Vollhardt Chemistry Notes Ch10-18

CHAPTER 10: Nuclear Magnetic Resonance
(1)
General information on spectroscopy

Spectroscopy: a technique for analyzing molecules based on how they absorb radiation.
In organic chemistry we use: NMR, IR, UV, MS to identify the structure of the molecules.
excited
state
Organic molecules absorb energy in discrete packages called: quanta.

The absorbed energy produces motion: excitation.
The absorbed energy E=h (: frequency, h: Planck's constant)
and = c/ (c: light velocity, : wavelength)
E=h
ground
state
NMR (Nuclear Magnetic Resonance) spectroscopy: is a technique that relies on the

principle that certain nuclei when they are in a magnetic field can absorb (i.e. resonance) and
reemit (i.e. relaxation) energy of a specific frequence (see figure below). The amount of
energy the can absorb-reemit depends on their electronic environment and thus allows us to
predict their attachment and proximity to other elements.
Nuclei of atoms with an odd mass number or odd atomic number have nuclear spin and are
assigned a spin quantum number : I. Only atoms with I0 give rise to NMR. In this case
the nucleus behaves as a small magnet and is allowed to exist in 2I+1 energy levels.
1H
and 13C (1% abundance) have an I=1/2 and they have (21/2+1)= 2 energy levels
2H (deuterium) and 14N have an I =1
and they have (21+1)= 3 energy levels
12C and 16O have an I=0 and they have (20+1)= 1 energy levels (NMR inactive)
Example: alignment of protons in the absence and presence of a magnet
-h
resona
nce
relaxati
on
E=h
protons in the
absence of a
magnet
protons in the
presence of a
magnet
protons in
resonance
protons
after
relaxation
(2)
Run an NMR experiment: (in 140B we will only look at 1H and 13C NMR experiments)
a. solubilize the unknown compound in a solvent that has no protons thus there is no interference from the
solvent protons. The solvent of choice is CDCl3 (deuterated chloroform).
b. add the solution of compound/CDCl3 inside an NMR tube and place it inside the magnetic field.
In most cases we have the CDCl3 solution contains a small amount of (CH3)4Si (tetramethyl silane, TMS) that
we use as an external reference standard (arbitrarily the TMS defines the 0 ppm value in both 1 and 13C NMR
spectra).
c. start the experiment and record the spectrum. For a 1H NMR we use the scale 0-10 ppm. For a 13C NMR
we use a scale of 0-200ppm.
Example of a 1H NMR experiment: the unknown compound is Cl2CH-CH(OCH2CH3)2
(3)
General observations obtained from NMR spectra:

1. The number of different signals (peaks) indicates how many different (non equivalent)
families of nuclei are in a molecule and provides information about the overall symmetry of
the molecule.
2. The integration of peaks (measuring the relative area of the peaks) shows the relative
amounts of protons/peak. (This is very reliable for 1H NMR but integration of a 13C NMR
spectrum is problematic).
3. The chemical shift (position of peaks) depends on the electronic environment of the
nuclei due to the presence of elecronegative groups, substitution and multiple bonds.
4. The splitting pattern (appearance of peaks) reveals which nuclei are close enough so
they can interact under the influence of a magnet (spin-spin coupling). Very useful in 1H
NMR but not often done in 13C NMR experiments.
Integration of peaks (only for 1H NMR)

The NMR absorption of nuclei is cumulative. This means that the more the protons of the
same family the bigger the overall area of the peak as compared to other peaks. By
integrating the peaks we can estimate the ratio of equivalent protons. The integration is
reliable only for protons but not for carbons.
Chemical shift
Chemical shift is the relative position of a peak using (CH3)4Si=TMS as reference.
The shift is reported in ppm values (or values) relative to TMS (0 ppm) and the higher
the number the more to the left of the spectrum is the peak.
A 1H NMR is usually recorded between 0-10 ppm, while a 13C NMR is recorded between
0-200 ppm. Note that there is a better resolution for the carbon NMR.
The value of a proton is independent of the spectrometer with which it was recorded and
depends only on the electronic (magnetic) environment of the nucleus that we observe.
Electron density around a nucleus shields the nucleus from the effect of the magnet and
shifts the corresponding peak to the right of the NMR spectrum (higher field, aka
upfield shifting). In contrast, removing electron density deshields the nuclei and
causes resonance at lower fields (left on the NMR spectrum aka downfield shifting).
The chemical shift of a nucleus depends on (a) its attachment to electronegative
groups; (b) the degree of carbon substitution; and (c) the presence of multiple bonds.
(4)
Chemical shift: effects of electron density and relative electronegativity

In general, adding electron density around a nucleus shields the nucleus from the effect of
the magnet and shifts the peak to the right of the NMR spectrum (higher field or upfield
shift). In contrast, removing electron density deshields the nuclei and causes resonance at
lower fields (left on the NMR spectrum) also referred to as downfield shift.
1. Attaching more electronegative atoms on a nucleus decreases its electron density and shifts
its NMR signal downfield. The effect decreases by increasing the distance between the
nucleus we observe and the electronegative element. The electronegativity values of elements
from the periodic table can help us predict the chemical shift of the nuclei.
75
29
10
-24
50
-2
CH3F CH3Cl CH3Br CH3I CH3OH CH3SH CH3CH3 CH3H (CH3)4Si

4.3
3.0
2.7
2.1
3.4
4.8
2. The effect of electron density is

cumulative which means that more
electron withdrawing groups enhance the
deshielding effect of a nucleus
2.0
96
3.1
0.9
77
0.2
54
25
CCl4 CHCl3 CH2Cl2 CH3Cl

7.2
3. The 1H chemical shift of hydrogens bound

to oxygens varies depending on the extent of
the hydrogen bonding, which depends on the
concentration. In general acid hydrogens
are more deshielded.
5.3
3.0
O
CH3COH
2.0
10
7.3-6.8
OH
CH3OH
5.1
3.4 4.8
Chemical shift: effects of carbon substitution

The more substituted the carbon is the more deshielded the 13C and the related 1H NMR is
and thus its resonates to the left of spectrum or at higher values.
3.0
H
H
Cl
H
29
1.5
H
20
3.4
H H
Cl
H H
38
3.8
1.55
H H
H
28
Cl
H
47
HH H
HHH
H
H
Cl
36 H
H H H 51
1.6
(5)
Chemical shift : Effect of multiple bonds

Double bonds: Elements found on sp2-hybridized carbon centers (double bonds or aromatic
rings) are much more deshielded than would be expected based only on electronegativity
arguments. Explanation: The motion of electrons of a double bond creates an induced
magnetic field that reinforces the external magnet, producing an overall deshielding effect.
Double bond 1H resonate at about 5 ppm, and 13C at about 120 ppm. In the aromatic rings this
electronic motion is referred to as ring current and further shifts 1H at about 7 ppm.
Triple bonds: Elements found on sp-hybridized carbon centers (triple bonds) are much
more shielded than would be expected based only on electronegativity arguments.
Explanation: The motion of electrons of a triple bond creates an induced magnetic field that
weakens the effect of the external magnet, producing an overall shielding effect.
Triple bond 1H resonate at about 1.8 ppm, and 13C at about 70 ppm.
flow of p
electrons
effect:
H0-Hl
effect:
H0+Hl
local
field:
Hl
H
local
field:
Hl
local
field:
Hl
local
field:
Hl
flow of p
electrons
local field:
Hl
local field:
Hl
external
field: Ho
external
field: Ho
examples of 1H and 13C NMR chemical shifts for multiple bonds

130 116
130
31
7.2
H
120
156
CH2=CH2
5.2
H
6.9
128
80
6.8
1.7
68
H3C C C H
1.8
1.8
2.0
H
9.6
2.2
7.2
4
H3C
O-H
200
117
21
H3C
171
O
60
O CH2-CH3
H3C C N
2.1
14
4.1
1.2
(6)
Chemical shift and NMR

General rule: The chemical shift of a nucleus moves downfield (to the left) due to: (a) attachment to
electronegative elements; (b) degree of carbon substitution; and (c) the presence of double bonds.
1H
NMR spectrum (usually recorded between 0-10 ppm using TMS to define 0 and residual CHCl3 for 7.2).
Predict the chemical shift of the protons by considering/remembering:

a. cumulative effect of electronegative groups (remember: CH3Cl at 3; CH2Cl2 at 5.2 and CHCl3 at 7.2 ppm)
e.g. since CH3Cl is at 3.0 ppm so CH3Br would be around 2.7 ppm.
b. degree of carbon substitution (e.g. CH3Cl is at 3.0ppm, CH3CH2Cl is at 3.4 and (CH3)2CHCl is at 3.8)
c. effect of double bonds (remember CH2=CH2 at 5.2; C6H6 at 7.2 and aldehyde proton at 9 ppm)
d. triple bond proton at 1.8 ppm
O
protons on
heteroatoms
H-OR, H-SR, H2-NR variable (1-5)
H-O
multiple
bonds
13C
CH3Cl
CH2Cl2
CHCl3
electro
negativity
10
ppm
ROCH3
TMS
NMR spectrum (usually recorded between 0-200 ppm using TMS to define 0 and CDCl3 for 77 (triplet)).
Predict the chemical shift of the 13C by considering/remembering:

a. cumulative effect of electronegative groups (remember: CH3Cl at 30; CH2Cl2 at 54 and CHCl3 at 77 ppm)
e.g. since the CH3Cl carbon is at 30 ppm, the CH3Br carbon would be around 10 ppm.
b. degree of carbon substitution (e.g. CH3Cl is at 30ppm, CH3CH2Cl is at 38 and (CH3)2CHCl is at 47)
c. effect of double bonds (remember CH2=CH2 and C6H6 are both at 130 and aldehyde carbon is at 200 ppm)
d. triple bond proton at 70 ppm
O
multiple
bonds
H
O
H-O
H
remember:
CDCl3 as a triplet
(1:1:1) at 77.0
CHCl3
electro
negativity
ppm
200
180
160
140
ROCH3
120
100
80
CH2Cl2 CH3Cl
60
40
TMS
20
(7)
Spin-spin coupling and splitting patterns (appearance of peaks)

