Lecture 2 Organic Reactions
We will look at organic reactions in the context of:
 hydrolysis
 Acid / Base
1. definition of acids and bases
2. nucleophilic and electrophilic compounds
3. nucleophilic substitution reactions
4.Elimination Reactions
5.acid and base catalyzed hydrolysis rates and life
times in the environment
6. Hammett and Taft rate constant observations
halomethanes
DDT and DDE
carboxylic acid esters
carboxylic acid amides
carbamates
1
Bronstead-Lowry acid - bases
acid is defined as a species that can give up a proton, [H+]
a base is a species that will accept a proton.
HNO3---> H+ NO3CH3COOH ---> H+ CH3OO-
conjugate bases
C6H5OH ---> H+ +C6H5O-
2
Lewis Acids and Bases (1923)
Acids have less than a full octet of electrons and are
“electron deficient or electron poor” (electrophiles)
Gould, Mechanism and Structure in Organic Chemistry, Holt, Rinehart
and Winston, NY,1993 p 115, 1963
What the Lewis system does for us is allow species
besides the hydrogen ion to display acidic behavior
page 116, Holt
3
Nucleophilic compounds:
From a reaction perspective nucleophilic species carry a
negative charge and are usually polar in character.
They may have an electron rich bond or unbonded electron
pair which is often the site of attack.
In the environment the majority of the nucleophiles that react
with organics are inorganic
Table 12.5
page 359, Schwarzenbach
4
Because of its great abundance, water plays a pivotal role
among the nucleophiles in the environment
A reaction in which water (or hydroxide) substitutes for
another atom or group is called hydrolysis.
The resulting organic products of hydrolysis are typically
more polar than their parent compounds and generally of
less environmental concern
CH3-Br + H2O ---> CH3-OH + H+ + BrChlorinated organics often find their way into the
environment and hence their reaction with nucleophiles is of
interest
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Relative Nucleophilicty of inorganic
Nucleophiles
Swain and Scot (see page363, Fig. 12.5 old book)
observed that for different nucleophiles, x, attacking
different methyl halides that
X- + CH3-Br 
-
X--CH3--Br - CH3-X + Br -
log (kx/kH2O) = s x n
n is an indicator of the attacking ability of x,
the nucleophile, and s is the sensitivity of the organic to
Where
nucleophilic attack; n is really important because it
represents the ability of the nucleophile to donate
electrons
As a standard for methyl bromide, s is set equal to 1; we
can now ask what does the concentration of a given
nucleophile have to be to compete with water; ie when
is its rate similar?
6
log (kx/kH2O) = 1 x n; so kH2O/kx = 10-n
To be similar, the nucleophilic rate must equal the water,
d(CH3BrH2O /dt) or d CH3Brx/dt = d(CH3BrH2O)
for the nucleophile CN- as an example,
d(CH3BrCN-)/dt = kCN [CN- ] and d CH3BrH2O /dt = kH2O [H2O ]
so kCN [CN- ]50% = kH2O [H2O ] and using the ratio of the
rate constants above
[CN- ]50% = [H2O ] X 10-n
using values for n (page 359) for different
nucleophiles and [H2O ]= 55 mol/L
see Table 12.6 page 364 of Schwarznebach for [x-]50%
NO3= 6 molar
Br- =
7x10-3
SO42= 2x10-1
OH-=
4X10-3
Cl= 6x10-2
I= 6X10-4
In fresh water Cl-= 10-3; SO42-= 2x10-4; OH-=10-6 mol/L;
so what do we conclude??
7
SN2 substitution (Substitution, nucleophilic bimolecular)
A nucleophile attacks a carbon from the opposite side of the
leaving group. An intermediate is theorized in which the
nucleophile is partially bonded to the molecule, while the
leaving group is partially dissociated.
The nucleophile donates two electrons and the leaving
group takes two electrons
blow up page 109 of Richard Larson’s book on
Environmental Organic Mechanisms
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The free energy of activation G‡ and the rate of
reaction will depend on the:
nucelophlicity of Y:
steric factors
Hydrolysis t1/2 of chloromethanes (years)
CH3Cl
CH2Cl2
CHCl3
CCl4
0.93
704
3,500
7,000
9
Sterioisomers,dieldrin and endrin, are two examples of
insecticides that contain epoxide moieties. Both hydrolyze
by SN2 reaction with H2O and OH-, resulting in diols
Richard A. Larson and Eric J. Weber. Reaction Mechanisms in
Environmental Organic Chemistry, Lewis Publishers, Ann Arbor,
1994
Carbon skeleton sterically impedes nucleophilic attack by
H2O and OH-. As a result persistence in aquatic ecosystems are long and they have been banned in the US, but
still used in other countries.
