = faster EAS

Deactivating groups (aka. Electron withdrawing groups) = slower EAS
In general:
substituents with lone pairs on the atom directly attached to the ring and alkyl
substituents favor ortho, para.
Substituents without lone pairs directly attached to the ring and are not alkyl favor meta.
Special cases:
Acetals are ortho/para directors.
Halogens are ortho/para directors.
Substituents that have charge on the atom directly attached to the ring are meta
directors.
When there are multiple substituents on a ring, the strongest activating group determines
regiochemistry.
No substitution between meta substituents occurs on a ring.
 38

A note on EAS mechanisms

For the DAT, a common question asked is to identify the most stable intermediate/resonance
structure during a specific EAS reaction. If none of the answer choices have structures in
which all atoms have a full octet, then:

A meta director will have the intermediate looking like this.

A para director will have an intermediate looking like this.

An ortho director will have an intermediate looking like this.

For more information, please visit the site
http://www.chem.ucla.edu/harding/notes/notes_14D_EAS02.pdf. Fantastic source for
EAS!
Halogenation of aromatic rings
Add FeBr3 + Br2 or FeCl3 + Cl2 to add chlorine or iodine to an aromatic ring.
Note, you cannot use iodine.
FeBr3/FeCl3 are lewis acids that are designed to help making Br2 and Cl2 better leaving
groups.
Phenols over-halogenate unless you leave out the FeX3 catalyst.

Anilines over-halogenate unless one of the R groups is a carbonyl.

 39

Nitration of aromatic rings

Add cat. H2SO4 and HNO3 to nitrate an aromatic ring.

-NO2 group is a meta director and is strongly deactivating. Below is the lewis structure.

Reduction of NO2 into NH2

Add H2, Pd-C or 1) Sn, HCl and 2) NaOH
We reduce to an amine since -NH2 is an ortho, para director and is strongly activating. In
addition, the amine group useful for reactions beyond EAS.
Friedel-crafts acylation of aromatic rings
Add an acid chloride and AlCl3 to a benzene ring to add a carbonyl group to the ring.
AlCl3 is a lewis acid and is used in the reaction to help make a strong electrophile.

Reduction of carbonyl group into an alkyl group

Add H2NNH2, NaOH, heat OR Zn(Hg), HCl

Friedel-crafts alkylation of aromatic rings

Add secondary or tertiary alkyl halide (rarely primary but possible) and AlCl3 to alkylate the
ring.
Must add alkyl halide in excess.
Watch for carbocation shifts of the alkyl halide!
 40

Exceptions to friedel-crafts alkylation and acylation

If there is a meta director on the ring, then no friedel-crafts will occur.

Annilines (-NH2) do not participate in friedel-crafts.

Oxidation of alkyl benzenes

Add KMnO4 to turn the alkyl group into a carboxylic acid group.

If a ring is attached to the aromatic ring, each connector point (each point where the ring
attaches to the benzene ring) turns into COOH.

If there are no allylic hydrogens, then there is no reaction.

Sulfonation of aromatic rings

Add cat. H2SO4 and SO3 to add an -SO3H group to the aromatic ring.
-SO3H is a meta director and is deactivating.
 41

LiAlH4 vs. NaBH4

aldehyde primary alcohol (use either to achieve this)
ketone secondary alcohol (use either to achieve this)
ester primary alcohol (LiAlH4 only)
carboxylic acid primary alcohol (LiAlH4 only)
LiAlH4 and NaBH4 cannot reduce alkenes.
Stereochemistry: retention and inversion (leads to racemic mixtures). Similar to Sn1
stereochemistry.

Organometallic reagents: synthesis and properties

To create a grignard reagent, add Mgo with Et2O or THF to an alkyl halide.

To create an organolithium reagent, add 2 equivalents of lithium metal to an alkyl halide.

Organometallic reagents are VERY basic and nucleophilic.

