Ch. 4: Analyzing Organic Reactions Flashcards
summary: what happens in an acid-base reaction? (3)
- an acid and a base react
- resulting in the formation of the conjugate base of the acid and the conjugate acid of the base
- this reaction proceeds so long as the reactants are more reactive, or stronger, than the products that they form
in the MCAT, we will focus on Lewis and Bronsted-Lowry definitions of acids and bases, summarize each of these definitions focus on
Lewis concerns itself with the transfer of electrons in the formation of coordinate covalent bonds
Bronsted Lowry focuses on proton transfer
defn: Lewis acid
what is going on with their p-orbitals? are they positive or negative?
are they electrophiles or nucleophiles?
an electron acceptor in the formation of a covalent bond
have vacant p-orbitals into which they can accept an electron pair
are positively polarized atoms
tend to be electrophiles
defn: Lewis base
what is going on with their p-orbitals? are they positive or negative?
are they electrophiles or nucleophiles?
an electron donor in the formation of a covalent bond
have a lone pair of electrons that can be donated
are often anions, carrying a negative charge
tend to be nucleophiles
why do coordinate covalent bonds form? + defn
they form when Lewis acids and bases interact
these are covalent bonds in which both electrons in the bond came from the same starting atom (the Lewis base)
defn: Bronsted-Lowry acid and base
acid: a species that can donate a proton (H+)
base: a species that can accept a proton
defn: amphoteric
molecules, like water, that have the ability to act as either Bronsted-Lowry acids or bases
explain how water is amphoteric
can act as an ACID: by donating its proton to a base, and thus becoming its conjugate base OH-
can act as a BASE: by accepting a proton from an acid to become its conjugate acid H3O+
the degree to which an amphoteric molecule acts as an acid or base is dependent on what?
it depends upon the properties of the solution – water can only act as a base in an acidic solution, and only as an acid in a basic solution
what are 3 common amphoteric molecules other than water?
Al(OH)3
HCO3-
HSO4-
func + eqn: acid dissociation constant (Ka)
measures the strength of an acid in solution
Dissociation: HA <–> H+ + A-
eqn + intepretation: pKa
more acidic molecules: smaller (or negative) pKa
more basic molecules: larger pKa
what range of pKa’s corresponds to strong acids? weak acisd?
pKa < -2 = strong acids (almost always dissociate completely in aqueous solution)
-2 < pKa < 20 = weak organic acids
what 2 periodic trends commonly contribute to acidity? describe how they increase or decrease with acidity. which takes precedence when they oppose each other?
bond strength decreases down the periodic table –> acidity increases
the more electronegative an atom –> acidity increases
when they oppose each other: low bond strength takes precedence
defn: alpha-hydrogens
connected to the alpha-carbon (the carbon adjacent to the carbonyl) in carbonyl compounds
why are alpha-hydrogens easily lost?
because the enol form of carbonyl-containing carbanions is stabilized by resonance
what functional groups act as acids? (5)
- alcohols
- aldehydes at the alpha-carbon
- ketones at the alpha-carbon
- carboxylic acids
- most carboxylic acid derivatives
what type of reactants are these acidic functional groups easy targets of? why?
these compounds are easier to target with basic (or nucleophilic) reactants because they readily accept a lone pair
what are the two main functional groups that act as bases?
where should we keep an eye out for these compounds?
- amines
- amides
keep an eye out for them in the formation of peptide bonds
how can amines form coordinate covalent bonds?
the nitrogen atom of an amine can form coordinate covalent bonds by donating a lone pair to a Lewis acid
what two groups can almost all reactions in orgo be divided into?
- redox reactions
- nucleophile-electrophile reactions
nucleophiles, electrophiles, and leaving groups are particularly important to the reactions of what 2 types of compounds?
- alcohols
- carbonyl-containing compounds
defn: nucleophiles
nucleus-loving species with either lone pairs or pi bonds that can form new bonds to electrophiles
good nucleophiles tend to be good bases, however what is the distinction between the two?
nucleophile strength is based on relative rates of reaction with a common electrophile (and is thus a kinetic property)
base strength is related to the equilibrium position of a reaction (and is thus a thermodynamic property)
what 3 groups are common examples of nucleophiles?
- anions
- pi bonds
- atoms with lone pairs
as long as the nucleophilic atom is the same, the more basic the nucleophile, the more or less reactive it is?
does this hold when comparing atoms within the same row of the periodic table? what about down a column?
the more reactive it is
holds across a row, does not hold down a column
what 4 major factors if nucleophilicity determined by? how does nucleophilicity increase or decrease in relation to these?