Theory: Nuclear spin active atoms (I0) whose nuclei are in close proximity interact with each
other. This effect (spin-spin coupling) is transmitted through covalent bonds and depends on
the number and type of bonds that separate the nuclei as well as on their spatial distance and
stereochemical relationship. These interactions produce different splitting patterns which
provide information on the number of atoms that split the observed nuclei and their stereochemical relation. The measure of interaction is called coupling constant J (given in Hertz).
For example each proton (I=1/2; 2 energy levels) can exist in two different energy levels in a
ratio statistically 1:1. As such it can split the proton on the next carbon in 2 peaks of equal
intensity (1:1 ratio) producing a doublet with a well defined coupling constant (J). In a 1HNMR
the spliting between H-H is observed 3 bonds apart. In a 13CNMR there is only splitting
between H-C and is observed 1 bond apart (see 1H-coupled 13C NMR experiment).
A practical way to understand spin-spin coupling.
Example 1: The case of non-identical neighbors (i.e. 1H that have different J values)
a. Lets say that the 1H that we want to study resonates at a magnetic value of 10. If there is no
other magnet in close proximity, then the 1H will resonate once when the external magnet has a
value of 10 (see below). Thus, it will appear as a singlet at 10.
b. Lets now assume that another proton (Ha) exists in proximity the 1H and can spin in two energy
levels thus producing a micromagnet of -3 and +3 (splitting power Ja of Ha is 6). Based on this, our
1H will resonate at two different values of external magnet: at value of 7 (because 7+3=10) and a
value of 13 (because 13-3=10). Thus due to Ha, our 1H will resonate as a doublet at external
magnet values of 7 and 13 and the 1H will be a doublet of Ja=6.
c. Lets again assume that another proton (Hb) exists in proximity the 1H and can produce a
micromagnet of -1 and +1 (splitting power Jb of Hb is 2). Based on this, our 1H will resonate at four
different values of external magnet: at value of 6 (because 6+1+3=10), at 8 (because 8-1+3=10),
at 12 (because 12+1-3=10) and at 14 (because 14-1-3=10). Thus, due to Ha and Hb magnets, our
1H will resonate as a doublet of doublets of J =6 and J =2.
a
b
external
magnet
Ha
Ha
1H
no neighbors
One neighbor
Ha (J= 6Hz)
1H
1H
singlet
Hb
Two neighbors
Ha (J= 6Hz)
Hb (J= 2 Hz)
Ja= 6Hz
Jb= 2Hz
Jb= 2Hz
6
doublet (d, Ja=6 Hz)
10
doublet of doublets
(dd, Ja=6 Hz, Jb=2 Hz)
12 13 14
General rule: If the proton that we want to study has x non-identical (i.e. different J
values) protons neighbors (count only the ones that are 3 bonds apart), then it will be
split 2x times and will appear as x times a doublet of doublets of identical intensity.
(8)
A practical way to understand spin-spin coupling.

Example 1: The case of identical neighbors (i.e. 1H that have same J values) N+1 rule
a. Lets say that the 1H that we want to study resonates at a magnetic value of 10. If there is no
other magnet in close proximity, then the 1H will resonate once when the external magnet has a
value of 10 (see below). Thus, it will appear as a singlet at 10.
b. Lets now assume that another proton (Ha) exists in proximity the 1H and can spin in two energy
levels thus producing a micromagnet of -1 and +1 (splitting power Ja of Ha is 2). Based on this, our
1H will resonate at two different values of external magnet: at value of 9 (because 9+1=10) and a
value of 11 (because 11-1=10). Thus due to Ha, our 1H will resonate as a doublet at external
magnet values of 9 and 11 and the 1H will be a doublet of Ja=2.
c. Lets again assume that another proton (Hb) exists in proximity the 1H and can produce a
micromagnet of -1 and +1 (splitting power Jb of Hb is 2). Based on this, our 1H will resonate at
three different values of external magnet: at value of 8 (because 8+1+1=10), at 10 twice as strong
(because 10+1-1=10 and 10-1+1=10) and at 12 (because 12-1-1=10). Thus, due to Ha and Hb
magnets, our 1H will resonate as a triplet of Ja,b=2 with relative intensity of the triplet peaks 1:2:1.
d. Lets again assume that a third proton (Hc) exists in proximity the 1H and can produce a
micromagnet of -1 and +1. Due to the identical neighbors Ha, Hb and Hc our 1H will resonate as a
quartet of Ja,b,c=2. Note the relative intensity of the quartet peaks will be 1:3:3:1.
General rule 2: If the proton that we want to study has N identical (i.e. same J values)
protons neighbors (count only the ones that are 3 bonds apart), then it will be split N+1
times. The relative intensity of the peaks can be predicted by the Pascal's triangle.
1H
singlet
No neighbors
doublet
(1:1 ratio)
(J= 2 Hz)
split by 1 H
(J= 2 Hz)
triplet
(1:2:1 ratio)
(J= 2 Hz)
split by 1 H
(J= 2 Hz)
split by 1 H
(J= 2 Hz)
quartet
(1:3:3:1 ratio)
(J= 2 Hz)
7
10
11
12
13
14
General rule 3:
Protons of the same family have always identical J value. Thus the N+1 rule always applies.
Protons of different families could sometimes have identical J values (e.g. in aliphatic side
chains although the protons may not belong in the same family, they split the neighboring
protons with the same constant coupling (usually 7 Hz) due to free rotation. In these
cases, they are considered identical and they are subject to the N+1 rule.
(9)
Spin-spin coupling and splitting patterns

For the same reason a proton (2 spin energy levels) can split its neighboring carbon
producing a doublet of 1:1 ratio which can be observed in a "proton-coupled" carbon
spectrum.
One could, however, excite all protons to the highest energy level and then record the 13C
NMR spectrum. In this case the carbon peaks will become singlets. This experiment is
referred to as a "proton-decoupled" carbon spectrum.
Example
Cl
Cl
Cl
1
C
3
H
13C
NMR spectrum of compound A under "proton decoupled conditions" :

The C1 carbon should appear at 71 ppm (due to the 2 Cl atoms) as a singlet. For similar
reasons, the C2 carbon will be a singlet at 50 ppm.
13C
NMR spectrum of compound A under "proton coupled conditions" :

The C1 carbon should appear at ca 71 ppm (due to the 2 Cl atoms) and should be a doublet
of equal intensity, due to the H1 spin-spin coupling. (Spin-spin couplings between carbons
cannot be detected and the H2 and H3 atoms are too far..). The C2 carbon is split by 2
hydrogens (H2 and H3), so it should appear as a triplet at ca 50 ppm.
The 1H NMR spectrum of compound A:
The H1 is attached to a carbon having two Cl groups. It should be deschielded and appear
at ca 5 8 ppm. Its peak integration should be 1. It is split by two equivalent protons (H2
andH3) so it should be a triplet.
The H2 and H3 protons are equivalent and are attached to a carbon having one Cl group.
They should appear at ca 4 ppm and should integrate for 2. Both of them are split by one
proton (H1) so they should appear as a doublet.
CHAPTER 11: Alkenes and IR, MS spectroscopy
(1)
General Information
This chapter deals with a class of compounds, referred to as alkenes, that are characterized
by the presence of a carbon-carbon double bond. It includes information related to the
stability of the double bond, general methods to prepare alkenes and hydrogenation
(reduction) of alkenes. It also includes information on IR spectroscopy.
Alkene nomenclature and stereochemistry