Due to their high basicity, organometallic reagents will react in acid-base reactions over
anything else if there are protons available, so watch out!
 42

Addition-elimination reactions
Use 1) organometallic reagent and 2) H3O+ to turn an aldehyde or ketone or ester into a
tertiary alcohol.
This reaction goes through a ketone intermediate.
Use 1) LiAlH4 + THF and 2) H3O+ to turn an ester and an aldehyde into a primary alcohol
and a ketone into a secondary alcohol.
This reaction goes through an aldehyde intermediate.

How can we stop at the aldehyde or ketone, given an ester as the starting material?
Use 1) DIBAL-H and 2) H2O to stop at the aldehyde.

Use 1) organocuprate reagent (R)2CuLi and 2) H3O+ to stop at the ketone

Alpha-beta unsaturated ketone and aldehyde additions

An alpha-beta unsaturated carbonyl is when there is a double bond between the alpha
(one carbon away from the carbonyl carbon) and the beta (two carbons away from the
carbonyl carbon) carbon of a carbonyl compound.
ketone aldehyde

These compounds react with organometallic reagents in 1,2- and 1,4-addition reactions.
What is does 1,2- and 1,4-addition mean? Note that oxygen is numbered 1 in counting.
 43

Add (1) organolithium or a grignard reagent and (2) H3O+ to do a 1,2-addition. 1,2-
additions turn the ketone into an alcohol.

Add (1) organocuprate reagent and (2) H3O+ to do a 1,4-addition.

A new way to make acetylide anions

We previously discussed adding NaNH2 to terminal alkynes generates acetylide anions.
We can also use organometallic reagents to make them too in an acid-base reaction.
 44

How can you add nucleophiles to aldehydes and ketones?

Look at the resonance structure for a carbonyl compound:

Notice how in the right structure (a minor resonance contributor), the carbonyl carbon is
positively charged, meaning that it is electrophilic.
For a given molecule with multiple resonance structures, all structures exist all the time, at
the same time. Therefore, the carbonyl carbon is slightly positively charged, meaning it is
somewhat electrophilic and therefore can react with nucleophiles.
Cyanides and cyanohydrins
Add NaCN and catalytic acid (HCl) to an aldehyde or ketone to generate a cyanohydrin.

Cyanohydrins can be converted back into aldehydes and ketones by applying a strong base.

Cyanohydrins can be converted into carboxylic acids with H2O, heat, and catalytic acid.

Acetylide ions
Acetylide ions can add to aldehydes or ketones. Use catalytic acid to push the reaction
forward.

Wittig reaction
Preparing the wittig reagent
(1) React Ph3P with an alkyl halide. Mechanism is Sn2 so do not use a hindered alkyl
halide.
 45

(2) React product from step 1 with a strong base (NaNH2, organometallic reagent, etc.)
to generate the wittig reagent (a triphenyl phosphonium ylide).

Wittig reaction
Wittig reagent + aldehyde/ketone alkene
stereochemistry:
If the substituent sizes on both sides of the carbonyl are around the same, you will
get the cis and trans products.
If the substituent sizes are unequal, then the trans product is favored.
Mechanism involves 3 main steps:
1) Nucleophilic attack on the carbonyl

2) Formation of a 4 membered ring (oxaphosphetane intermediate)

3) Formation of the alkene

Addition of primary and secondary amines to aldehydes and ketones

aldehyde/ketone + primary amine + catalytic acid imine
aldehyde/ketone + primary amine + catalytic acid enamine
solvent tolune/benzene + reflux + dean stark apparatus (this removes water to push the
reaction forward via le-chatelier's principle)
 46

both reactions are reversible

Mechanism for enamine and imine generation:

Hydrolysis of imines and enamines

Add water and catalytic acid to imines/enamines to revert them back to the aldehyde or
ketone.

Add H2O to aldehydes and ketones to generate geminal diols

H2O + catalytic acid or base + aldehyde or ketone geminal diol
This is a reversible reaction.
 47

Adding alcohols to aldehydes and ketones

Add one equivalent alcohol + catalytic acid to aldehyde/ketone hemiacetal
Hemiacetals are unstable!
Add 2 equivalents of alcohol + catalytic acid to aldehyde/ketone acetal
Instead of adding 2 equivalents of alcohol to generate the acetal, you can use 1 molecule
with two hydroxyl groups!
Both reactions are reversible.

