Chemistry XXI The central goal of this unit is to help you identify the structural and environmental...
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Transcript of Chemistry XXI The central goal of this unit is to help you identify the structural and environmental...
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The central goal of this unit is to help you identify the structural and environmental factors that can
be used to control chemical reactions.
Unit 6How do we control chemical change?
M4. Selecting the Reactants
M2. Changing the Environment .
M3. Analyzing the ProductsAnalyzing the effect of charge
stability.
Exploring the influence of external factors.
Evaluating the impact of electronic and steric effects.
M1. Characterizing InteractionsRecognizing interactions
between reacting molecules.
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IUnit 6
How do we control chemical change?
Module 4: Selecting the Reactants
Central goal:
To identify the steric and electronic factors that determine the outcome of chemical processes.
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The Challenge
Many drugs work by binding to the active site of enzymes and receptors in our body, stimulating or inhibiting their function. Binding occurs through
intermolecular forces between the drug molecule and atoms in the target site.
TransformationHow do I change it?
How can we design and synthesize drugs with specific binding capacities?
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Binding ForcesThe forces that bind drugs to active sites or receptors
are the same as those that control from phase behavior to the tertiary structure of proteins: ionic,
hydrogen bonding, and dispersion interactions.
CH3
C
O
C
O-
O
OH
H3N+
-Dispersion
H-bonding
Ion-Ion
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Binding GroupsIn developing drugs, we may be interested in
introducing or eliminating different binding groups to enhance the pharmacological activity of a substance
Identify the main functional groups with binding capacity and the types of intermolecular forces
they may able to establish.
Let′s think!
NH2
CH
C
CH
CH
C
CH
OH
CH
C
O
NH
CH
CN
O
CH
S
C
CH3
CH3
CH
C
O
OH
Amoxicillin: An antibiotic
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NH2
CH
C
CH
CH
C
CH
OH
CH
C
O
NH
CH
CN
O
CH
S
C
CH3
CH3
CH
C
O
OH
Binding Groups
Hydroxyl(H-bonding)
Carboxyl(H-bonding and Ion-Ion)
Alkyl(Dispersion)
Phenyl(Dispersion)
Amine(H-bonding and Ion-Ion)
Ketone(H-bonding)
Amoxicillin
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Polar Reactions
Chemists have developed a wide variety of reactions to introduce or eliminate specific binding
groups in molecules.
Most of these synthesis reactions result from
the interaction between electron-rich sites in a
molecule (the nucleophile)
and electron-poor sites in another molecule (the electrophile).
Nucleophile(Negative or with high e- density)
-
+
Electrophile(Positive or with low e- density)
-
+
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Substitution Reactions
To illustrate some of the central ways of thinking in the synthesis of new substances, let us analyze a class of reactions that allow to “substitute” one
nucleophile for another in a molecule.
R-X + Nu: R-Nu + X:
We could try to use:
HO:
Nucleophile
X
Imagine that we were interested in
introducing an hydroxyl –OH group
to enhance H-bonding in a drug.
+
Electrophile
-
Electronegative
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Experiments
Kinetic experiments indicate that there are two main routes through which this reaction
may happen:
R-X + Nu: R-Nu + X:
Under some conditions:
Rate = k [Nu-][R-X]
2nd Order
Change in Chirality
Under other conditions:
Rate = k [R-X]
1st Order
Racemization
How do we explain it?
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Mechanism 1One possibility is:
One-Step Bimolecular process:
Rate = k[OH-][R-X]
2nd OrderSN2
Important:
The configuration of the carbon atom is inverted
in this process.
(Configuration Inversion)
OH C
CH3
R
H + xx C-
H R
CH3
OH- x
Transition State
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Mechanism 2A second possibility for this reaction, is a
two-step mechanism:
x C-
CH3
H R
Intermediate
+Step 1Slow
Step 2Fast
C
CH3
OHH
R
Two-step process:
Rate = k [R-X]
1st Order
Important:
The reaction produces both enantiomers.
(Racemization)SN1
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Given that drugs act by interacting with active sites that can be expected to be
chiral, controlling their “stereochemistry” is of
central importance during the development process.
How can we control whether the reaction mechanism is SN1 or SN2?
Reaction Control
We may try to control the rate of each type of process (kinetic control).
