Kaplan MCAT Organic Chemistry chapter 4: Analyzing Organic Reactions

Lewis Acid

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

coordinate covalent bonds

form when lewis acids and bases interact

-electrons in the bond come from the same starting atom (the Lewis base)

Bronsted-Lowry acid

proton donor

amphoteric

ability to act as either Bronsted-Lowry acid or base (e.g. water, Al(OH)3, HCO3−, and HSO4−)

Al(OH)3

aluminum hydroxide,

acts as base:

3 HCl + Al(OH)3 → AlCl3 + 3 H2O

acts as acid:

Al(OH)3 + OH− → Al(OH)4−

Bronsted-Lowry base

proton acceptor

acid dissociation constant (ka)

measures the strength of an acid in solution

Ka equation

In the dissociation of an acid HA (HA ⇋ H+ + A-), the equilibrium constant is given by:

pKa

-logKa

-the lower the pKa the stronger the acid

-some pKa can be negative

strong acid

pKa below -2

weak acid

pka between -2 and 20

pKa values for common functional groups

acidity increases with decreasing bond strength to H.

The more electronegative the atom, the higher the acidity

When the above two trends oppose each other, low bond strength takes precedence.

functional groups that act like acids:

alcohols, aldehydes, ketones (at the lphaa-carbon), carboxylic acids, and most carboxylic acid derivatives.

Easier to target basic or nucleophilic reactants because they accept a lone pair

functional groups that act like bases:

amines, amides. N can form coordinate covalent bonds by donating a lone pair to a Lewis acid

Nucleophile

defined as nucleus loving species, with either lone pairs or pi bonds that can form new bonds to electrophiles

Difference between nucleophile strength and base strength

nucleophile strength: is based on the relative rates of reaction with a common electrophile, so it is a kinetic property.

base strength: related to the equilibrium position of the reaction and is therefore a thermodynamic property

good nucleophiles tend to be good bases

the more basic a nucleophile, the more reactive it is

Four factors that determine nucleophilicity

1. charge: nucleophilicity increases with increasing electron density (more negative charge)

2. electronegativity: nucleophilicity decreases as electronegativity increases since these atoms are less likely to share their electron density

3. steric hindrance: bulkier molecules are less nucleophilic

4. 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 ________ down the periodic table

increases

-protons in solution will attract nucleophile, instead of electrophile attracting nucleophile

In order from most nucleophilic to least nucleophilic

I-, Br-, Cl-, F-

in aprotic solvents, nucleophilicity ________ as you go up the periodic table

increases

-no protons get in the way of the attacking nucleophile. in these solutions, the nucleophilicity relates directly to basicity

In order from most nucleophilic to least nucleophilic:

F-, Cl-, Br-, I-

Examples of polar protic and polar aprotic solvents

can you use a nonpolar solvent in a nucleophile-electrophile reaction?

no since the reactants are polar. in a nonpolar solvent they would not dissolve

Examples of strong nucleophiles

HO-, RO-, CN-, N3-. Amine groups tend to be good nucleophiles

examples of fair nucleophiles

NH3, RCO2-

examples of weak nucleophiles

H2O, ROH, RCOOH

electrophiles

"Electron-loving" atoms with a positive charge or positively polarized atom that accepts an electron pair when forming bonds with a nucleophile

-almost always act as lewis acid in reaction

-greater degree of positive charge increases electrophilicity: carbocation is more electrophilic than a carbonyl carbon

-if electrophile does not empty orbital, then better leaving groups makes it more likely reaction would occur, leading to greater electrophilicity

-if electrophile contains empty orbital, nucleophile can bond without displacing leaving group

-Ex: alcohols, aldehydes, ketones, carboxylic acids and their derivatives

comparisons of electrophilicity of carboxylic acid derivatives

anhydrides are most reactive, followed by carboxylic acids and esters, 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, where 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. Resonance and inductive effects from electron withdrawing groups can stabilize negative charge.

-weak bases make good leaving groups (conjugate bases of strong acids, like I-,Br-, Cl-)

-alkanes and hydrogen ions will almost never serve as leaving groups since they form very reactive and strong basic anions

-Another way to think about leaving group: the weaker the base is the leaving group while the stronger base (nucleophile) replaces the weaker base

heterolytic reactions

opposite of coordinate covalent bond formation: a bond is broken and both electrons are given to one of the two products.

Nucleophilic substitution

A type of substitution reaction in which a nucleophile is attracted to an electron-deficient center or atom, where it donates a pair of electrons to form a new covalent bond.

the nucleophile must be more reactive than the leaving group, otherwise leaving group will attach right back.

Unimolecular nucleophilic substitution (SN1) reactions

Step 1: leaving group leaves and is the rate-limiting step. this generates a positively charged carbocation

Step 2: nucleophile attacks the carbocation

the more substituted the carbocation, the more stable it is because the alkyl groups act as electron donors which stabilize the positive charge, so SN1 only occurs for secondary or tertiary carbon

since first step is rate limiting step, the rate of reaction only depends on substrate: rate-k[R-L], where L is leaving group.