Acetal hydrolysis
Add excess water, heat, and catalytic acid to hyrdolyze the acetal back into the carbonyl
compound.
The excess of water drives the equilibrium toward the formation of the ketone or aldehyde.
 48

Carboxylic acid family reactivity

Most reactive to least reactive
(1) acid chloride
(2) acid anhydride
(3) ester
(4) carboxylic acid
(5) amide
(6) carboxylate salt

You will see that in general, acid chlorides and acid anhydrides won't need a catalyst for
nucleophilic acyl substitution whereas for esters, carboxylic acids, and amides, a catalyst
will be needed.
Making acid chlorides
Carboxylic acid + SOCl2 acid chloride + SO2 + HCl

Making carboxylic acid

Theme: Add H2O to make the carboyxlic acid!
Esters, carboyxlic acids, and amides also require catalytic acid or base:
Using a catalytic acid generates the carboxylic acid
Using a catalytic base generates the carboxylate salt
Acid chloride and acid anhydride requires pyridine as well.
Acid anhydrides generate 2 carboyxlic acids:
 49

Generating acid anhydrides

Acid chloride + carboxylate anion/carboxylic acid acid anhydride + Cl-/HCl

Heat a dicarboxylic acid to generate the anhydride

Making esters
Theme: Add ROH to make the ester!
You can't use amides as reactants here. Only use carboxylic acids, acid chlorides, and acid
anhydrides.

Acid chloride requires pyridine as well.

Carboxylic acids require catalytic acid (this is called the Fischer Esterification).
 50

Making nitriles and reactions of nitriles

Alkyl halide + CN- nitrile + X-
Sn2 mechanism = inversion of stereocenter + unhindered alkyl halides only!

Reducing nitriles with LiAlH4 and DIBAL-H

use 1) LiAlH4 and 2) H2O to make the primary amine

use 1) DIBAL-H and 2) H2O to generate the aldehyde

Reducing nitriles with organometallic reagents

use 1) organometallic reagent and 2) H2O to make the ketone

Saponification
Ester + strong base carboxylate salt + alcohol
Saponification is base promoted, not base catalyzed!

Making amides
Theme: Add an amine to make the amide!
For acid chlorides and acid anhydrides, add 2 equivalents.
For esters, add 1 equivalent.
For carboxylic acids:
Use 1 equivalent
If you use NH3 as your amine, add heat
If you use a primary or secondary amine, add DCC
 51

Enols and Enolates

In water, ketones and aldehydes are in equilibrium with the enol tautomer.
A tautomer is a constitutional isomer that readily inter-converts through movement of
hydrogen atoms via a process called tautomerization.
The enol tautomer is in equilibrium with the deprotonated form, the enolate.
Enols and enolates are nucleophilic at the alpha carbon!

Acid-catalyzed enol formation

Add strong, aqueous acid to an aldehyde or ketone to generate the enol.
Note that the reaction is reversible (reactant favored!).

Base-catalyzed enolate formation and kinetic vs. thermodynamic enolates

Add strong base to an aldehyde or ketone to generate the enolate.

Note that the reaction is reversible and reactant favored.

Unsymmetrical aldehydes/ketones can generate 2 different enolate products:

A B

Product A is the thermodynamic enolate because it has the more substituted double
bond. It is more stable than product B for this reason.
Product B is the kinetic enolate because the base is attacking at the less hindered side.
When is which product favored?
Kinetic enolates are favored when you use a very strong base like LDA (pka > 25), a
polar aprotic solvent, and low temperatures.
Thermodynamic enolates are favored when you use a weaker strong base (15 < pka <
25) such as NaOC2H5, HOC2H5, protic solvents, and room temperature.
 52

1,3 diketones have a very acidic alpha carbon so all reactions will take place at the carbon
between both ketones. These molecules are more reactive than normal aldehydes and
ketones.