10
Epichlorlhydrin is used for the manufacture of glycerol and
expoy resins. Its calculated half-life in distilled water at 20oC
is 8 days
Page 122 Larson
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The SN1 Mechanism
This mechanism (nucleophilic substitution, monomolecular)
differs from the SN2 in that a dissociation of the organic
molecule 1st takes place to form a carbonium ion
(carbocation). The carbonium ions is then attacked by a
nucleophile
 exhibits 1st order behavior
 factors that stabilize the carbonium ion
will increase reactivity, such as resonance or
inductive effects
12
Figure 12.4 page 362
13
SN1 vs. SN2
For mono and di halomethanes, an increase in the # of
halogen substituents on carbon increases the hydrolysis
half-life. Why?
R-Cl+H2O --> R-OH + HCl
Cl
H-C-Cl
H
Cl
Cl-C-Cl
Cl
SN2
By contrast, as the steric bulk in the form of methyl addition
to the central carbon bearing the halogen occurs, a
significant INCREASE in reactivity can be observed. Why?
Cl
CH3-C-CH3
H
38 days
Cl
CH3-C- CH3
CH3
23 seconds
14
As halogen electronegativity decreases (F>Cl>Br) hydrolysis
rates increase
Page 366 Table 12.7
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Explaining mechanisms
Under neutral or basic conditions nucleophilic attack on the
primary carbon occurs by SN2; the epoxide opens up and the
deuterated oxygen appears at the primary carbon site
Under acidic conditions, the high conc. of [H]+ attacks the
epoxide oxygen and water attacks the primary carbon.
16
Write analogous SN1 and SN2 mechanisms for the neutral
hydrolysis of a substituted epoxide.
H
O
C
R2
R2
C
R3
to be SN1 a bond breaks and water adds
to be SN2 water adds and the OH leaves
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Elimination Reactions
 sterically hindered nucleophilic substitution
 when acidic protons are present next to the carbon of
the leaving group
 presence of strong bases
-C-CH X
-elimination
-------------------->
-HX
C=C
example of such a reaction is the conversion of 1,1,2,2tetrachlorethane to trichloroethylene. This can be viewed as
an SN2 reaction followed by elimination
18
DDT conversion to the more environmentally stable DDE via
elimination as a function of increasing pH or increasing
strength of nucleophilic OH-
19
Carboxylic Acid Esters: Esters are important because they
are derived from many organic acids and show up in lipids,
plasticizers, pesticides, etc
X
R1- C
O-R2
the ester bond; if x is oxygen,
its a typical called an acid ester;
If it is sulfur it is thioester
O
R1-C
R1COOH + R2OH-->R1COOR2
O-R2
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Hydrolysis Rates (page 514 Figure 13.8 new book)
R1COOR2 + H2O -->R1COOH + R2OH
Influence of pH
Basic hydrolysis seems to occur for all species; acid
hydrolysis is important for only the slow reacting compounds
A mechanism for acid catalyzed reactions of esters
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Acid catalyzed reactions (page 521 new book)
Are steric and inductive forces important in acid
catalyzed reactions of carboxylic acid esters?
OH
O
+ H3O+
R1 -C
O-R2
ester
R1 -C
+
+ H2O
O-R2
protonated-species
The equilibrium for the protonated species is
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K’a = [ ester] [H+]/ [p-species]
The concentration of [p-species]
[p-species] = [ ester] [H+]/ K’a
d[ester]/dt = k’a [p-species] [H2O]
substituting
d[ester]/dt = k’a / K’a [ester] [H2O] [H+]
so the overall rate constant k’a
ka = k’a / K’a [H2O] [H+]
so let’s look at what influences k’a / K’a
looking at page 521 Figure 13.10 (new book)
OH
R1 -C
+
O-R 2
+ H2O
R1 -C O-R 2
k'A
OH2+
2nd step is the rate determining step with a rate constant of
k’A
23
what will electron with drawing groups do to the
protonated species [p-species]??
OH
+
R1 -C
???
O-R2
It will make the [p-species] more +
What will this do in terms of water attack on the positive
carbonyl carbon and the rate constant k’A??
Going back to the 1st reaction in the acid catalyzed
reaction, what will increase with electron drawing R1
groups do to the equilibrium??
OH
O
R1 -C
+ H3O+
O-R2
R1 -C
+
+ H2O
O-R2
We said the rate constant was
ka = k’a / K’a [H2O] [H+] and both k’a and K’a
Increase with increasing with drawing groups; these are
approximately the same order of magnitude and hence
qualitatively, ka does not change with induction
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-------------------------------------------
Base catalyzed ester reactions
Page 523
Figure 13.11 (new book)
electron with drawing R1 and R2 groups will promote the
addition of OH-and HOH. Goes through a tetrahedral
intermediate (stable)
25
Base –catalyzed reactions (Figure 13.11page 523)
kB1slow
O
R1 -C O-R2
+ HO-
R1 -C
OH
O-R2
kB2 fast
[ester]
O-
tetrahedral intermediate [I]
kB3 fast to slow
R1 -C O-R 2
OH
O
R1 -C
OH
O-
O
+ - O-R2
R1 -C
kB4 slow
OH
fast
O
+ - O-R2
+ HO-R 2
R1 -C
fast
O-
What is the rate for d [I]/dt ??