-anything that accelerates the formation of the carbocation will increase the rate of SN1 reaction

usually yield racemic mixture since the incoming nucleophile can attack the carbocation from either side

Mechanism of SN1 Reaction

bimolecular nucleophilic substitution (Sn2)

reactions contain only one step (concerted reaction): the nucleophile attacks the compound at the same time as the leaving group leaves'

-cause an inversion of absolute configuration (S and R will switch)

nucleophile actively displaces the leaving group in backside attack

nucleophile must be strong and the substrate cannot be sterically hindered

the less substituted the carbon, the more reactive it is in SN2 reactions

Mechanism of SN2 Reaction

stereospecific reaction

configuration of the reactant determines the configuration of the products due to the reaction mechanism

oxidation-reduction reaction

any chemical change in which one species is oxidized (loses electrons) and another species is reduced (gains electrons)

oxidation state

an indicator of the hypothetical charge that an atom would have if all bonds were completely ionic

CH4 is the most reduced form of carbon, as C has oxidation state of -4.

CO2 is the most oxidized form of carbon, as C has oxidation state of 4

Don't need to know how to assign oxidation states

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, other carbons, nitrogen, or halides and removal of bonds to H). Bond between C and a atom less electronegative than C is replaced with bond to an atom more electronegative than C.

reduction

refers to the decrease in oxidation state, which means gaining of electrons (increasing the number of bonds to hydrogen or removal of bonds to O)

functional groups from least to most oxidized

Level 0 (no bonds to heteroatoms): alkanes

Level 1 (1 bond to heteroatoms): alcohols, alkyl halides, amines

Level 2 (2 bonds to heteroatoms): aldehydes, ketones, imines

Level 3 (3 bonds to heteroatoms): carboxylic acids, anhydrides, esters, amides

Level 4 (four bonds to heteroatoms): carbon dioxide

Note that oxidation is in reference to the C atom

oxidizing agent

element or compound in a redox reaction that accepts an electron from another species

-it is reduced

-good oxidizing agents have a high affinity for electrons or high oxidation states ex: O2, O3, Cl2, MnO4-, Mn7+, Cr6+, and CrO4(2-)

Two themes:

1. oxidation reactions tend to feature an increase in the number of bonds to oxygen

2. oxidizing agents often contain metals bonded to a large number of oxygen atoms

Oxidation of alcohols

Primary alcohols can be oxidized by one level to become aldehydes, or can be further oxidized to form carboxylic acids.

-This reaction commonly proceeds all the way to the carboxylic acid when using strong oxidizing agents such as chromium trioxide (CrO3) or sodium or potassium dichromate (Na2Cr2O7 or K2Cr2O7), but can be made to stop at the aldehyde level using specific reagents such as pyridinium chlorochromate (PCC).

secondary alcohols can be oxidized to ketones only

reduction of carbon atom

when a bond between a carbon atom and an atom that is more electronegative than carbon is replaced by a bond to an atom that is less electronegative than carbon.

In practice, this usually means increasing the number of bonds to hydrogen and decreasing the number of bonds to other carbons, nitrogen, oxygen, or halides.

Aldehydes and ketones would be reduced to primary and secondary alcohols.

Amides can be reduced to amines, carboxylic acids can be reduced to alcohols, and esters can be reduced to a pair of alcohols using LiAlH4

Two themes:

1. reduction reactions tend to feature an increase in the number of bonds to hydrogen

2. reducing agents often contain metals bonded to a large number of hydrides

good reducing agents

sodium, magnesium, aluminum, and zinc, metal hydrides (NaH, CaH2, LiAlH4, and NaBH4 since they contain the H- ion).

Chemoselectivity

preferential reaction of one functional group in the presence of another functional group

Nucleophilic-eletrocphilic reactions occur on the highest priority functional group since it usually contains the most oxidized carbon.

Nucleophile is looking for electrophile (positive partial charge on C).

Aldehydes generally more reactive toward nucleophiles than ketones because they are less sterically hindered

common reactive site: the carbon of a carbonyl

-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

-alpha- Hydrogens are much more acidic than in a regular C-H bond. This occurs due to resonance stabilization of the enol form after H is pulled off. 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.

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

The Prevention of the formation of alternative products using a protecting group such as a mesylate or tosylate.

protecting group

uses sterics to protect leaving groups.

-a reactive leaving group can be temporarily masked with a sterically bulky group, forcing reactive nucleophile to look elsewhere to react

Steps in Problem Solving

1. know your nomenclature

2. identify the functional groups

3. identify the other reagents

4. identify the most reactive functional group (s): more oxidized C tend be more reactive to both nucleophile-electrophile interactions and redox reactions.

5. identify the first step of the reaction (ex: HOCH2CH2OH is commonly used as protecting group)

6. consider stereoselectivity