Alpha-halogenation and alpha-deuteration of aldehyes and ketones

Alpha-halogenation
aldehyde/ketone + cat. Acid/base + X2 halogenated product
If you use catalytic acid, the reaction proceeds through an enol intermediate.
If you use catalytic base, the reaction proceeds through an enolate intermediate.
NOTE: If there is more than 1 alpha proton, then all sites will be halogenated!
Mechanism shown below (In reality, all 3 alpha protons would get halogenated and this
mechanism would repeat itself 3 times):

Alpha-deuteration
This is the exact same reaction as above, but you use D2O instead of X2.
D2O is dueterated water. An isotope of hydrogen called Deuterium is used instead of
normal hydrogen.
All features of this reaction are the same as alpha-halogenation.

Haloform reaction
This reaction is a special type of alpha-halogenation where one of the alpha carbon has 3
alpha protons (like the one shown in the mechanism for alpha-duteration). These types of
molecules are called methyl ketones.
Methyl ketone + cat. Acid/base + X2 carboxylate salt + CX3H
 53

Adding alkyl halides to the alpha carbon

Aldehyde/ketone + cat. Base + R-X alkylated carbonyl + X-
Mechanism is Sn2 = inversion of stereocenter and only unhindered alkyl halides can be
used

Acetoacetic ester synthesis

Must use ethyl acetoacetate as your reactant.

Ethyl acetoacetate + 1) base + 2) R-X + 3) H3O+, heat ketone

For base, use NaOC2H5/HOC2H5 to prevent acyl reactions with the ester.
Alkyl halide adds via. Sn2 mechanism
Use reagents twice in a row for double alkylation. Notice how in the picture below the
reaction scheme is applied twice.

Malonic ester synthesis

Same reagent scheme as the acetoacetic ester synthesis, but you use diethyl malonate as
your reactant instead.
What is diethyl malonate?
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Diethyl malonate + 1) base + 2) R-X + 3) H3O+, heat carboxylic acid

Use reagents twice in a row for double alkylation.
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General principle
We have seen carbonyl compounds act as an electrophile at the carbonyl carbon.
We have also seen carbonyl compounds act as a nucleophile at the alpha carbon.
Therefore, we can react carbonyl compounds with other carbonyl compounds by selectively
choosing which one acts as the electrophile and which one acts as the nucleophile!
Aldol condensations, dehydrations, self-aldol, intramolecular aldol, and cross-aldol reactions
General mechanism:

1) Take an aldehyde or ketone and treat it with base to generate the enolate.
2) React the enolate with another aldehyde or ketone. The enolate's alpha carbon
(nucleophile) will attack the carbonyl carbon of the aldehyde/ketone (electrophile), thus
creating a new carbon-carbon bond. Acid is then used to protonate the alkoxide anion.
self aldol reaction
2 aldehydes/ketones + H2O + base aldol compound
If the ketones used are not symmetrical, then you will generate a mixture of products
(bad)!

directed aldol reaction

aldehyde/ketone + 1) base + 2) aldehyde/ketone + 3) base + H2O aldol compound
The order is important. The first added aldehyde/ketone will act as your enolate; hence,
this is why you add base in step 1 (to generate the enolate). The second added
aldehyde/ketone acts as the electrophile.
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cross aldol reaction

aldehyde/ketone + unenolizable aldehyde/ketone + H2O + base aldol compound

What is an unenolizable carbonyl? For a carbonyl compound to become an enolate, it

must have alpha protons. Therefore, an unenolizable carbonyl compound has no alpha
protons. Therefore it cannot ever turn into an enolate! This gives you regiochemical
control over your product.
Aldol dehydration
Add acid/base, water, and heat to dehydrate the aldol product.
The key is look for heat!
Intramolecular aldol reaction

This will occur when there are 2 carbonyls in the same molecule. It is only good if you
can form a 5-6 carbon ring.