- CHARGE = nucleophilicity increases with increasing electron density (more negative charge)
- ELECTRONEGATIVITY = nucleophilicity decreases as electronegativity increases because these atoms are less likely to share electron density
- STERIC HINDRANCE = bulkier molecules are less nucleophilic
- SOLVENT = protic solvents can hinder nucleophilicity by protonating the nucleophile or through hydrogen bonding
summarize: the solvent effect on nucleophilicity
in polar protic solvents, nucleophilicity increases DOWN the periodic table
in polar aprotic solvents, nucleophilicity increases UP the periodic table
what is the main difference in the functionality of protic solvents and aprotic solvents?
protic solvents can hydrogen bond, aprotic solvents can’t hydrogen bond
what are 2 common groups of protic solvents?
what are 3 common aprotic solvents?
PROTIC: carboxylic acids, water/alcohols
APROTIC: DMF, DMSO, acetone
if a solvent is not given on test day, should you assume that the reaction occurs in a polar or nonpolar solvent? why?
polar
polar solvents, whether protic or aprotic, can dissolve nucleophiles and assist in any reaction in which electrons are moved
the halogens are good examples of the effects of the solvent on nucleophilicity. explain.
in PROTIC solvents, nucleophilicity DECREASES in the order: I- > Br- > Cl- > F-
because the protons in solution will be attracted to the nucleophile
F- is the conjugate base of HF, a weak acid, so it will form bonds with the protons in solution and be less able to access the electrophile to react
I- is the conjugate base of HI, a strong acid, so it is less affected by the protons in solution and can react with the electrophile
in APROTIC solvents, nucleophilicity DECREASES in the order: F- > Cl- > Br- > I-
because there are no protons to get in the way of the attacking nucleophile
nucleophilicity relates directly to basicity in protic or aprotic solvents?
aprotic solvents
what are 4 examples of strong nucleophiles? 2 fair? and 3 weak or very weak?
STRONG: HO-, RO-, CN-, N3-
FAIR: NH3, RCO2-
WEAK/VERY WEAK: H2O, ROH, RCOOH
in terms of functional groups, what groups tend to make good nucleophiles?
amine groups
defn: electrophiles
electron-loving species with a positive charge or positively polarized atom that accepts an electron pair when forming new bonds with a nucleophile
True or false: electrophiles will almost always act as Lewis acids in reactions
true
what are 2 factors that increase electrophilicity?
- a greater degree of positive charge
- the nature of the leaving group in species without empty orbitals (better leaving groups make it more likely a reaction will happen)
how does the activity of a leaving group change if empty orbitals are present on the electrophile?
if empty orbitals are present, an incoming nucleophile can make a bond with the electrophile without displacing the leaving group
how do the carboxylic acid derivatives rank in terms of electrophilicity?
Anhydrides (most reactive)
carboxylic acids and esters
amides
defn: leaving groups
the molecular fragments that retain the electrons after heterolysis
defn: heterolytic reactions
essentially the opposite of coordinate covalent bond formation: a bond is broken and both electrons are given to one of the two products
what factors (3) or groups (@) makes good leaving groups?
- are able to stabilize the extra electrons
- weak bases (because they are more stable with an extra set of electrons)
- the conjugate bases of strong acids
- can be augmented by resonance and by inductive effects from electron-withdrawing groups (which help delocalize and stabilize negative charge)
why will alkanes and hydrogen ions almost never serve as leaving groups?
because they form very reactive, strongly basic anions
explain how we can think of leaving groups and nucleophiles as serving opposite functions
in substitution reactions, the weaker base (the leaving group) is replaced by the stronger base (the nucleophile)
what is true about both Sn1 and Sn2 reactions?
a nucleophile forms a bond with a substrate carbon and a leaving group leaves
steps: unimolecular nucleophilic substitution (Sn1) reactions
- the rate-limiting step in which the leaving group leaves, generating a positively charged carbocation
- the nucleophile then attacks the carbocation, resulting in the substitution product
why is a more substituted carbocation more stable?
because the alkyl groups act as electron donors, stabilizing the positive charge
since the rate-limiting step is the formation of the carbocation, the rate of the reaction depends only on what?
