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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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SN2

Grxn

Ea

G

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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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SN1

Ea1

Ea2

Grxn

G

Rate Limiting

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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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I Assess what you know

Let′s apply!

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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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Are You Ready?

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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!