The prefix -ene indicates the presence of one double bond in the molecule of interest.
Possibility of stereoisomers due to the relative position of substituents of the double bond.
H3C
Cis (Z): the biggest substituents at
the same side of double bond.
Trans (E): the biggest substituents
at opposite sides of double bond.
CH3
H3C
H
CH3
cis-2-butene
trans-2-butene
(Z)-2-butene
(E)-2-butene
The Pi bond: stability, geometry

bond
bond
120
120
bond
Alkenes are characterized by a planar geometry, with two trigonal carbons and bond angles
close to 120. This is called sp2 hybridization (ethene is shown as an example).
Two sp2 orbitals from each carbon form the bonds with substituents (here H), while the other
forms the C-C bond.
The non-hybridized 2p orbitals (one in each carbon) overlap to form the bond. The electron
density of the bond is localized above and below the plane of the alkene .
Due to orbital overlap the bond is stronger than the bond.
The strength of the bond can be experimentally measured by measuring the energy of
interconversion of a cis to a trans isomer. During such process the bond of the cis alkene
is broken, the p orbitals rotate around and eventually the more stable bond of the trans
alkene is formed (thermal isomerization).
CHAPTER 11: Alkenes and IR spectroscopy
(2)
Physical properties
The double bond does not affect significantly the physical properties of alkenes as compared to
alkanes.
In cis disubstituted alkenes there is a net molecular dipole that is not present in the trans isomers.
There is an increased acidity of
CH3-CH2-H
the alkenyl hydrogen as compared

to that of the alkanyl hydrogen due
to the electron attracting property
of the sp2 carbon.
H
H
K= 10
-50
H
H
CH3-CH3
H
K= 10
-44
+ H+
+ H+
NMR of alkenes
In the presence of a magnetic field, the pi electrons of the double bond move ina way that
deshields the alkenyl hydrogens (see outline in Chapter 10). Alkenyl hydrogens resonate at
ca 5-7 ppm.
For the same reason, the alkenyl carbons are also deshilded and resonate at about 120ppm.
Due to the rigid geometry of the double bond, the distance of the cis protons is different
than that of the trans. In NMR, this effect translates into different coupling constants for the
cis and trans proton. These constants, (J values, measured in Hz) are very characteristic of
the structure of the alkene.
cis
geminal
H
H
cis coupling constant: between 6-14 Hz, usually ca 10Hz

trans coupling constant: between 11-18 Hz, usually ca 16Hz
trans geminal coupling constant: between 0-3 Hz, usually ca 2Hz
(3)
Infrared spectroscopy (IR)

Absorption of energy that leads to changes in the vibration levels of atoms.
Atoms move constantly changing both bond lengths (stretching vibrations) and bond angles
(bending vibrations). When the energy of radiation is the same with the energy of vibrational
levels, then the radiation is absorbed and the molecular vibration is increased leading to IR.
The streching energy of a bond is related to the masses of the two atoms that are involved in
the bond, the dipole moment of the bond and the type of the bond formed (Hooke's law).
v= k
Hooke's law
v= frequency
k= constant
f= bond constant
m1+ m2
m1 m2
m1, m2= masses of atoms
The stronger the bond is the higher the frequency of streching vibration is.
Conjugation decreases the dipole moment of a functionality and thus it decreases
the streching frequency.
Also the intensity of the vibration increases with the increase of the dipole moment
of the bond.
C C H
C C
H
O
1730 (s)
O-H
C-H
N-H
C
O
2160 (w)
C
O
C
1710 (s)
C C
2260 (m)
C
O
1750 (s)
C N
H
2900 (s)
3000 (s)
3300 (s)
O
C C
NH
C C
C
C
1680 (s)
C C
C C
C N
C N
C O
1650 (s)
1600 (m)
C-C
C-O
C-N
C-H bending
N O
fingerprint area
4000
2300
1800
1400
-1
wavenumber (cm )
600
Review: general concepts of organic reactions

Activation energy (Ea): energy needed to be
consumed to allow reaction from S to P.
energy
transition state ()
Catalyst: A molecule that can decrease the Ea

of S->P without participating in the structures
of S,P.
Ea activation
energy
Ea(cat)
Transition state: the energetically highest

point on the reaction coordinates
heat of
formation
Heat of formation (H): defines the overall

reaction as exothermic or endothermic
Chemical reaction is a process that involves changes in positions of electrons in forming and
breaking bonds between atoms ultimately resulting in transformation of one type of chemical structures
to another. Chemical reactions do not involve changes in the nuclei of atoms (aka nuclear reactions).
A chemical reaction takes place when an electronically rich atom (defined as nucleophile or base)
collides with an electronically poor atom (defined as electrophile or acid) and forms new chemical
structures by "permanently" changing the position of electrons.
Thus, nucleophile is the reactivity profile of an electronically rich atom that uses its electrons to make a
new bond with an electronically deficient carbon electrophile.
Base is the reactivity profile of an electronically rich atom that uses its electrons to make a new bond
with an electronically deficient hydrogen atom (acid).
Example:
The Grignard reagent (RMgX) acts as

a nucleophile in the presence of an
electronically deficient carbonyl carbon
The Grignard reagent (RMgX) acts as

a base in the presence of an
electronically deficient (acidic) proton.
+ MgX
R
MgX
O
+
R
H
OH
+
H
O MgX
HO-MgX
Reaction mechanism is a stepwise sequence of electron movements that describes a chemical reaction.
Note:
a. For movements of two electrons we use the double hook arrow, for movements of one electron (radical
reactions) we use the single hook arrow.
b. The arrow always starts from the atom that has the available electron(s) (thus the electronically rich
atom) and ends at the atom that needs the electron(s) (thus the electronically poor atom).
c. To propose a mechanism we need to be able to assign partial charges or charges in atoms and define
the electronically rich and electronically poor centers.

Any electronically rich species can react with an electronically poor species to form new bonds.
There are two different types of reaction:
(a) nucleophilic substitution (SN) where the elelctronically rich species acts as a nucleophile and
makes a new carbon bond with the electronically deficient (+) carbon center of a reactant (aka
electrophile). A new bond (C-Nu) is formed and a preexisting bond is broken (departure of the
electronegative group (Br-) (aka leaving group).
(b) -elimination (or elimination) where the electronically rich species reacts as a base with an
acidic proton at the carbon (two carbons away from the electronegative atom) of a reactant. A
new bond is formed (B-H), the reactant has been converted to an alkene and the C-Br bond is
broken (departure of the electronegative group (Br-) (aka leaving group).
Nu
Br
Nu
nucleophilic
substitution
(SN)
Br
Because of the electronegativity of Br, the - carbon of the Br is + (good electrophile).

The Nu attacks this carbon and substitutes the Br atom (nucleophilic substitution).
Br
+ B
Br
elimination
(-elimination)
(E)
H
Because of the electronegativity of Br, the hydrogens at the -carbon of the Br are + (acidic).
The B attacks this acidic hydrogen, forms alkene and eliminates Br_ (-elimination).
Sequence of events during SN or E reactions (mechanisms)

To predict the reaction mechanism we need to know if the reaction is unimolecular or bimolecular.
Unimolecular reaction: its reaction rate depends only on the concentration of R-Br. This means
that the rupture of the R-Br bond to form R+ and Br- is the rate limiting step. The unimolecular
reaction proceeds stepwise and has an intermediate step where R+ is formed.
Bimolecular reaction: its reaction rate depends on the concentration of both reagents. This means
that the reaction proceeds in one step.
Unimolecular versus bimolecular nucleophilic substitution (SN1 versus SN2)

Nu
R
(el. rich
not charged)
+
Nu
(charged)
Br
Nu
Br
Nu
SN1
Br
unimolecular
nucleophilic
substitution
(SN1)
bimolecular
nucleophilic
substitution
(SN2)
Br
SN2
reaction rate:
unimolecular
(substrate only)
bimolecular
(substrate and Nu)
"big barrier"
carbocation stability
steric hindrance
alkyl halide
3o > 2o >> 1o
1o > 2o >> 3o
nucleophile
weak (neutral)
strong (charged)
solvent
polar protic (e.g. alcohols)
polar aprotic (e.g. DMSO)
stereochemistry
mixture
inversion
Stereochemical consequences of SN1 and SN2

In SN1 the C-L bond is broken (slow step) before the C-Nu is formed. Thus, there is mixture of
isomers at the newly formed C center.
Nu
X
X
L
fast
slow
Nu
Nu
In SN2 the C-Nu and C-L bond are formed and broken at the same time. Thus, there is inversion
of configuration at the newly formed C center.
X
L
Y
Z
Nu
Y
+
Z
X
Nu
Z
+ L-

Unimolecular versus bimolecular elimination (E1 versus E2)
R
B
(el. rich
neutral)
Br
+ B
+ B
Br
unimolecular
elimination
(E1)
Br
bimolecular
elimination
(E2)
B
(charged
strong)
Br
E1
(a)
E2
reaction rate:
unimolecular
(substrate only)
bimolecular
(substrate and Nu)
"big barrier"
carbocation stability
accessibility of proton &

steric hindrance of base
(Saytzev/Hofmann rule) (a)
alkyl halide
3o > 2o >> 1o
1o > 2o >> 3o
base
weak (neutral)
strong (charged)
solvent
polar protic (e.g. alcohols)
polar aprotic (e.g. DMSO)
stereochemistry
mixture
(usually favors more
stable alkenes)
leaving group should be

anti to hydrogen removed
Effect of base on E2 elimination

H
H2C Br
EtO Na
H3C
+ EtOH
H
C
HCH3
H3C
H3C
CH3
Br +
CH3
CH2CH3
ca 30%
ca 70%
Saytzev rule: Non bulky bases form more stable alkenes

H
H2C Br
H3C
C
HCH3
Me3CO K
+ Me3COH
Br +
H3C
H3C
CH3
ca 30%
CH3
CH2CH3
ca 70%
Hofmann rule: Bulky bases form less stable but faster to form alkenes
(4)
Degree of unsaturation
Degree of unsaturation is defined as the sum of the numbers of rings and bonds present in
the molecule. Alkanes have a formula: CnH2n+2 (degree of unsaturation= 0), while alkenes
with one bond or alkanes with one ring have formula: CnH2n (degree of unsaturation= 1).
Catalytic hydrogenation of alkenes
C C
Pd or Pt
H-H
+ heat (ca -30 Kcal/mol)
C C
H H
The addition of molecular hydrogen to an alkene proceeds in the presence of Pd or Pt as

catalysts and produces the corresponding alkane. The reaction is exothermic (produces heat)
and the heat of hydrogenation is a measure of the relative stability of the alkene. The more
stable the alkene the less its heat of hydrogenation.
increased stability
>
C C
>
C C
>
C C
R
C C
>
R
C C
>
increased heat of hydrogenation
R
C C
R
The E1 and E2 elimination reactions (review from 7.6 and 7.7)