+ rate eqn
the concentration of the substrate
rate = k[R-L] where R-L is an alkyl group containing a leaving group
what order reaction is an Sn1 reaction?
first order
why are the product of Sn1 reactions usually a racemic mixture? what is the impact of this?
because Sn1 reactions pass through a planar intermediate before the nucleophile attacks
impact: the incoming nucleophile can attack the carbocation from either side, resulting in varied stereochemistry
steps: bimolecular nucleophilic substitution (Sn2) reactions
only one step in which the nucleophile attacks the compound at the same time as the leaving group leaves
why are Sn2 reactions referred to as concerted? why are they bimolecular?
CONCERTED = the reaction only has one step
BIMOLECULAR = the single rate-limiting step involves 2 molecules
defn + requirements for (3): backside attack of Sn2 reactions
the nucleophile actively displaces the leaving group in a backside attack
- the nucleophile must be strong
- the substrate cannot be sterically hindered
- the less substituted the carbon, the more reactive it is in Sn2 reactions
what are the two reacting species involved in the single step of an Sn2 reaction?
- the substrate (often an alkyl halide, tosylate, or mesylate)
- the nucleophile
based on this, the concentrations of both have a role in determining the rate (eqn)
rate = k[Nu:][R-L]
Sn2 reactions are accompanied by an inversion of relative configuration (explain, 2)
- the position of substituents around the substrate carbon will be inverted
- if the nucleophile and leaving group have the same priority in their respective molecules, this inversion will also correspond to a change in absolute configuration from R to S or vice versa
defn: stereospecific
a reaction in which the configuration of the reactant determines the configuration of the product due to the reaction mechanism
what is the main change that occurs in redox reactions?
oxidation states of the reactants change
func: oxidation state
an indicator of the hypothetical charge that an atom would have if all bonds were completely ionic
defn + how will we view in orgo: oxidation vs. reduction
OXIDATION = an increase in oxidation state = a loss of electrons = increasing the number of bonds to oxygen or other heteroatoms (atoms besides carbon and hydrogen)
REDUCTION = a decrease in oxidation state = a gain in electrons = increasing the number of bonds to hydrogen
when does oxidation occur?
what does this mean in practice?
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
in practice: decreasing the number of bonds to hydrogen and increasing the number of bonds to other carbons, nitrogen, oxygen, or halides
defn: oxidizing agent
the element or compound in a redox-reaction that accepts an electron from another species
because it is gaining electrons, it is said to be reduced
char (2): good oxidizing agent
- high affinity for electrons (such as O2, O3, Cl2)
OR
- unusually high oxidation states (like Mn7+ in permanganate, MnO4-, and Cr6+ in chromate, CrO42-)
organize the different functional groups by “levels” of oxidation:
Level 0 = no bonds to heteroatoms: alkenes
Level 1: alcohols, alkyl halides, amines
Level 2: aldehydes, ketones, imines
Level 3: carboxylic acids, anhydrides, esters, amides
Level 4 = 4 bonds to heteroatoms: carbon dioxide
what can primary alcohols be oxidized to by one level? by another level?
which is more common when using strong oxidizing agents?
can it be made to stop?
primary alcohols –> aldehydes –> carboxylic acids
commonly proceeds all the way to the carboxylic acid when using strong oxidizing agents
can be made to stop at the aldehyde level using specific reagents
what are 3 examples of strong oxidizing agents?
- chromium trioxide (CrO3)
- sodium dichromate (Na2Cr2O7)
- potassium dichromate (K2Cr2O7)
What specific reagent can stop the oxidation of primary alcohol to aldehyde to carboxylic acid at the aldehyd level?
pyridinium chlrochromate (PCC)
what are secondary alcohols oxidized to?
ketones
what are the 2 key themes you should remember with oxidation reactions?
- 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
when does reduction to a carbon occur?
what does this mean in practice?
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
what are good reducing agents? why? (2 groups each with 4 examples)
- sodium, magnesium, aluminum, zinc: have low electronegativies and ionization energies
- metal hydrides (NaH, CaH2, LiAlH4, NaBH4): contain H- ion
what are aldehydes reduced to? what are ketones reduced to?
aldehydes –> primary alcohols
ketones –> secondary alcohols
LiAlH3 is a common reducing agent, what does it reduce …
amides to?
carboxylic acids to?
esters to?
amides –> amines
carboxylic acids –> primary alcohols
esters –> a pair of alcohols
what are the 2 key themes you should remember with 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
defn: chemoselectivity
the preferential reaction of one functional group in the presence of other functional groups
which site is the reactive site of a molecule depends on what?