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Let’s Think
Transition State
C-
H R
CH3
OH- x
Intermediate
C-
CH3
H R
+
SN2
SN1
If we are able to reduce the activation energy
required to form either the transition state in SN2 or
the intermediate carbocation in SN1 we may
favor one mechanism over the other
What characteristics (composition, structure) of the reactants may influence the formation and stability
of the transition state or the intermediate?
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Major Effects
The formation and stability of different chemical species is essentially determined by:
Steric Effects
How do different parts of a molecule interact with others?
Electronic Effects
How is the charge distributed among atoms?
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IFactor 1
How bulky is the electrophile (or substrate)?
The degree of substitution on the carbon that is attacked by the nucleophile has a strong influence on the reaction rate via SN2 and SN1 mechanisms.
R1
H
H
C X
R1
R2
H
C X
R1
R2
R3
C XPrimary Secondary Tertiary
1o 2o 3o
SN1Let′s think!
How do you explain these trends?
Rate
1o 2o 3o
SN2
C-
H R
CH3
OH- x C
-
CH3
H R+ (Hint: Think of the these
species’ stability.)
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IFactor 1
How bulky is the electrophile (or substrate)?
The bulkier the electrolyte, the more difficult for the nucleophile to attack (steric effects).
R1
R2
R3
C X
Nu:Rate
Ea
SN2
C+
R1
R3
R2
Substituents can stabilize the carbocation by charge induction or delocalization (electronic effects).
+
Nu:
Planar Trigonal
RateEa
SN1
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Let’s ThinkImagine that you have three possible drug
precursors that you want to modify to generate an H-bonding product with well defined chirality.
Which of these
precursors is your best
option? Why?
Br
CH
CH2CH2
CH2
CH2 CH
CH2
CH3
Br
CH
CHCH
CH
CH C
CH
CH3
Br
CHCH
CH
CH C
CH
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IFactor 2
How strong is the nucleophile?
The strength of nucleophiles depends on their charge and the stability of such a charge:
N-
R RR O
-
C
R
O
O-
Cl Br IModerate:
HOStrong:
O
H H
N
R HH
N
H HH
Same period:Nucleophilicity increases with
basicity.
Same group:Nucleophilicity increases with polarizability.
Weak:
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Rate
S M W S M W
SN2 SN1
Let′s think!
How would you expect the rate to change with the strength of the nucleophile? How would the
strength affect the energy profile for the reaction?
Factor 2How strong is the nucleophile?
More reactive nucleophiles tend to be less stable.
RateEa
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IFactor 3
How stable is the leaving group?
We can expect that the more stable a leaving group is, the easier will be to displace it.
Increasing Leaving Ability
O
H H
N
H HH
N-
R RBr IClHO F
Bad Excellent
Let′s think!
How would you explain this trend? How would you expect this factor to affect the SN2 and SN1 mechanisms?
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Rate
Ex Good Bad
SN2 SN1
Factor 3How stable is the leaving group?
Ex Good Bad
The effect is similar, but more pronounced for the SN1 mechanism.
The rate limiting step in SN1 is precisely the loss of the leaving group.
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O
CH2
CH
CH2 CH2
CH
CH2
O
S
O
CH3
O
CH3
Let’s Think
Imagine that in the synthesis of a drug you were interested in substituting one of the
groups attached to the ring. Which one would be easier to eliminate? Why?
CH2CH2
CH
CH2 CH2
CHN NH
C
O
CH3CH3
CH3
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IFactor 4
What is the solvent?
The solvent in which the reaction takes place may have a strong impact on the reaction mechanism.
A solvent’s effect depends on its ability to stabilize the nucleophile (SN2) or the transition state (SN1).
G
Reaction Progress
Less Polar
More PolarSN1
How can we explain these results?
Polar (protic)
G
Reaction Progress
Polar (aprotic)
SN2H2O
CH3OH
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IFactor 4
What is the solvent?
Polar solvents stabilize the carbocation in SN1, reducing Ea and increasing the rate.
Polar protic solvents tend to trap negatively charged nucleophiles.
They stabilize the nucleophile, increasing Ea in SN2 mechanisms
and thus reducing the rate.
Polar aprotic solvents leave the nucleophile free, favoring an SN2 mechanism.
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The analysis in this module reveals central issues in the prediction and control of chemical reactions:
By changing the composition and structure of the reactants, or of their environment, we can control both the extent (Grxn; thermodynamic control) and rate (Ea, mechanism; kinetic control) of a reaction.
The outcome of a chemical reaction is largely controlled by steric (exclusion factors) and electronic (charge stability) effects.
