Transcript s think!
Unit 6 How do we control chemical change? Chemistry XXI The central goal of this unit is to help you identify the structural and environmental factors that can be used to control chemical reactions. M1. Characterizing Interactions Recognizing interactions between reacting molecules. M2. Changing the Environment Exploring the. influence of external factors. M3. Analyzing the Products Analyzing the effect of charge stability. M4. Selecting the Reactants Evaluating the impact of electronic and steric effects. Unit 6 How do we control chemical change? Chemistry XXI Module 4: Selecting the Reactants Central goal: To identify the steric and electronic factors that determine the outcome of chemical processes. Chemistry XXI The Challenge Transformation How do I change it? 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. How can we design and synthesize drugs with specific binding capacities? Binding Forces The 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. H-bonding H O Chemistry XXI O C H3C Dispersion O C -- O + H3N Ion-Ion Binding Groups In 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. Chemistry XXI NH2 CH HC Let′s think! C HO CH C CH CH3 S NH C HC HC C O C N HC CH C O Amoxicillin: An antibiotic CH3 O OH Binding Groups Alkyl (Dispersion) Amine (H-bonding and Ion-Ion) NH2 CH HC Chemistry XXI C HO Hydroxyl (H-bonding) CH3 S CH NH C C CH O HC HC C C N HC CH Phenyl (Dispersion) C O OH O Ketone (H-bonding) Amoxicillin CH3 Carboxyl (H-bonding and Ion-Ion) Polar Reactions Chemistry XXI 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). d- Nucleophile (Negative or with high e- density) d+ d- Electrophile d+ (Positive or with low e- density) 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: Chemistry XXI Electronegative Imagine that we were interested in introducing an hydroxyl –OH group to enhance H-bonding in a drug. We could try to use: H3C HO: Nucleophile C H R Br X d+ Electrophile d- Experiments R-X + Nu: R-Nu + X: Chemistry XXI Kinetic experiments indicate that there are two main routes through which this reaction may happen: Under some conditions: Under other conditions: Rate = k [Nu-][R-X] Rate = k [R-X] 2nd Order 1st Order Change in Chirality Racemization How do we explain it? Mechanism 1 One possibility is: CH3 H3C HO - + C H x Br HO R - C H - CH3 x HO C H +x R R Chemistry XXI Transition State One-Step Bimolecular process: Rate = k[OH-][R-X] 2nd Order SN2 Important: The configuration of the carbon atom is inverted in this process. (Configuration Inversion) Chemistry XXI SN2 DG Ea DGrxn Mechanism 2 A second possibility for this reaction, is a two-step mechanism: HO - + C H R CH3 CH3 H3C x - C+ Br Step 1 Slow H C R Step 2 Fast HO R H Chemistry XXI Intermediate Two-step process: Important: Rate = k [R-X] The reaction produces both enantiomers. 1st Order SN1 (Racemization) SN1 DG Rate Limiting Ea2 Chemistry XXI Ea1 DGrxn Reaction Control Chemistry XXI 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? We may try to control the rate of each type of process (kinetic control). Let’s Think CH3 Chemistry XXI SN2 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 HO - C - H x R Transition State CH3 SN1 - C+ H R Intermediate What characteristics (composition, structure) of the reactants may influence the formation and stability of the transition state or the intermediate? Major Effects The formation and stability of different chemical species is essentially determined by: Electronic Effects Chemistry XXI How is the charge distributed among atoms? Steric Effects How do different parts of a molecule interact with others? Factor 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. H Primary Secondary C H X R1 Chemistry XXI C R2 X R2 C X R1 R1 Rate Let′s think! SN2 SN1 - C H 1o - How do you explain these trends? CH3 CH3 HO R3 Tertiary H x - C + H R 2o 3o 1o 2o R 3o (Hint: Think of the these species’ stability.) Factor 1 How bulky is the electrophile (or substrate)? The bulkier the electrolyte, the more difficult for the nucleophile to attack (steric effects). SN2 R3 R2 Nu: Chemistry XXI C X Ea Rate R1 Substituents can stabilize the carbocation by charge induction or delocalization (electronic effects). Planar Trigonal R3 C+ Ea + SN1 Nu: R1 R2 Rate Let’s Think Imagine that you have three possible drug precursors that you want to modify to generate an H-bonding product with well defined chirality. Chemistry XXI Br CH Which of these precursors is your best option? Why? C HC Br CH CH CH CH CH CH2 HC CH CH Br CH3 C HC CH CH H2C CH2 CH2 CH2 CH3 Factor 2 How strong is the nucleophile? The strength of nucleophiles depends on their charge and the stability of such a charge: Weak: H H Moderate: Chemistry XXI N O H H H R H O Cl C R Strong: N O HO Br I - R - - N O R R H Same period: Nucleophilicity increases with basicity. Same group: Nucleophilicity increases with polarizability. Factor 2 How strong is the nucleophile? 