E1 elimination (unimolecular): The dissociation of the starting material to a carbocation is the
rate limiting step. The reaction rate depends only on the concentration of the starting material.
H3C
H3C
Br
CH3OH
CH2CH3 (solvolysis)
Br
H3C
H2C
H
H
H
CH3
CH2CH3
H3C
H3C
CH3
+ CH3OH
H
CHCH3
H
CH3OH
(5)
The E1 and E2 elimination reactions (review from 7.6 and 7.7)

E2 elimination (bimolecular): The reaction rate depends on the concentration of both the
base and the starting alkane. The overall reaction proceeds in a single step that includes
deprotonation by the base, creation of the double bond and departure of the leaving group.
H
H2C
H3C
Br
H
C
HCH3
Br
H3C
H3C
CH3
+ BH
CH3
CH2CH3
faster to form
more stable
Effect of base on E2 elimination

H
H2C
H3C
Br
H
C
HCH3
EtO Na
Br
H3C
H3C
CH3
+ EtOH
CH3
CH2CH3
ca 70%
ca 30%
Saytzev rule: Non bulky bases form more stable alkenes

H
H2C
H3C
Br
H
Me3CO K
C
HCH3
+ Me3COH
Br
H3C
H3C
CH3
ca 30%
CH3
CH2CH3
ca 70%
Hofmann rule: Bulky bases form less stable but faster to form alkenes
Formation of alkenes via alcohol dehydration

H
H2C
H
OH
H
C H
CH3
H2SO4
- HOH
H
H3C
CH3
H
CH2CH3
The order of reactivity is: primary < secondary < tertiary

The most stable alkene is the major product
In secondary and tertiary cases we have E1 elimination
CHAPTER 12: Reactions of alkenes
(1)
General Information
This chapter deals with reactions of alkenes. In general, the bond of alkenes is weak and
electronically rich. In most reactions this bond behaves as a nucleophile and attacks
electrophilic reagents. Overall, this is an addition reaction and is often exothermic.
A B
C C
C C
Reaction mechanisms:
Based on the stereochemistry of the product formed, there are two types of reactions of
alkenes with A-B:
(a) the syn addition (also called anti-Markovnikov addition) where A,B are added from the
same face of the double bond. This implies that the B-A bond is not broken prior to the reaction
with the alkene. The reaction proceeds in a concerted manner via a four-membered
intermediate. To predict the structure of the product we should orient the A-B reactant across
the alkene in a manner that complements the relative polarization of all centers.
- B
- B
A +
Examples: hydrogenation, hydrometalation, osmylation, hydroboration/oxidation.

Note: The hydroboration/oxidation produces an alcohol where the hydroxyl group is at
the least sustituted carbon (anti-Markovnikov hydration).
(b) the anti addition (also called Markovnikov addition) where A,B are added from
opposite faces of the double bond. In this case the A-B bond is broken before the reaction
with the alkene. The addition proceeds in a stepwise manner via an initial three-membered
intermediate (alkene reacts with electrophile), then the nucleophile reacts in an SN2 manner
(thus from oposite face) at the most substituted (most +) carbon center.
Markovnikov rule: The nucleophile reacts at the most substituted carbon center, due to the
relative stability of the +.
A
A
A
+
R
+
R
In certain cases we observe carbocationic rearrangements.
Examples: hydrohalogenation, halogenation, hydrometalation, acid-catalyzed hydration.

Note: The acid-catalyzed hydration produces an alcohol where the hydroxyl group is at the
most sustituted carbon (Markovnikov hydration).
(2)
Markovnikov additions (anti additions)

12.3 Electrophilic addition on the double bond
H
H Cl
Cl
Cl
In certain cases we
observe carbocationic
rearrangements.
12.4 Electrophilic hydration of alkenes (Formation of alcohols)
HO
H-OH
H+ -OSO3H
classical Markovnikov
hydration of alkenes
anti addition
-H+
H+
H
H-OH
catalytic in acid
produces the most
substituted alcohol
OSO3H
reversible
12.5 Electrophilic halogenation of alkenes

Br
Br-Br
Br
Br
Br
Br
anti addition
12.6 General considerations on the electrophilic addition
Br
Br2
trapping of bromonium
ion by other nucleophiles
NaOH
O
H2O
OH
Me
Br2
Me OH
Me
H2O
Me
anti addition
cyclopropanation
Markovnikov addition
Br
(3)
anti-Markovnikov additions (syn additions)

12.2 Hydrogenation
Proceeds only in the presence of a catalyst, like Pd or Pt.
Exothermic
syn addition (the hydrogens are from the same face of double bond).
Hydrogenation proceeds predominantly from the less hindered face.
H2
H2
H2,
PtO2
not this
12.8 Hydroboration/Oxidation (preparation of anti-Markovnikov alcohols)
+ H
H2B
+
R
-
+ H2B H
H2B
R
H2O2
anti-Markovnikov addition of water
H
NaOH
B
produces least substituted alcohol .
HO
syn addition of BH3 (thus H2O)
H2O
R
on the double bond.
The regioselectivity of the reaction can be improved by using bulky boranes (9-BBN).
H
R 3
12.11 Osmylation (syn dihydroxylation with OsO4)

O
R1
Os
O
R2
R1
O
O
R2
Os
H2S
R1
OH
R2
OH
The dihydroxylation with OsO4 produces after reductive cleavage a syn diol.
During osmylation, the Os(VIII) is reduced to Os(VI).
The osmylation can be catalytic in osmium by the use of an oxidant (such as H2O2).
Alkene dihydroxylation can also be done with KMnO4 (analytical test).
12.7 Oxymercuration-Demercuration Do not study
(4)
Reactions that form 3-membered rings

12.9 Cyclopropanation
hv, , Cu
CH2:
CH2N2
CH2
H
KOtBu
CCl2:
CHCl3
CCl2
H
Zn-Cu
CH2:
CH2I2
CH2
H
Simmons-Smith cyclopropanation
12.10 Epoxidation
O O
R1
R2
H
R1
O H
R1
R2
R2
Note:
** The reaction proceeds with syn stereospecificity (trans alkene gives trans epoxide)
** The commonly used peroxide is MCPBA.
** The epoxidation proceeds faster with more substituted double bonds.
** The acid catalyzed openig of epoxides in water gives anti diols
H
H
R1
R2
H+
H2O
O
H
R1
R2
H
H
R1
O
R2
OH2 H
-H+
R
HO
OH
R2
H
(5)
12.12. Ozonolysis of alkenes (oxidative cleavage of double bonds)

R2
R4
R1
R3
R2
R4
R1
R3
Me2S
-70 C
-70 C
R2
R4
R1
O
R1
R4
R2
R4
+ Me2S=O
R2
R3
R1
R4
R3
R2
R1
R3
O
R2
R1
O3
R3
R4
O
R3
SMe2
12.13. Radical bromination of alkenes
RO-OR
R1
H-Br
heat
H
R1
Br
Note: Anti-Markovnikov addition of

HBr in the presence of peroxides
(indicates radical reaction)
no need to study the mechanism of the radical bromination
12.14-12.17: Do not study
CHAPTER 13: Alkynes
(1)
General Information
This chapter deals with physical and chemical properties of the triple bonds. In general,
the triple bond is formed by two bonds that are perpendicular to each other The sp
hybridization is characterized by a linear geometry. Triple bonds participate as
electronically rich species in several reactions similarly to alkenes. Also the alkynyl
hydrogens are relatively acidic (pK=25) and can easily removed.
13.2 Properties:
sp hybridization: one bond, two bonds, linearity
bond strength: triple (220) > double (180) > single (90)
bond length: triple (1.2A) < double (1.3A) < single (1.5A)
acidity:
pka
C
H
44
25
50
13.3 Spectroscopy
Alkynyl hydrogens are shielded due to the orientation of the triple bond inside the
magnet. These hydrogens resonate about 2 ppm.
Alkynyl hydrogens are split by other protons that are four bonds apart.
Alkynyl carbons resonate at about 70-90 ppm
In the IR, the triple bond absorbs at ca 2100 cm-1 and the C-H bond at 3300 cm-1.
13.4. Preparation
1. From dihaloalkanes by a double elimination
X
H
R2
R1
H
base (2 eq)
Usual base: NaNH2/NH3

R1 C
R2
- 2HX
Br
Br2,
CCl4
Br
Br
Br
1. NaNH2
NH3
2. H2O, H+
For terminal alkynes we

need 3 equiv of base
CHAPTER 13: Alkynes
(2)
13.5. Preparation
2. By addition of an alkynyl group to electrophiles
H
Bu Li
R1
- Bu-H
R2
R2-X
Li
R1
- LiX
R1
Commonly used bases: BuLi, NaNH2/NH3 or EtMgBr

Common electrophiles: epoxides, carbonyl groups and alkyl halides (possibilities
for E2 elimination in secondary and tetriary alkyl chlorides)
13.6. Alkyne reduction

1. Formation of cis alkenes or/and alkanes
R2
H H
H2/ Pd
R2
R1
R1
syn addition
reduction to alkanes
H H
R2
Pd/CaCO3/
quinoline
R1
H2/
Lindlar catalyst: a
"poisoned" Pd catalyst that
reduces alkenes very slowly.
R2
H
R1
2. Formation of trans alkenes

R2
R1
1. Na, liquid NH3

2. H+, H2O
stepwise one electron reduction
R2
H
H
R1
produces thermodynamically
stable trans alkene
mechanism not required
CHAPTER 13: Alkynes
(3)
13.7. Electrophilic additions of alkynes (Markovnikov additions)

R1
R1
HBr, Br-
anti addition (use excess X-)

Br
Markovnikov addition
often double addition that produces
geminal dihaloalkanes
H
R1
R1
Br2
Br
R1
Br
Br2
Br
HOH,
R1
R1
Br
Br
R1
R1
Br
R1
H+
tautome
-rization
OH
R1
H
O
HgSO4
H
The acid-catalyzed hydration of alkynes follows the Markovnikov rule.
The hydration is catalyzed by HgSO4
The intermediate enol tautomerizes to the ketone
13.8. Anti-Markovnikov additions to alkynes
R1
R2B-H
Br
RO-OR,
heat
R1
HBr,
R1
cis-trans mixtures
H
R2B
radical addition
R1
Br
H2O2
NaOH
R1
HO
R1
H
R1
13.9. Reactivity of alkenyl halides

H
Nu
Alkenyl halides do not react with nucleophiles.