Reaction Control
All of the factors that influence a chemical reaction can be identified and understood by carefully examining the reaction mechanism.
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Drug Development
In general, chemical reactions can be used to introduce structural changes that:
Increase activity; Reduce side-effects; Facilitate drug administration.
Main strategies
Variation of substituents;
Structural extension and rigidification.
Morphine
Receptor
Derivatives
Receptor 1 Receptor 2
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Let′s apply!
The following processes have been chosen to introduce structural changes in some drugs. Predict whether the reaction will proceed via
SN1 or SN2 mechanisms.
Predict
CH2
CH2
CH2
CH
CH2
CH2
CH2CH2
ClOH-
Solvent
Nuc-
CH2
CH2
CH2
CH2C
CH2
CH3
Br H2O
DMSO
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Let′s apply! Design
Imagine that you need to add a H-bonding site to a specific region of a drug molecule.
You want also to produce a chiral product.
What reactants and reactions conditions would you choose:
Nuc-: OH-, H2O, R-O-
Solvent- H2O, DME
CH3
CH
CH2
CH3
Cl
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Substrate Nucleophile Leaving Group Solvent
1o- Strong- Bad- Polar protic-
2o- Moderate- Good- Polar aprotic-
3o- Weak- Excellent-
Work in pairs to complete the summary table below. In each case, indicate the type of mechanism, SN1 or/and
SN2, that is favored.
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Selecting the Reactants
Summary
The effect of these factors may be identified and understood by carefully examining the
reaction mechanism.
The extent and rate of these processes are influenced by multiple factors that can be classified into two
main groups: electronic and steric effects.
Many chemical reactions result from the interaction between electron-rich sites in a molecule (the nucleophile) and electron-poor sites in another
molecule (the electrophile).
-
+
-
+
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Substitution Reactions
Substrate Nucleophile Leaving Group Solvent
1o- SN2 Strong- SN2 Bad- Neither Polar protic- SN1
2o- Both Moderate- Both Good- Both Polar aprotic- SN2
3o- SN1 Weak- SN1 Excellent- SN1
For example, substitution reactions are used to “substitute” one nucleophile for another in a molecule.
R-X + Nu: R-Nu + X:
They may occur via SN1 or SN2 mechanisms, depending on the effect of these types of factors:
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Malic acid is a weak carboxylic acid. It is a common ingredient in many sour or tart foods. Malic acid is found mostly in unripe fruits and it
is an important intermediate in many biochemical cycles.
Malic Acid
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Malic acid is a polyprotic acid (an acid that can lose more than one proton)
Polyprotic Acids
In particular, malic acid is a diprotic acid.
Identify the two acidic protons in this molecule and decide which is
more acidic. Justify your reasoning.Let′s think!
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Write the chemical equations that represent the two dissociation processes undergone by
malic acid when dissolved in water.
Calculate the pKa and identify the conjugate acid/base pairs in each case.
+ H2O1)
2)
K1 = 3.98x10-4
K2 = 7.94x10-6
- + H3O+
Let’s Think
-+ H3O+
--+ H2O
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pH
The average concentration of malic acid (C4H6O5) in apple juice is close to 8.0 g/L.
Estimate the pH of this solution by assuming that the acidity of the solution is determined by the first dissociation of
malic acid (pK1 = 3.4).Let′s think!
C4H6O5 + H2O C4H5O5- + H3O+
Co = 8.0/134.09 = 6.0x10-2 x
32/1 109.4)( xKCKCx aoaopH = -log (x) = 2.3
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Dissociation
H2A + H2O HA- + H3O+
The dissociation of malic acid in water can be represented as:
HA- + H2O A2- + H3O+
4.31 10K
1.52 10K
How many times larger is the concentration of H2A than HA- in our stomach (pH = 2.0)
when we drink apple juice?Let′s think!
25~1010][
][ 4.12 1
pHpK
HA
AH
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Chirality
Malic acid has one chiral carbon
Which is it?
Let′s think!
L
D
In Nature, almost all malic acid appears in the L- form.
Malic acid is produced commercially in the
D-/L- racemic mixture.
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Synthesis
The presence of D-malic acid in juice or wine thus indicates that artificial flavor has been added.
Imagine you want to synthesize L-malic acid using this reactant
Cl
How could you ensure the formation of the right optical isomer using a substitution reaction?
a) What nucleophile would you use?
b) What solvent?
Justify your reasoning.Let′s think!