The Analyzing Organic Reactions section provides High Yield information for the MCAT, USMLE, COMLEX, and Medical School. Prepare and Learn Ahead!
Acids and Bases
- 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
- 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.
- 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.
- 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.
- 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
- 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.
- 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 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.
- The preferential reaction of one functional group in the presence of another functional group.
- 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 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
- Know your Nomenclature
- Identify the functional groups: Look at the organic molecules in the reaction, what functional groups are in the molecules.
- Do the functional groups act as acids or bases?
- How oxidized is the carbon?
- Are there functional groups that act as good nucleophiles, electrophiles or leaving groups?
- 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?
- Identify the Most Reactive Functional Group(s): more oxidized carbon tends to be more reactive to both types of reactions.
- Identify the First Step of the Reaction:
- If acid-base: protonation or deprotonation
- Nucleophile: nucleophile attacks the electrophile to form a bond with it.
- If oxidizing or reducing agent: the most oxidized functional group will be oxidized or reduced, accordingly.
- Consider Stereospecificity/Stereoselectivity
- Stereospecificity: consider whether the configuration of the reactant necessarily leads to a specific configuration in the products. (Like in SN2 reactions)
- Stereoselectivity: reactions where one configuration of product is more readily formed due to product characteristics.
- More strained molecules are less likely to form
- Products with conjugation (alternating single and multiple bonds) are significantly more stable than those without.