Analyzing Organic Reactions

The Analyzing Organic Reactions section provides High Yield information for the MCAT, USMLE, COMLEX, and Medical School. Prepare and Learn Ahead!

Table Of Contents
1 Acids and Bases
1.1 Definitions
1.2 Acid and Base Strengths
1.3 Common Functional Groups
2 Nucleophiles, Electrophiles, and Leaving Groups
2.1 Nucleophiles
2.2 Solvent Effects
2.3 Electrophiles
2.4 Leaving Groups
3 Nucleophilic Substitution Reactions
3.1 SN1 Reactions
3.2 SN2 Reactions
4 Oxidation-Reduction Reactions
4.1 Oxidizing Agents and Reactions
4.2 Reducing Agents and Reactions
5 Chemoselectivity
5.1 Reactive Locations
5.2 Steric Protection
6 Steps to Problem Solving

Acids and Bases

Definitions
  • Lewis Acid: defined as an electron acceptor in the formation of a covalent bond.
    • Tend to be electrophiles
    • Have vacant p-orbitals which can accept an electron pair, or are positively polarized atoms
  • Lewis Base: electron donor in the formation of a covalent bond.
    • Tend to be nucleophiles
    • Have a lone pair of electrons that can be donated and are often anions
  • When Lewis acid and base react, they form coordinate covalent bonds (electrons in the bond came from the same starting atom (the Lewis base).
  • Bronsted-Lowry: Acid is a species that can donate a proton and a base is a species that can accept a proton.
    • Amphoteric: have the ability to donate or accept a proton (e.g – water, Al(OH)3. HCO3–, HSO4–
Acid and Base Strengths
  • Acid dissociation constant (Ka) measures the strength of an acid in solution. In the dissociation of an acid HA:
          •  
  • More acidic molecules will have a smaller pKa, while more basic molecules will have a bigger one.
  • Strong acid is considered strong when pKa is below -2. Weak organic acids often have pKa between -2 and 20.
  • Bond Strength decreases as you move down the periodic table, and acidity therefore increases since it is easier to dissociate. The more electronegative the atom, the higher the acidity.
    • When these two trends oppose each other, low bond strength takes precedence.
Common Functional Groups
  • Functional groups that act like acids includes alcohols, aldehydes, and ketones (at the a – carbon), carboxylic acids, and most carboxylic acid derivatives.
    • These compounds are easier to target with basic/ nucleophilic reactant
  • Amines and amides are the main functional groups that act as a base.
    • Nitrogen atoms of an amine can form coordinate covalent bonds by donating a lone pair to a lewis acid.