Under strong basic conditions they eliminate
O
H
X
Mg
H
Mg-X
13.10-13.11: Do not study
1.
R1
H
R2
2. H+, H2O
R1
O-H
R2
alkenyl halides can be

converted to good
nucleophiles
CHAPTER 13: Alkynes
(4)
13.9. Reactivity of alkenyl halides (The Heck reaction)

Pd (or Ni)
catalyst
C
H
Mechanism:
metal
oxidative
insertion
Pd
C X
C C
HX
X= I, Br, Cl
catalytic in metal (1-5% used)
retention of stereochemistry
C Pd X
X
C Pd
H C
H
Pd +
H Pd X
HX
E2 elimination
(reductive)
of metal
C C
new C-C bond

formation
Pd X
C C
H
Applications/examples:
Br
1% Pd(OAc)2
CO2Me Ph3P, 100C
HBr
H
Br
CO2Me
+
+
Me3Sn
+
(HO)2B
1% Pd(OAc)2
Ph3P, 100C
CO2Me
HBr
CO2Me
1% Pd(OAc)2
CO2Me Ph3P, 100C
CO2Me
Stille reaction
(use of R3Sn
instead of H)
CO2Me
Suzuki reaction
(use of B(OH)2 instead
of H)
Me3SnI
1% Pd(OAc)2
CO2Me Ph3P, 100C
(HO)2BI
R
I
1% Pd(OAc)2
Ph3P, CuI
HI
Sonogashira reaction
(use of alkynes instead
of alkenes but needs
also CuI as catalyst)
CHAPTER 14: Delocalized -systems
(1)
General Information
This chapter deals with the reactivity of carbons next to a double bond (allylic), reactivity
of conjugated systems and UV spectroscopy.
14.1 Stabilization of allyl system: RESONANCE
H2C
H2C
-H
1/2
1/2
H2C
CH2
H2C
CH2
H2C
CH2 H2C
CH2
H2C
CH2
H2C
CH2
H2C
CH2 H2C
CH2
-X
1/2
1/2
H2C
-H
H2C
H2C
CH2
CH2
H2C
CH2 H2C
CH2
1/2
1/2
Experimental observations: Electronic changes at the carbon next to a double bond are
facilitated due to the participation of the adjacent framework.
Explanation: Formation of an "almost symmetric" system formed by 3 sp2 hybridized
carbons. This three carbon intermediate is called allyl and the carbon next to the double
bond is called allylic. This is an example of stabilization by resonance that allows the
newly formed charge to be distributed simultaneously, or delocalized, in two different
carbons.
14.2 radical allyl substitution

H
H2C
CH2
X2
h
H2C
CH2
X
CH2
H2C
+ HX
eq. 1
X
H
H2C
CH2
X2
h
X
C
H2
CH3
C
H2
eq. 2
CH3
Equations 1 and 2 are two competitive reactions that lead to either radical allylic substitution
or radical addition to a double bond.
O
Radical allylic substitution is favored at low concentrations of X2
Radical allylic substitutions are done usually with a succinimide
derivative in suspension in CCl4
N Br
O
NBS
(2)
14.2 Radical allyl substitution (cont)

NBS
R
CH2
H2C
C
H
H2C
H2C
N Br
H2C
NBS
NBS
NBS
C
H
C
H
Br
C
H2
Br
(terminal alkene: 20%)
NBS
Br
C
H
C
H2
(cis and trans alkenes: 80%)
14.3 Nucleophilic substitutions of allylic halides

H
H
C
H
C
Cl
-Cl
Cl
CH2
CH2
CH2
H2O
OH
OH
SN1
CH2
SN1 reactions at the allylic centers proceed much faster than those in related saturated
hydrocarbons, because the orbitals stabilize the charges, and lead to a mixture of adducts.
H
H
C
Cl
H
C
reaction
rate
73
SN2 reactions at the allylic

centers proceed much faster
than those in related
saturated hydrocarbons,
because the orbitals
stabilize the transition state.
SN 2
H
H
C
Cl
H
C
14.4 Allylic nucleophiles

H
H
C
+ Bu-Li
H
C
Br
+ Mg
Li
H
C
MgBr
+ Bu-H
CHAPTER 14: Delocalized -systems -REVIEW-
energy
transition state ()
Ea(cat)
SM
(3)
Transition state: the energetically

highest point on the reaction coordinates
Ea
activation
energy
heat of
formation
Pr
SN2 reaction
Ea: Defines the energy that needs

to be used to activate the process
H: Defines the overall reaction
as exothermic or endothermic
SN1 reaction
E
Ea2
Ea1
Ea
Me-I + HO-
energy
energy
HO--CH3--I
H
MeOH +
Me3C+
Me3C-I + HO-
I-
H
Me3COH + I-
kinetic/thermodynamic control
E
Ea2
energy
Ea1
Prod1: formed faster due to lower Ea1,

but is less stable than Prod2 (kinetic
control).
SM
Prod1
Prod2
Prod2: formed slower due to higher Ea2,

but is more stable than Prod1
(thermodynamic control).
(4)
14.5 Conjugated dienes (two double bonds separated by a single bond)

Conjugated dienes are more stable than related nonconjugated dienes that contain two
"isolated" double bonds ( as shown by producing lower heat of hydrogenation).
Conjugated dienes have 4 contiguous p orbitals that overlap
and allow distribution of electrons across 4 carbon centers.
Conjugated dienes can adopt two possible
"extreme" coplanar conformations: s-cis: the
H
two double bonds lie on the same face of the
single bond and s-trans: the two double bonds
are on opposite sides of the single bond. The strans conformation is more stable than the s-cis.
H
H
H
H H
- 3 Kcal/mol
s-trans
s-cis
14.6 Electrophilic additions on conjugated dienes

Br
H-Br
1,2 addition
H
Br
1,4 addition
Experimental data & explanations
Pure 1,2 or 1,4 adducts when in solution

convert to the "equilibrium mixture".
Attack of Br- at the internal carbon is favored
kinetically by the greater partial positive
charge at this center and the proximity to the
newly released nucleophile.
Attack of Br- at the primary carbon is favored
thermodynamically by the greater stability
of the internal alkene.
energy
1,2 addition predominates at low T kinetic

control. 1,4 addition predominates at
higher T (thermodynamic control).
Ea2
Ea1
Br
H
Br
H
(5)
14.7 Extended conjugation
Br
Br
Br2
Br
Br
Br
Br
Br
Br
Br
1,2 addition predominates at low T (kinetic control). 1.6 addition predominates at higher T
(thermodynamic control), because it retains an internal conjugated diene system.
14.9-14.10 will not be covered

14.11 UV/Vis (Ultraviolet/visible spectroscopy)
UV/Vis spectroscopy gives energy for
the -* or n-* electronic transitions.
Typically the UV spectrum of a molecule is
informative when there are several double
bonds in conjugation. The conjugation
decreases the gap of energy between the
bonding-antibonding orbitals.
H
H
H
=A/bc
(A: absorbance, b: length of cell,

c: concentration)
1
excited
state
E=h
Molar absortivity
ground
state
excited
state
E'
ground
state
Information obtained from UV-Vis spectra:

UV/Vis spectra reveal the presence of conjugated systems (aka chromophores).
The more extended the conjugation the longer the wavelength of absorption
and the greater the intensity of the peak.
Added substitution on the conjugated system increases the absorption wavelength.
(6)
14.8. Diels-Alder cycloadition reaction

Diels-Alder reaction: reaction of a conjugated
diene with an alkene (dienophile) to form a
cyclic product. This reaction requires the
participation of 6 electrons and is often called
[4+2] cycloaddition
Rules:
During the DA reaction the diene must assume
the s-cis conformation. If this is impossible then
there is no DA reaction.
H
H
H
NO2
The DA reaction is accelerated when the diene

contains electron donating groups (it becomes
electronically richer).
RO
Me
<
<
<
O
The DA reaction is accelerated when the

dienophile contains electron withdrawing
groups (becomes electronically poorer).
OR
<
OR <
<
The DA reaction is concerted (bond breaking and bond making happens at the same time)
and stereospecific (the stereochemistry of the starting materials is retained in the structure
of the products).
H
H CO Me
CO2Me
CO2Me
CO2Me
2
+
CO2Me
CO2Me
MeO2C
CO2Me
The DA reaction forms preferentially the endo product.