Retrosynthetic analysis of aldol products

A common DAT question gives you an aldol product and asks you which 2 carbonyl
compounds can be used to generate the product given.
If the aldol product given is not dehydrated:
1) locate the carbon bound to the OH group.
2) cut the carbon-carbon bond that is closer to the carbonyl carbon
3) re-convert the alcohol into a carbonyl by swapping the -OH for =O
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If the aldol product given is dehydrated:

1) locate the double bond
2) cut the double bond to generate the 2 molecules
3) add a carbonyl to the molecule that lacks the carbonyl to the carbon that
participated in the double bond in the aldol product.

If the aldol product is an intramolecular aldol product

1) locate the double bond
2) cut the double bond to open the ring
3) add a carbonyl to the carbon furthest from the original carbonyl that participated
in the double bond.

Michael reaction
alpha/beta unsaturated aldehyde/ketone + aldehyde/ketone + base/solvent 1,4 addition
The product is a 1,5-diketone (if you see this type of molecule, think micheal reaction!)

Mechanism (explained on next page):

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1) Base attacks the aldehyde/ketone to generate the enolate.

2) The alpha carbon of the enolate reacts with the beta carbon of the alpha/beta
unsaturated aldehyde/ketone. A carbon-carbon bond is formed.
3) The double bond participates in an acid-base reaction with a water molecule
(solvent), generating the 1,5 dicarbonyl.
Claisen condensation and diekmann condensation
Claisen condensation
This is the ester analogue of the aldol condensation! Esters have alpha protons like
aldehydes and ketones so they can turn into enols and enolates. Therefore, they can
participate in the same reaction as the aldol condensation.
2 esters + 1) base + 2) acid 1,3 dicarbonyl ester

There can also be a crossed claisen condensation, just like a crossed aldol.

Diekmann condensation
This is the ester analogue of an intramolecular aldol condensation.
This will occur when there are 2 esters in the same molecule. It is only good if you can
form a 5-6 carbon ring.
Add 1) base and 2) acid
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Synthesizing Amines
Nitration of an aromatic ring, followed by reduction:

You can also use Sn, HCl or Fe, HCl instead of H2, Pd-C to carry out the reduction step.
Reducing an amide with lithium aluminum hydride and water
1) LiAlH4 and 2) H2O

Reducing a nitrile with lithium aluminum hydride and water

1) LiAlH4 and 2) H2O
Note that you generate the primary amine.

Reducive amination via sodium cyanoborohydride of aldehydes and ketones

aldehyde/ketone + amine + NaBH3CN amine
The choice of the amine reagent affects the amine product:
NH3 reagent primary amine product
primary amine reagent secondary amine product
secondary amine reagent tertiary amine product
tertiary amine reagents cannot be used!

Gabriel synthesis of primary amines

Nitrogen analogue of anhydride + alkyl halide + KOH/EtOH primary amine +
carboxylate
Step 1)
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Step 2)

Step 3)

NOTE: you can only use CH3X or primary alkyl halides!

Hoffmann rearrangement
primary amide + X2 + NaOH + heat amide (with one less fewer carbons)

Nucleophilic substitution with alkyl halides

amine + alkyl halide product mixture
There is no control in this reaction. Some recants will be alkylated once, twice, or even
multiple times.

Hoffmann elimination
primary amine + 1) excess CH3I, K2CO3 + 2) Ag2O, H2O + 3) heat alkene
Less substituted alkene is favored.
E2 elimination mechanism.
Silver oxide switches out halogen with OH- so that when product is heated, OH- will cause
elimination.
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Diazonium Salts
Add NaNO2 + HCl to a secondary amine to get N-nitrosamine.

Add NaNO2 + HCl to a primary amine to get a diazonium salt.

Diazonium salts can undergo many substitution reactions:

add H2O to generate the phenol
add CuX (X = Br, Cl) to generate the halide.
add CuCN to generate the nitrile.
add HBF4 to generate the fluoro compound.
add NaI or KI to generate the iodide.
add H3PO2 to reduce the diazonium salt.