Nucleophiles, Electrophiles, and Leaving Groups

Nucleophiles
  • Defined as nucleus loving species, with either lone pairs or pi bonds that can form new bonds to electrophiles.
  • Good nucleophiles tend to be good bases. Difference is that Nucleophile strength is based on the relative rates of reaction with a common electrophile, so it is a kinetic property.
    • Base strength is related to the equilibrium position of the reaction and is therefore a thermodynamic property.
  • The more basic a nucleophile, the more reactive it is. Nucleophilicity is determined by four major factors:
    • Charge: increases with increasing electron density (more negative charge)
    • Electronegativity: decreases as electronegativity increases since these atoms are less likely to share their electron density.
    • Steric Hindrance: bulkier molecules are less nucleophilic
    • Solvent: Protic (hydrogen attached to an oxygen or nitrogen) solvents can hinder nucleophilicity by protonating the nucleophile or through hydrogen bonding.
Solvent Effects
  • In polar protic solvents, nucleophilicity increase down the periodic table.
    • Protons in solution will attract nucleophile instead of electrophile.
  • In aprotic solvents, nucleophilicity increases as you go up the periodic table
    • No protons get in the way of the attacking nucleophile. In these solutions, the nucleophilicity relates directly to basicity.
  • Nonpolar solvents cannot be used with nucleophile-electrophile reactions since these reactants are polar. In a non-polar solvent, the reactants would not dissolve
  • Strong Nucleotides: HO–, RO–, CN–
  • Fair Nucleotides: N3–, NH3, RCO2–
  • H2O, ROH, and RCOOH are weak or very nucleotides
  • Amine groups tend to make good nucleotides.
Electrophiles
  • Electron loving species with a positive charge or positively polarized atom that accepts an electron pair when forming bonds with a nucleophile.
  • Will almost always act as a Lewis acid in reactions.
  • Greater degree of positive charge increases electrophilicity. Carbocation is more electrophilic than a carbonyl carbon.
  • Better leaving groups make it more likely that a reaction will happen
  • Electrophilicity and acidity are effectively identical properties when it comes to reactivity.
    • Alcohols, aldehydes, ketones, carboxylic acids and their derivatives act as acids and electrophiles
    • Carboxylic acid derivatives: Anhydrides are most reactive, followed by carboxylic acids and esters, and then amides.
      • Derivatives of higher reactivity can form derivatives of lower reactivity, but not vice-versa.
Leaving Groups
  • The molecular fragments that retain the electrons after heterolysis.
  • Heterolytic Reactions: opposite of coordinate covalent bond formation. A bond is broken and both electrons are given to one of the two products.
  • The best leaving group will be able to stabilize extra electrons.
    • Weak bases make good leaving groups.
  • Alkanes and hydrogen ions will almost never serve as leaving groups since they form very reactive and strong basic anions.
  • Can think of leaving groups and nucleophiles as serving opposite functions. The weaker base is the leaving group while the stronger base (nucleophile) replaces the weaker base.

Nucleophilic Substitution Reactions

SN1 Reactions
  • Unimolecular nucleophilic substitution
    • First step: leaving group leaves and is the rate-limiting step. This generates a positively charged carbocation.
    • Second Step: Nucleophile attacks the carbocation
  • The more substituted the carbocation, the more stable it is since the alkyl groups act as electron donors which stabilize the positive charge.
  • Since first step is rate limiting step, the rate of reaction only depends on the concentration of the substrate.
    • Anything that accelerates the formation of the carbocation will increase the rate of an SN1 reaction.
  • Will usually be a racemix mixture since the incoming nucleophile can attack the carbocation from either side.
SN2 Reactions
  • Bimolecular Nucleophilic Substitution reactions contain only one step (concerted reaction): The nucleophile attacks the compound at the same time as the leaving group leaves.
  • Nucleophile actively displaces the leaving group in a backside attack.
    • Nucleophile must be strong and the substrate cannot be sterically hindered
  • The less substituted the carbon, the more reactive it is in these type of reactions (opposite of SN1 reaction).
  • Cause an inversion of relative configuration.
    • If the nucleophile and leaving group have the same priority, this will also change the absolute configuration from (R) to (S) or vice versa.
    • Stereospecific Reaction: configuration of the reactant determines the configuration of the products due to the reaction mechanism.

Oxidation-Reduction Reactions

  • Oxidation state is an indicator of the hypothetical charge that an atom would have if all bonds were completely ionic.
  • Oxidation refers to the increase in oxidation state, which means a loss of electrons (easier to view oxidation as increasing the number of bonds to oxygen)
  • Reduction refers to the decrease in oxidation state, which means gaining of electrons (increasing the number of bond to hydrogen).
Oxidizing Agents and Reactions
  • Oxidation of a carbon atom occurs when a bond between a carbon atom and an atom that is less electronegative than carbon is replaced by a bond to an atom that is more electronegative than carbon.
    • I.e. – decreasing the number of bonds to hydrogen and increasing the number of bonds to other carbons, nitrogen, oxygen or halides.
  • Oxidizing Agent: element or compound in an oxidation-reduction reaction that accepts an electron from another species.
    • Good oxidizing agents have a high affinity for electrons or high oxidation states.
  • Primary alcohols can be oxidized by one level to become aldehydes, or can be further oxidized to form carboxylic acids.
  • Secondary alcohols can be oxidized to ketones
  • Should not need to memorize, goal is to recognize two themes:
    • Oxidation reactions tend to feature an increase in the number of bonds to oxygen
    • Oxidizing agents often contain metals bonded to a large number of oxygen atoms.
Reducing Agents and Reactions
  • Reductions refers to a decrease in oxidation state. Reduction occurs when a bond between a carbon atom and atom that is more electronegative than carbon is replaced by a bond to an atom that is less electronegative than carbon.
    • I.e. – increasing the number of bonds to hydrogen and decreasing the number of bonds to other carbons, nitrogen, oxygen and halides.
  • Good reducing agents: sodium, magnesium, aluminum, zinc, metal hydrides (NaH, CaH2, LiAlH4, NaBH4 since they contain an H– ion).
  • Aldehydes and ketones will be reduced to primary and secondary alcohols
    • Reaction is exergonic but slow without the presence of a catalyst.
  • Reduction reactions tend to feature an increase in the number of bonds to hydrogen
  • Reducing agents often contain metals bonded to a large number of hydrides.