o
endo
MeO2C
MeO2C
H
H
CO2Me
CO2Me
i
en
ex
en
ex
en
ex
i
ex
i
o
i o
en
CHAPTER 15: Benzene/aromaticity
(1)
General Information
This chapter deals with the principles of aromaticity and includes benzene and
electrophilic aromatic substitutions.
15.1- 15.4 (not 15.3): Aromaticity, benzene NMR spectroscopy

Aromaticity
+ 3H2
1,3,5 cyclohexa
triene
+ 2H2
+ 1H2
1,3 cyclohexadiene
+ 3H2 29.6
Kcal/mol
-78.9
Kcal/mol
benzene
-54.9
Kcal/mol
cyclohexene
-28.9
Kcal/mol
-49.3
Kcal/mol
cyclohexane
Experimental observations: The heat of hydrogenation of benzene is ca 30 Kcal/mol less

than that of the "calculated" structure for 1,3,5 cyclohexatriene. This means that the
benzene has extra stability, which is referred to as aromaticity or resonance energy.
Aromaticity is the property of certain polyunsaturated compounds with conjugated double
bonds to be more stable than related compounds with the same number of unsaturations.
The structure of benzene is a regular hexagon composed of 6 sp2 hybridized carbons.
The C-C bond length is between those of a single and double bond. The p electrons form a
cloud above and below the ring.
In the 1H NMR, the cloud of p electrons forms an electric current, called ring current, that
deshields aromatic protons. This is why aromatic protons resonate at about 7 ppm. In the
13
C NMR the carbons resonate at about 120 ppm.
H
7.2 ppm
120 ppm
EWG
EDG
EWG
H
H
EDG
H: more deshielded protons, H: more shielded protons, H: less affected protons
(2)
15.5-15.7 Aromaticity in polycyclic/macrocyclic systems

A compound can be characterized as aromatic if:
a.
b.
c.
d.
Huckel criteria
for aromaticity
It has a cyclic structure

It contains (4n+2) pi electrons.
It has one p orbital on each atom of the ring.
It is planar (continuous overlap of all p orbitals of the ring).
Examples of aromatic compounds
N H
benzene
naphthalene
pyrrole
N
pyridine
cyclopentadienyl
anion
cyclopropenyl
cation
Examples of non-aromatic compounds

Cyclobutadiene has only 4 electrons and thus it is nonaromatic. It is
air-sensitive, very reactive, and can be spectroscopically observed only
at very low temperatures. Due to its high reactivity it can react both as a
diene and as a dienophile in Diels-Alder reactions.
1,3,5,7-cyclooctatetraene has only 8 electrons
and thus it is nonaromatic. It is air-sensitive, very
reactive, and can also non-planar.
(3)
15.8 Electrophilic aromatic substitution

In this reaction the benzene behaves as the nucleophile and attacks an external electrophile.
One of the hydrogens of benzene is replaced ("substituted") with the electrophile, restoring
thereby the aromaticity of the ring.
H
+
E---X
+ H--X
Examples of EAS:
15.9 Halogenation of benzene

+ X2
FeX3 or AlX3 act as catalysts,

to activate the electrophile
FeX3
X+-----FeX4-
FeX3 + X2
15.10 Nitration and sulfonation of benzene

NO2
SO3H
+ SO3
NO2
HNO3 + H2SO4
HNO3 + H2SO4
H2SO4
H2SO4 reacts with HNO3 to make +NO2
SO3H
cat H2SO4
+ H2O
100 C
The sulfonation of benzene takes place in the presence of SO3 in concentrated H2SO4
(fuming sulfuric acid). The sulfonation is reversible and can be reversed by heating
benzenesulfonic acid in diluted aqueous acid.
(4)
15.11-12: Friedel-Crafts alkylation of benzene
+ R-X
AlX3 serves as a catalyst to

activate the electrophile...
AlX3
R+-----AlX4-
AlX3 + R-X
BF3, heat
+
OH
HF
The Friedel-Crafts alkylation requires the presence of a catalyst that can generate
carbocations, which then participate in electrophilic aromatic substitution of benzene.
The Friedel-Crafts alkylation often suffers from side reactions of carbocations
(rearrangements, hydrogen shifts) and from poloyalkylation processes.
15.13: Friedel-Crafts acylation of benzene

AlX3 serves as a catalyst to
activate the electrophile...
O
O
AlX3
+
R
AlX3 +
O
R
-----AlX4-
O
Cl
NaBH4
AlCl3
OH
Br
LiAlH4
HBr
The Friedel-Crafts acylation is easier to perform and produces less side reactions
than the FC alkylation.
CHAPTER 16: Benzene derivatives
(1)
General information
This chapter deals with the effect of benzene substituents on the reactivity and regioselectivity
of aromatic substitutions. With every substituent we consider two effects: induction and
resonance. Induction occurs through bonds is the polarization of bonds due to the relative
electronegativity of atoms and diminishes rapidly with distance. Resonance occurs through
conjugated bonds by delocalization of charges across alylic centers and has a longer range.
16.1, 2 Effect of substituents (activation/deactivation)
D
-
+
-
An electron donating group (D) attached on benzene increases the overall electronic
density ("activates") of the benzene ring and by induction and/or resonance localizes more
density at the ortho and para carbons. The ortho and para carbons become more
electronically rich and they behave as the nucleophilic centers during EAS.
Donor groups: -OR, -NR2 (strong donors by resonance), -R (weak donation by induction).
A
+
An electron withdrawing group (A) attached on benzene decreases the overall electronic
density ("deactivates") of the benzene ring and by induction and/or resonance removes
electron density from the ortho and para carbons. The meta carbons become more
electronically rich and they behave as the nucleophilic centers during EAS.
Acceptors: -CO2R, -NO2 (strong donors by resonance), -CF3 (weak acceptor by induction).
Exception: Halogens are weak electron withdrawing groups, which means that they remove
electronic density from the benzene. However they localize density at the ortho and para
carbons.
(2)
16.1-16.3 cont.
CH3
CH3
CH3
Br
Br-Br
D
-
FeBr3
60%
40%
Br
The Me group is donating by induction, so it activates the EAS (faster) and directs o,p.
The second bromination, although possible, it is slowed down due to the inactivating
power of the first Br group.
Para substitution predominates due to the steric hindance of the ortho substitution.
A
CF3
CF3
HNO3
H2SO4
NO2
The CF3 is withdrawing by induction, so it deactivates (retards) the EAS and directs m.
The second nitration is slowed down due to the inactivating power of the first NO2 group.
NH2
NH2
Br-Br
Br
Br
FeBr3
D
-
Br
OH
OH
Br-Br
Br
Br
FeBr3
Br
D
-
+
-
The NH2 and OH groups are donating by resonance but withdrawing by induction. The
resonance effect is stronger, so they both activates the EAS (very fast) and direct o,p.
The EAS is so activated that catalyst is not needed and the product is tribrominated.
(3)
16.1-16.3 continued
A
NO2
NO2
HNO3
H2SO4
NO2
The NO2 is withdrawing by resonance, so it deactivates (retards) the EAS and directs m.
The second nitration is slowed down due to the inactivating power of the first NO2 group.
X (D/A)
Br
Br
Br-Br
Br
Br
Br
FeBr3
+
-
Haloges are an exception: They are withdrawing by induction but they direct o,p..
They deactivate the EAS but behave like the donrs in directing the EAS
16.4 EAS on polysubstituted benzenes

OH
OH
EAS
OH
CH3
NO2
NO2
EAS
CH3
EAS
CH3
OH
CH3
CH3
CH3
NO2
NO2
EAS
CH3
CH3
The most powerful electron donor dictates the site for EAS substitution.
In general: D by resonance > D by induction > A by induction > A by resonance
For substituents of equal activating power, the product may be subject to steric effects.
(4)
16.5 Synthetic strategies

Interconversion of NO2 group (m
director) to NH2 group (o, p director)
NO2
Reversible sulfonation
as a blocking strategy
NH2
CF3CO3H
Zn(Hg)/HCl
or H2, Pd
Interconversion of alkanoyl group (m

director) to alkyl group (o, p director)
Zn(Hg)/HCl
or H2, Ni
1. SO3/
H2SO4
2. HNO3/
H2SO4
H
R
CrO3, H2SO4
R
NO2
H2O/ H+
NO2
SO3H
NaOH, MeI
Reversible protection of
amines or/and phenols to
moderate their activating
power
O-Me
O-H
conc. HI
CH3COCl, pyr.
N-COCH3
N-H2
NaOH, H2O
16.6 Reactivity of polyaromatic rings

Br
Br
Br-Br
major
minor
Attack at the C1 center is favored due to the two possible resonance forms
that can be written for the intermediate having intact benzene structure.
CHAPTER 17: Carbonyl group
(1)
General Information
This chapter deals with the reactivity of the carbonyl group and preparations and
reactions of aldehydes (R=H) and ketones (R= carbon chain).
17.2-17.3 Structure of the carbonyl group and spectroscopy