the type of chemistry that’s occurring BUT the more oxidized the functional group, the more reactive it is in BOTH nucleophile-electrophile reactions and redox reactions
why are aldehydes generally more reactive toward nucleophiles than ketones?
because they have less steric hindrance
a nucleophile is looking for a good electrophile, so why are carboxylic acids and their derivatives the first to be targeted by a nucleophile? what follows?
the more oxidized the carbon –> the more electronegative groups around it –> the larger partial positive charge it will experience
carboxylic acids + derivatives
aldehyde or ketone
alcohol or amine
why is the carbonyl carbon a common reactive site? (3)
- the carbon of the carbonyl acquires a positive polarity due to the electronegativity of the oxygen
- thus, the carbonyl carbon becomes electrophilic and can be a target for nucleophiles
- further, the alpha-hydrogens are much more acidic than in a regular C-H bond due to the resonance stabilization of the enol form
what happens when the alpha hydrogens of the carbonyl can be deprotonated easily with a strong base? (2)
- an enolate forms, which can then become a strong nucleophile
- alkylation can result if good electrophiles are available
consider the potential of the substrate carbon as a reactive site in Sn1 and Sn2 reactions
Sn1: prefer tertiary to secondary carbons as reactive sites and secondary to primary due to them having to overcome the barrier of carbocation stability
Sn2 (have a bigger barrier in steric hindrance): methyl and primary carbons are preferred over secondary, tertiary carbons won’t react
defn: steric hindrance/steric protection
the prevention of reactions at a particular location within a molecule due to the size of substituent groups
in what 2 circumstances can steric protection be helpful? how so?
- in the synthesis of desired molecules
- in the prevention of the formation of alternative products
bulky groups make it impossible for the nucleophile to reach the most reactive electrophile, making the nucleophile more likely to attack another region
explain how sterics come into play in the protection of leaving groups + when this is helpful to use
main concept + 2 steps
main concept: one can temporarily mask a reactive leaving group with a sterically bulky group during synthesis
- reduction of a molecule containing both carboxylic acids and aldehydes or ketones can result in reduction of all of the functional groups
- to prevent this, the aldehyde or ketone is first converted to a nonreactive acetal or ketal, which serves as a protecting group, and the reaction can proceed
what is another example of a protective reaction?
the reversible reduction of alcohols to tert-butyl ethers
what are the 6 steps to orgo problem solving?
- Know your nomenclature
- Identify the functional groups
- Identify the other reagents
- Identify the most reactive functional group(s)
- Identify the first step of the reaction
- Consider stereospecificity/stereoselectivity
explain step 1 to orgo problem solving: know your nomenclature
know which compounds IUPAC and common names refer to
explain step 2 to orgo problem solving: identify the functional groups
What functional groups are in the organic molecules? Do they act as acids or bases? How oxidized is the carbon? Are there functional groups that act as good nucleophiles, electrophiles, or leaving groups?
Helps to define a category of reactions that can occur
explain step 3 to orgo problem solving: identify the other reagents
determine the properties of 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?
explain step 4 to orgo problem solving: identify the most reactive functional group(s)
more oxidized carbons tend to be more reactive to both nucleophile-electrophile reactions and redox reactions
note the presence of protecting groups that exist to prevent a particular functional group from reacting
explain step 5 to orgo problem solving: identify the first step of the reaction
involves acid or base? nucleophile? oxidizing or reducing agent?
if it involves an acid or base: usually protonation or deprotonation
if it involves a nucleophile: usually for the nucleophile to attack the electrophile, forming a bond with it
if it involves an oxidizing or reducing agent: the most oxidized functional group will be oxidized or reduced, accordingly
once you know what will react, think through how the reaction will go:
did the protonation or deprotonation of a functional group increase its reactivity? when the nucleophile attacks, how does the carbon respond to avoid having 5 bonds? does a leaving group leave, or does a double bond get reduced to a single bond?
explain step 6 to orgo problem solving: CONSIDER STEREOSPECIFICITY and STEREOSELECTIVITY (does not apply to all)
stereospecificity: consider whether the configuration of the reactant necessarily leads to a specific configuration in the product (i.e. SN2)
stereoselectivity: occurs in reactions where one configuration of product is more readily formed due to product characteristics
- seen often bc different products have different traits that affect relative stability
- if there is more than one product: the major product will most often be determined by differences in strain or stability between the two molecules
- more strained molecules are less like likely to form molecules than less strained
- products conjugation (alternating single and multiple bonds) are more stable than those without