Chemoselectivity

  • The preferential reaction of one functional group in the presence of another functional group.
Reactive Locations
  • This depends on the type of reaction that is occurring:
    • Redox Reagent: tends to act on the highest priority functional group
    • Nucleophiles/ Electrophiles: occur on the highest priority functional group. Since it usually contains the most oxidized carbon.
      • Aldehydes are generally more reactive towards nucleophiles than ketones because they have less steric hindrance.
  • Common reactive site: the carbon of a carbonyl which is found in carboxylic acid and its derivatives, ketones and aldehydes.
    • Carbon acquires a positive polarity due to the electronegativity of the oxygen. Carbonyl carbon becomes electrophilic and can be targeted by nucleophiles
    • a– Hydrogens are much more acidic than in a regular C-H bond. These can be deprotonated easily with a strong base which would form an enolate.
      • Enolate then becomes a strong nucleophile and alkylation can result if good electrophiles available.
  • Common reactive site: substrate carbon in substitution reaction.
    • SN1 reactions prefer tertiary to secondary carbons as reactive sites, and secondary to primary.
    • SN1 reactions prefer methyl and primary carbon over secondary, and tertiary carbons wont react.
Steric Protection
  • Steric Hindrance describes the prevention of reactions at a particular location within a molecule due to the size of substituent groups. E.g. – SN2 reaction won’t occur with tertiary substrates.
    • Steric Protection uses this concept to aid in the synthesis of a desired molecule by preventing the formation of alternative products.
    • Bulky groups make it impossible for the nucleophile to reach the most reactive electrophile, this it makes the nucleophile more likely to attack another region.
  • Protecting Group: Uses sterics to protect leaving groups.
    • A reactive leaving group can be temporarily masked with a sterically bulky group

Steps to Problem Solving

  1. Know your Nomenclature
  2. Identify the functional groups: Look at the organic molecules in the reaction, what functional groups are in the molecules.
    1. Do the functional groups act as acids or bases?
    2. How oxidized is the carbon?
    3. Are there functional groups that act as good nucleophiles, electrophiles or leaving groups?
  3. Identify the other Reagents: Are they acidic or basic? Are they suggestive of a particular reaction? Are they good nucleophiles or a specific solvent? Are they good oxidizing or reducing agents?
  4. Identify the Most Reactive Functional Group(s): more oxidized carbon tends to be more reactive to both types of reactions.
  5. Identify the First Step of the Reaction:
    1. If acid-base: protonation or deprotonation
    2. Nucleophile: nucleophile attacks the electrophile to form a bond with it.
    3. If oxidizing or reducing agent: the most oxidized functional group will be oxidized or reduced, accordingly.
  6. Consider Stereospecificity/Stereoselectivity
    1. Stereospecificity: consider whether the configuration of the reactant necessarily leads to a specific configuration in the products.  (Like in SN2 reactions)
    2. Stereoselectivity: reactions where one configuration of product is more readily formed due to product characteristics.
      1. More strained molecules are less likely to form
      2. Products with conjugation (alternating single and multiple bonds) are significantly more stable than those without.