Carbonyl group: carbon bonded to an oxygen via a
double bond (sp2 hybridization and planar geometry).
The electron density of the double bond is polarizes
toward the oxygen that can use its lone pair to act as a
base or nucleophile. The carbonyl carbon is electrophilic.
- O
+
R
base or
nucleophile
electrophile
R (H)
In NMR the aldehyde ptotons resonate at ca 9.5 ppm due to the dual deshielding effect of the
double bond and the electronegative oxygen. The carbonyl carbon resonates at ca 200 ppm.
In the IR, the carbonyl group absorbs strongly at ca 1700 cm-1
17.4. Preparations
1. Ozonolysis of alkenes
R2
R4
R1
O3
Me2S
-70 C
R3
R2
R1
-70 C
R4
R3
2. Hydration of alkynes
R1
H
HOH,
H+
R1
R1
R2B-H
OH
HgSO4
tautome
-rization
R1
H
R2B
H
H
H
H2O2
HO
NaOH
R1
R1
H
O
O
3. Friedel Crafts acylation
AlX3
+
R
H
R1
(2)
4. Oxidation of alcohols [ use of Cr(VI)-based reagents]

HO
H
Cr
O
+6
- H2O
H
O
+4
Cr
HO
O
Cr +6
OH
+
H
R
H2O
H+ (cat)
O
HO
+4
Cr
HO
HO
+
HO
O
H
O
Cr +6
OH
+6
Cr
OH
OH
The oxidation of a primary alcohol to the carboxylic acid proceeds using CrO3 in aqueous
H2SO4 (Jones oxidation). The process involves initial oxidation to the aldehyde that in the
presence of H2O and acid exists in the form of a hydrate. The hydrate is then further
oxidized to the carboxylic acid.
Secondary alcohols produce ketones, while tertiary alcohols remain intact.
H
R
H
O
PCC
O +6
Cr O H N
O
Cl
H
R
PCC
An alternative method is the PCC oxidation (CrO3, HCl, pyridine) that oxidizes primary and
secondary alcohols only to the corresponding carbonyl groups (no overoxidation to acids).
The PCC oxidation is performed in organic solvents, such as CH2Cl2. In the absense of
H2O the primary aldehyde cannot be hydrated and therefore it does not undergo further
oxidation to acid. Aldehydes or ketones are the only products obtained.
5. Selective oxidation of allylic alcohols [ use MnO2]
OH
HO
OH
MnO2
O
Allylic alcohols are easier to oxidize than aliphatic alcohols and in the presence
of a mild oxidant they give rise to a,b unsaturated ketones.
(3)
17.5 Reactivity of the carbonyl group

base or
nucleophile
- O
+
acidic
H
attack by
a base
electrophile
H
attack by
electrophile
NOT acidic
O
+
attack by
nucleophile
H
Nucleophilic addition at the carbonyl group (under basic conditions)

(R1)H
Nu
(R1)H
R
H+, H2O
Nu
O
(R1)H
Nu
OH
This mechanism implies the use of a strong charged (anionic) nucleophile and is
irreversible if the Nu is C or H. It is reversible for most heteroatom nucleophiles.
Nucleophilic addition at the carbonyl group (under acidic conditions)

O
H+
R
(R1)H
O
(R1)H
H
R
(R1)H
Nu
Nu
OH
(R1)H
This mechanism indicates the use of an acid to protonate the carbonyl oxygen. This
makes the carbonyl carbon a better electrophile and allows weak nucleophiles (such
as heteroatoms) to react with it using their lone electron pairs.
Additions of hydride (H-) at the carbonyl carbon

(R1)H
R
NaBH4 or
LiAlH4
then H+, H2O
(R1)H
R
H
O
LiAlH4: a very strong hydride donor (H-). It reduces all carbonyl group or carboxylic acid
derivatives.
NaBH4: a very mild hydride donor (H-). It reduces only carbonyl groups to alcohols. It
does not reduce esters.
(4)
17.5 Reactivity of the carbonyl group

Additions of carbon nucleophiles (R-) at the carbonyl carbon
To prepare carbon nucleophiles, we have to either deprotonate a compound with a relatively
acidic C-H bond (ex. acetylide anions Eq.1,2), or treat an alkyl chloride with metals. In the
latter case we can insert Mg(0) between a C-X bond (ex. Grignard reagents, Eq. 3) or
exchange the C-X with a C-Li bond (ex. organolithium reagents, Eq. 4).
- +
H
- +
H
- +
Et-Mg-I
+
Na-NH2
+ R I + Mg
ether
- +
R Mg-I
+ R I + Li
ether
- +
R Li
ether
ether
- +
MgI
- +
Na
(Eq. 1: acetylenic
nucleophiles)
(Eq. 2: acetylenic
nucleophiles)
(Eq. 3: Grignard nucleophiles)
(Eq. 4: Lithium nucleophiles)
-LiI
The general mechanism for the addition of C nucleophiles at the carbonyl carbon is as follows:
O

R2 [M]
+
R
(R1)H
R2
[M]
R
(R1)H
MeMgI
H
H+,
H2O
then H+, H2O
Isolated double bonds do not react with nucleophiles
Me
-[M]-OH
OH
H
HO
R
R2
(R1)H
(5)
17.6 Addition of water to the carbonyl group

O
HO
H+, or HO-
(R1)H
+ H2O
OH
R
(R1)H
hydrate
Aldehyde carbonyl groups react with water (or alcohols) in a reversible manner to form
hydrates. This reaction can be catalyzed with H+ or OH-.
The more reactive (+) the carbonyl group is, the more tendency it has to be hydrated. Thus,
an aldehyde should be easier to hydrate than a ketone. The reactivity order is as follows:
O
O
O
O
Cl3C
17.7 Addition of alcohols to the carbonyl group

H
HO
OH
O
hemiacetal
(5,6 membered ring)
The proposed general mechanism of this type of reaction is as shown:

O
R
OH
H+
R2 OH
R
R1
R1
H
R2-O
R
- H+
O-R2
OH
R2 OH
O-R2
R
R1
R2-O
R
O-R2
R1
R1
HO
R1
-H2O
H2O
R
O-R2
R1
O-R2
H+
R1
- H+
HO
R
O-R2
R1
(6)
17.8 Acetals as protecting groups

Due to interference of functional groups during a reaction we often need to transform them to
"unreactive species". This is accomplished using "protecting groups" which should be inert to
the subsequent reactions. At the end of the synthetic strategy, these protecting groups
should be removable easily to reveal the original functionalities.
Ex. Compound 3 should be made using compounds 1 and 2 and any other reagent.
3
2
1
General approach:
Number all key carbons in the starting materials and identify where they are in the product.
Find what bond connections need to be built or cleaved.
Try to construct (or cleave) the bonds you need to form on the basis of the functionalities
present in the starting materials. Consider E/Nu, B/A or ox./red. chemistry.
Look at the starting materials and think about potential interference with other functional
groups. Then protect the functional groups that interfere with your strategy.
O
a. protect the
carbonyl group I
6
4
HO
H+
OH
4
Bu-Li
b. form C3-C6
bond
Li
1
c. deprotect
the carbonyl
2
1
H+, H2O
1
HO
HO
H
O
(7)
17.9 Nucleophilic addition of ammonia and derivatives

R2
RNH2
amine
HO-NH2
hydroxylamine
hydrazine
+ R2
(R1)H
R2
(R1)H
(R1)H
R2NH
sec. amine
oxime
N OH
(R1)H
R2
-H2O
H2N-NH2
imine
N R
hydrazone
N NH2
R2
NR2
enamine
(R1)H
17.10 Deoxygenation of the carbonyl group

O
R
+ H2N-NH2
R1
H
R
N-NH2
-H2O
R
N H
N
OH
R
R1
H
R1
R1
H-OH
R1
-N2
H
R
R1
R1
H-OH
heat -N2
R1
NaOH
R1
N N
OH
R1
Deoxygenation via the thioketal functionality
+
R
R1
HS
SH
H+
-H2O
R1
thioketal
Raney Ni
H
R
H
R1
(8)
17.11 Addition of HCN to carbonyl group (formation of cyanohydrins)

O
Na CN
R
C N
Na
(R1)H
H+,
H2O
HO
C N
(R1)H
(R1)H
17.12 The Wittig reaction (conversion of carbonyls to alkenes)

Wittig reaction: The reaction between phosphorus ylids and aldehydes or ketones to form
an alkene.
+ Ph3P=O
Ph3P
Proposed mechanism:
+
+ -
Ph3P
PPh3
PPh3
Preparation of Wittig ylids (phosphorus ylids)
I
Ph3P +
Bu-Li
Ph3P
Ph3P
17.13 The Baeyer-Villiger reaction (from carbonyls to carboxyls)

O
R
O
R2
HO
R1
O
O H O
HO
R2
O O
Oxidation of carbonyl groups to carboxylic acid groups

Migration order of R2: Me < primary < secondary < tertiary
R1
O
O
R2
CHAPTER 18: Enols and aldol
(1)
General information
Due to the carbonyl group, hydrogens on the -carbon are acidic and can be
easily removed (aldehydes: pKa=16-18, ketones pka= 19-21. This chapter
deals with the chemistry associated with the -carbon to the carbonyl group.
O
H
18.1-2 Enols and enolate ions

Tautomerization between enol-keto forms
O
acid
catalysis
H+
OH
H
OH
- H+
protonated carbonyl
keto form
basic
catalysis
OH
OH
B:
enol
+ H+
keto form
enolate anions
are ambident
enolate ions
enol
O-alkylation
(R3Si-X)
C-alkylation
(R-X)
O-SiR3
O
R
Consequences of tautomerization between enol-keto forms