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? Chemistry XXI Rate SN2 SN1 W S Let′s think! S M More reactive nucleophiles tend to be less stable. M Ea W Rate Factor 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. - HO N R F R Cl Br H Bad Chemistry XXI N O I H H H Excellent Increasing Leaving Ability Let′s think! H How would you explain this trend? How would you expect this factor to affect the SN2 and SN1 mechanisms? Factor 3 How stable is the leaving group? SN2 Rate Chemistry XXI Ex Good Bad SN1 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. 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? CH3 O H3C CH2 CH2 S O Chemistry XXI O HC CH CH2 O O CH2 H3C CH2 N H3C HC CH2 CH CH2 CH2 C NH CH3 Factor 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). Chemistry XXI DG Less Polar DG SN2 SN1 More Polar Reaction Progress Polar (aprotic) Polar (protic) H 2O CH3OH Reaction Progress How can we explain these results? Factor 4 What is the solvent? Chemistry XXI 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. Reaction Control The analysis in this module reveals central issues in the prediction and control of chemical reactions: Chemistry XXI All of the factors that influence a chemical reaction can be identified and understood by carefully examining the reaction mechanism. The outcome of a chemical reaction is largely controlled by steric (exclusion factors) and electronic (charge stability) effects. By changing the composition and structure of the reactants, or of their environment, we can control both the extent (DGrxn; thermodynamic control) and rate (Ea, mechanism; kinetic control) of a reaction. Chemistry XXI Let′s apply! Assess what you know Drug Development In general, chemical reactions can be used to introduce structural changes that: Increase activity; Reduce side-effects; Facilitate drug administration. Derivatives Morphine Chemistry XXI Main strategies Variation of substituents; Receptor Structural extension and rigidification. Receptor 1 Receptor 2 Predict 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. CH2 CH2 HC H2C CH2 Chemistry XXI H2C Cl CH2 OH- Nuc- DMSO Solvent CH2 CH2 CH3 H2C C H2C CH2 CH2 Br H2O Design Let′s apply! 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: Chemistry XXI Cl CH H3C CH3 CH2 Nuc-: OH-, H2O, R-OSolvent- H2O, DME Chemistry XXI Work in pairs to complete the summary table below. In each case, indicate the type of mechanism, SN1 or/and SN2, that is favored. Substrate Nucleophile Leaving Group Solvent 1o- Strong- Bad- Polar protic- 2o- Moderate- Good- Polar aprotic- 3o- Weak- Excellent- Selecting the Reactants d- Summary Chemistry XXI 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). d+ d- d+ The extent and rate of these processes are influenced by multiple factors that can be classified into two main groups: electronic and steric effects. The effect of these factors may be identified and understood by carefully examining the reaction mechanism. Substitution Reactions For example, substitution reactions are used to “substitute” one nucleophile for another in a molecule. R-X + Nu: R-Nu + X: Chemistry XXI They may occur via SN1 or SN2 mechanisms, depending on the effect of these types of factors: 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 Chemistry XXI Are You Ready? Malic Acid Chemistry XXI 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. Polyprotic Acids Malic acid is a polyprotic acid (an acid that can lose more than one proton) Chemistry XXI In particular, malic acid is a diprotic acid. Let′s think! Identify the two acidic protons in this molecule and decide which is more acidic. Justify your reasoning. Let’s Think Write the chemical equations that represent the two dissociation processes undergone by malic acid when dissolved in water. K1 = 3.98x10-4 Chemistry XXI 1) - + H2O + H3O+ K2 = 7.94x10-6 2) - + H2O - - + H3O+ Calculate the pKa and identify the conjugate acid/base pairs in each case. pH The average concentration of malic acid (C4H6O5) in apple juice is close to 8.0 g/L. Chemistry XXI Let′s think! 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). C4H6O5 + H2O C4H5O5- + H3O+ Co = 8.0/134.09 = 6.0x10-2 x Co K a (Co K a )1/ 2 4.9 x103 x pH = -log (x) = 2.3 Dissociation The dissociation of malic acid in water can be represented as: H2A + H2O HA- + H3O+ Chemistry XXI HA- Let′s think! + H2O A2- + H3O+ K1 103.4 K 2 10 5.1 How many times larger is the concentration of H2A than HA- in our stomach (pH = 2.0) when we drink apple juice? [ H 2 A] pK1 pH 1.4 10 10 ~ 25 [ HA ] Chirality Malic acid has one chiral carbon Which is it? Chemistry XXI Let′s think! In Nature, almost all malic acid appears in the L- form. L Malic acid is produced commercially in the D-/L- racemic mixture. D 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 Chemistry XXI 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!