d [I]/dt = 0 = kB1[ester] [OH-]- kB2 [I] -kB3 [I]
solving for [I] = kB1[ester] [OH-]/{ kB3 + kB2}
If we assume that the rate of reaction of the tetrahedral
intermediate is what determines the overall rate of
reaction
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O-
kB3 fast to slow
R1 -C O-R 2
O
R1 -C
OH
+ - O-R2
OH
kB4 slow
d[ester]/dt = kB3 [I]
d[ester]/dt = {kB1 kB3}/{kB2 + kB3}[ ester] [-OH]
and kB = {kB1 kB3}/{kB2 + kB3}
kB1slow
O
R1 -C
R1 -C O-R2
+ HO-
O-R2
O-
OH
kB2 fast
If kB3 >> kB2, then kB = kB1; but not always!! depends on
pKa ; inductive effects also reinforce kB1 and kB3
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The Taft Relationship
Attempts to extend Hammett type LFERs to
aliphatic compounds.

G‡= G‡ref + G‡i,electronic+G‡i,steric
log
k
k ref
 *  *   E s

 = polar effects
Es= steric effects
 and  are fitting parameters to a reference
system
Taft chose the hydrolysis of carboxylic acid ester
system because he could use different R groups
with different steric and inductive effects
28
By varying R1 but keeping R2, solvent and
temp. constant, Taft proposed that the steric
effects of R1 as compared to a methyl group
and can be derived directly from the rate
constant kA for the acid-catalyzed hydrolysis
reaction.
Es = log (ka/ kA, ref)
This implies that the acid-catalyzed reaction compared
to the base catalyzed reaction does not have inductive
effects
To determine inductive effects (*)the reaction
is run under a basic catalyzed regime and
when both inductive and steric effects are
operative.
* = log (kB/kB,ref) – log (ka/ kA, ref )
In the literature, you will sometimes see
*’ = * /2.48 ,to put it on the same scale as the
Hammett  values.
29
The direction and tends of * values, is similar to
Hammett  values; ie withdrawing groups (Fl, Cl,
NO2) are positive and donating slightly positive or
negative (C2H5)
30
Steric effects are illustrated by the Taft relationship for
dialkyl-substituted phthalates
log


k
k ref
 *  *   E s
 = polar effects, Es= steric effects
log kb/kb-CH3= 4.59 * +1.52 Es
31
Neutral Hydrolysis
32
Hydrolysis rate constant as a function of pH
kh= kA[H+] + kH2O[H2O] + kB[OH-]
(units kh= sec-1; in kA[H+], kA is the second order rate
constant for hydrolysis reaction of H+ with an
electrophile )
if the system is dominated by acid catalysis
log kh= log kA+ log[H+]= log kA -pH
for bases
log kh= log kB+ log[OH-]; [OH-] = kw/[H+]
log kh= log kBkw + pH
1. Given the water environment [55.4 M], Is there a
range where kH2O[H2O] or kN is important?
the point at which kA[H+] = kB[OH-]
2pH= -log kBkw+logkA;
pH = 0.5 log (kA/ kBkw)= IAB
This pH we will call IAB which is defined as the point at
33
which acid and basic hydrolysis are equal.
2. We now want to describe the pH at which
hydrolysis via neutral water and [H+] are equal.
kN= kA[H+]
log[H+]= log(kN/kA);
pH= log (kA/kN) = IAN
3. for bases
kN= kB[OH-]
kw = [OH-][H+]
pH= log {kN/(kBKw)} = INB
We will next look at hypothetical hydrolysis rate constants,
kh as a function of pH and specifically
the pH points of IAB, IAN, INB
34
35
What are the t1/2(s) of compounds that have a large range where kh= kN
36
37



Organophosphorus Esters: Used as
extensively as insecticides- biologically,
acetylcholinesterase is inhibited. Balance between
target bioactivity and hydrolysis stability is sought.
X
R1 O-P-XR 3
OR2
X = O, S
Hydrolysis may occur by either nucleophilic substitution
a the central phosphorous or carbon atoms resulting in a
cleavage of the C-O or C-S bonds.
Base-catalyzed hydrolysis favors attack at the
phosphorous cite. Increasing the steric bulk at the at the
reactive P center increases t1/2 at 20oC
38
39
Carboxylic Acid Amides
This group of compounds are important because many
simple amides are used as herbicides
O
R2
R1- C-N
R3
The -NR2R3group is less electronegative than the
group of carboxylic acid esters.
The tendency of the -NR2R3group to leave is also much
lower than the O-R group.
for amines
R1R2NH  R1R2N- H+
much less than
ROH  RO- +H+
40
page 388 Table 12.12
4. Explain what IAB values are and then why are IABvalues for amides
higher than for esters. Calculate the IAB values for IAN and INB for methyl
amide, CH3-C(O)-R1R2 using the values in Table12.12
41
Carbamates
This class is an ester derivative of carbamic acid
O
HO-C-NH2
carbamic acid
O
R-O-C-NR2R3
carbamic acid ester
They exhibit both ester and amide charter
These compounds are widely used as herbicides
and insecticides
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