O
Deuterium exchange of all hydrogens in deuterated solvents
CH2-CH3
under either acid or base catalysis H3C
O
Racemization of optically active R2
R1
substituted carbonyl compounds
under either acid or base catalysis
H
B:
D+
or DOO
R1
R2
D3C
+ H+
CD2-CH3
R2
R1
H
(2)
18.3 Halogenations of aldehydes/ketones

Under acidic catalysis [Br2, CH3CO2H]
O
H3C
H3C
CH3
slower
H3C
H+
CH3
CH3
O
Br
H+
Br
O
-H+
CH3
- H-Br
CH3
CH3
H
H
Br-Br
H
Br
CH3
H
Under basic catalysis [Br2, NaOH]

O
H3C
C
H2
OH
H3C
O
CH2
H3C
Br
O
CBr3
Br
Br
H3C
CH2
O
Br
Br-Br
H3C
OH
C
CH2
H
Br
faster
Under acidic catalysis the halogenation -to a carbonyl group slows down and often stops
after the first halogen has been introduced. The rate of this reaction is independent of the
concentration of halogen. This is explained by considering that the rate limiting step is the
protonation of the carbonyl group. This protonation becomes slower if the ketone is already
partially halogenated.
Under basic catalysis the halogenation -to a carbonyl group accelerates after the first
halogen has been introduced and is difficult to stop at the stage of monohalogenation.
This is explained by considering that the introduction of halogens a-to the carbonyl group
increases the acidity of the adjacent hydrogens and facilitates their removal. This
accelerates the formation of the enolate and thus the polyhalogenation. This is also the
principle of the iodoform reaction.
(3)
18.4 Alkylations of aldehydes/ketones

O
CH3I
To avoid polyalkylation
the use of enamines is
often explored.
O
CH3
NaH,
CH3
(30%) CH3
(27%)
18.5 Aldol reaction

2x R
OH
OH
OH
-HOH
H H
aldol reaction
- H-B
H
H
-HOH
OH
H-B, -B:
aldol condensation
O
R
H R
Aldol reaction: The use of a carbonyl functionality both as a nucleophile at the a-carbon
and as an electrophile at the carbonyl carbon. The reaction involves attack of the enolate
anion at a carbonyl carbon of another molecule to produce a -hydroxy aldehyde (aldol
reaction), or after elimination of H2O an , unsaturated ketone (aldol condensation).
O
R
H+
OH
R
H
H H
O
R
H H
R
H
H
H
H2O
H
OH
-H2O
H
H
HO
H
R H
H
R
- H3O
H
OH
OH2
H
O
R
H
The aldol reaction is catalyzed by either base or acid and is reversible.
H
H
H
enol
(4)
18.6 Crossed aldol reaction

O
H3C
H3C
O
H
+
H
H3C
2. heat
CH3
1. NaOH
- H2O
H3C
O
H
H3C
H3C
H
CH3 CH3
CH3
Crossed aldol reaction: a reaction between the enolate of one aldehyde with the carbonyl
group of another aldehyde. The reaction gives a mixture of homo and cross aldol products.
In the above example, compound 1 does not have any enolizable protons, so the enolate of
2 would provide the only nucleophile. This is why we form only products 3 (cross aldol) and
4 (homo aldol). If 2 is added slowly to an excess of 1 and base then the reaction would give
predominantly compound 3.
18.7 Intramolecular aldol reaction

O
O
H
H
O
NaOH
-H2O
O
CH3
O
CH3
H3C
O
CH3
NaOH
-H2O
CH3
The intramolecular aldol is favored for the formation of 5 and 6-membered rings. Ketones
also participate in intramolecular aldol reactions, although they are usually less reactive in
the intermolecular aldol reactions.
(5)
18.8 Properties of , unsaturated carbonyl groups

Conjugation renders the carbonyl carbon less electrophilic and thus provides additional
stabilization to the molecule.
O
+
O
+
H+ or
O
O
-
HO
The tendency for conjugation is very strong and as a

result , unsaturated carbonyl groups "move into
conjugation" to afford ,-unsaturated systems under
either acidic or basic catalysis.
18.9-18.10: ,-unsaturated carbonyl groups (enones): 1,2 and 1,4 additions
O-A
1,2 addition:
1,4 addition:
A-B
O
+
A-B
O
B A
O-A
A-B
A=H
O
A
ketone
enol
, unsaturated carbonyl groups can undergo 1,2 additions across only the double
bond or the carbonyl group. In addition, due to their polarization, they can undergo 1,4
additions or "conjugate additions" (reactions across 4 adjacent atoms).
1,2 additions (at the carbonyl carbon) proceed under kinetic control.
1,4 additions (at the b-carbon) proceed under thermodynamic control.
In general, hard (very localized) nucleophiles react

at the carbonyl site (hard electrophile), while soft
(delocalized) nucleophiles react at the -carbon
(soft electrophile).
soft
electrophile
hard
electrophile
(6)
1,2 additions (examples):

H2, Pd/C
Hydrogenation of
double bond:
O
Br2
Me
Electrophilic halogenation
of double bond
Br
Me
Br
NH2OH, H
Formation of oxime
N-OH
1,4 additions (examples):

Li, NH3
Conjugate reduction with Li/NH3

(mechanism not required)
O
H
H-OH
Me
Hydration, or amine,
or HCN addition
O
Me
HO
1,2 and 1,4 additions of carbon nucleophiles

Me
Organolithium compounds
give 1,2 addition
2. H+
Organocuprate compounds
give 1,4 addition
Me
HO
H
1. R2-CuLi
Me
2. H
O
(and if instead of H+
we introduce the R+ )
Me
1. R-Li
Me
R
R
1. R2-CuLi
Me
2. R'-X
18.11 Conjugate additions of enolates

Michael addition
(1,4 addition of an
enolate anion)
Robinson annulation
(a Michael addition followed
by an intramolecular aldol
condensation)
O
Me
Me
- +
EtO K
Me
Me
O
Me
O
Me
- +
Me EtO K
+
O

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CHAPTER 10: Nuclear Magnetic Resonance

General information on spectroscopy

Organic molecules absorb energy in discrete packages called: quanta.

NMR (Nuclear Magnetic Resonance) spectroscopy: is a technique that relies on the

Example: alignment of protons in the absence and presence of a magnet

CHAPTER 10: Nuclear Magnetic Resonance

Example of a 1H NMR experiment: the unknown compound is Cl2CH-CH(OCH2CH3)2

CHAPTER 10: Nuclear Magnetic Resonance

General observations obtained from NMR spectra:

Integration of peaks (only for 1H NMR)

CHAPTER 10: Nuclear Magnetic Resonance

Chemical shift: effects of electron density and relative electronegativity

CH3F CH3Cl CH3Br CH3I CH3OH CH3SH CH3CH3 CH3H (CH3)4Si

2. The effect of electron density is

CCl4 CHCl3 CH2Cl2 CH3Cl

3. The 1H chemical shift of hydrogens bound

Chemical shift: effects of carbon substitution

CHAPTER 10: Nuclear Magnetic Resonance

Chemical shift : Effect of multiple bonds

examples of 1H and 13C NMR chemical shifts for multiple bonds

CHAPTER 10: Nuclear Magnetic Resonance

Chemical shift and NMR

Predict the chemical shift of the protons by considering/remembering:

H-OR, H-SR, H2-NR variable (1-5)

Predict the chemical shift of the 13C by considering/remembering:

CHAPTER 10: Nuclear Magnetic Resonance

Spin-spin coupling and splitting patterns (appearance of peaks)

doublet (d, Ja=6 Hz)

CHAPTER 10: Nuclear Magnetic Resonance

A practical way to understand spin-spin coupling.

CHAPTER 10: Nuclear Magnetic Resonance

Spin-spin coupling and splitting patterns

NMR spectrum of compound A under "proton decoupled conditions" :

NMR spectrum of compound A under "proton coupled conditions" :

CHAPTER 11: Alkenes and IR, MS spectroscopy

Alkene nomenclature and stereochemistry

The Pi bond: stability, geometry

CHAPTER 11: Alkenes and IR spectroscopy

the alkenyl hydrogen as compared

cis coupling constant: between 6-14 Hz, usually ca 10Hz

CHAPTER 11: Alkenes and IR spectroscopy

Infrared spectroscopy (IR)

m1, m2= masses of atoms

Review: general concepts of organic reactions

Catalyst: A molecule that can decrease the Ea

Transition state: the energetically highest

Heat of formation (H): defines the overall

The Grignard reagent (RMgX) acts as

The Grignard reagent (RMgX) acts as

Review: general concepts of organic reactions

Because of the electronegativity of Br, the - carbon of the Br is + (good electrophile).

Sequence of events during SN or E reactions (mechanisms)

Unimolecular versus bimolecular nucleophilic substitution (SN1 versus SN2)

polar protic (e.g. alcohols)

polar aprotic (e.g. DMSO)

Stereochemical consequences of SN1 and SN2

Review: general concepts of organic reactions

accessibility of proton &

polar protic (e.g. alcohols)

polar aprotic (e.g. DMSO)

leaving group should be

Effect of base on E2 elimination

Saytzev rule: Non bulky bases form more stable alkenes

CHAPTER 11: Alkenes and IR spectroscopy