Ch. 9: Carboxylic Acid Derivatives + Ch. 10 Nitrogen and Phosophorus-Containing Compounds Flashcards
what are 3 carboxylic acid derivatives that we focus on on the MCAT?
- amides
- esters
- anhydrides
what is a commonality between how these three carboxylic acid derivatives are formed?
they are each formed by a condensation reaction with a carboxylic acid
defn: condensation reaction
a reaction that combines two molecules into one, while losing a small molecule
what is the small molecule that is lost in the condensation reactions that create amides, esters, and anhydrides? how does this molecule form?
water!
created from the hydroxyl group of the carboxylic acid and a hydrogen associated with the incoming nucleophile
general formula + naming scheme: amides
general formula: RCONR2
naming: replace the -oic acid with -amide
alkyl substituents on the nitrogen atom are listed as prefixes, and their location is specified with N-
how are amides generally synthesized?
by the condensation reaction of other carboxylic acid derivatives with either ammonia or an amine
what is required for the synthesis of amides to occur? what does that imply about what type of amines will undergo this reaction?
the loss of hydrogen from the nucleophile is required
only primary and secondary amines will undergo this reaction
defn + naming scheme: lactams
cyclic amides
named according to the carbon atom bonded to the nitrogen: Beta-lactams contain a bond between the beta-carbon and the N, gamma-lactams contain a bond between the gamma-carbon and the N, and so on
amides may or may not participate in hydrogen bonding, what does this depend on?
how does this affect their boiling points?
depends on the number of alkyl groups they have bonded, and therefore their boiling points may be lower or on the same level as the boiling points of carboxylic acids
defn + how are they formed + how are they named: esters
the dehydration synthesis products of other carboxylic acid derivatives and alcohol
named: by placing the esterifying group as a prefix
the suffix -oate replaces -oic acid
defn: esterifying group
the substituent bonded to the oxygen
defn: Fischer esterification
under acidic conditions, mixtures of carboxylic acids and alcohols will condense into esters
how else can esters be obtained?
from the reaction of anhydrides with alcohols
defn + naming scheme: lactones
cyclic esters
named in the same way as lactams: with the name of the precursor acid molecule also included
why do esters usually have lower boiling points than their related carboxylic acids?
because they lack hydrogen bonding
defn (bio and chem): triacylglycerols
the storage form of fats in the body
esters of long-chain carboxylic acids (fatty acids) and glycerol (1,2,3-propanetriol)
defn: saponification
the process by which fats are hydrolyzed under basic conditions to produce soap
what does subsequent acidification of the soap regenerate?
the atty acids
explain the process of saponification of a triacylglycerol
treat the triacylglycerol with NaOH to produce fatty acid salts (soap) as well as glycerol
how do anhydrides form?
they are the condensation dimers of 2 carboxylic acids
aka + general formula: anhydride
aka: acid anhydride
general formula RC(O)OC(O)R
how are symmetrical anhydrides named? how are asymmetrical anhydrides named?
symmetrical: named by substituting the word anhydride for the word acid in a carboxylic acid
asymmetrical: name the two chains alphabetically, followed by anhydride
what are phthalic and succinic anhydrides?
cyclic anhydrides arising from intramolecular condensation or dehydration of diacids
how are acid anhydrides synthesized?
two molecules of a carboxylic acid come together and lose a molecule of water
what is another way that certain cyclic anhydrides can be formed?
simply by heating carboxylic acids
what is that reaction driven forward by? what kind of anhydrides form by this reaction?
the increased stability of the newly formed ring
only anhydrides with five or six membered rings are easily made
with all anhydride formations, what is the nucleophile?
the hydroxyl group of one -COOH acts as the nucleophile, attacking the carbonyl on the other -COOH
why do anhydrides often have higher boiling points than their related carboxylic acids?
solely on their much greater weight
in a nucleophilic substitution reaction, the reactivity of the carbonyl is determined by what?
its substituents
what is the order of carboxylic acid derivative reactivity?
anhydrides (most)
esters / tied with carboxylic acids
amides
explain the difference in derivative reactivity to nucleophilic attack based on the structure of the molecules
ANHYDRIDES –> with resonance stabilization and 3 electron-withdrawing oxygen atoms are the most electrophilic
ESTERS –> lack one electron-withdrawing carbonyl oxygen and are slightly less reactive
AMIDES –> with an electron-donating group, are the LEAST reactive towards nucleophiles
defn: steric hindrance
when a reaction does not proceed due to the size of the substituents
what is a good example of steric hindrance?
Sn2 reactions, which will not occur at tertiary carbons
what are two ways we can use steric hindrance to our advantage?
- if we want to push a reaction in an Sn1 direction, rather than an Sn2, we can use a tertiary substrate
- in the creation of protecting groups
how can steric hindrance have an effect in the context of carboxylic acid derivatives?
the size and substitution of the leaving group can affect the ability of a nucleophile to access the carbonyl carbon, thus affecting the reactivity of the derivative to nucleophilic acyl substitution
defn + process: induction
the distribution of charge across sigma bonds
electrons are attracted to atoms that are more electronegative, generating a dipole across the sigma bond
the less electronegative atom acquires a slightly positive charge, and the more electronegative atom acquires a slightly negative charge
is induction a strong or weak effect? does it get stronger or weaker as one moves further away within the molecule from the more electronegative atom?
induction is weak
it becomes increasingly weaker as one moves further away within the molecule from the more EN atom
what 3 characteristics of different carboxylic acid derivatives does induction explain?
- the dipole character of the carbonyl group
- the increased dipole character (and therefore susceptibility to nucleophilic attack) of carboxylic acids, which contain an additional oxygen atom in their leaving group
- the overall reactivity of anhydrides, esters, and amides toward nucleophilic attack
what is the distribution of charge on an anhydride as explained by induction? what about an amide?
anhydrides have 2 electron withdrawing groups, which leave a significant partial positive charge on the electrophilic carbon
this effect is smaller in amides because nitrogen is less electronegative than oxygen and the dipole is not as strong
defn: conjugation
the presence of alternating single and multiple bonds
what does the set-up of conjugation imply about the hybridization of the atoms involved in these bonds?
they are all either sp2 or sp hybridized and therefore have unhybridized p-orbitals
what happens when these unhybridized p-orbitals align?
they can delocalize pi electrons through resonance, forming clouds of electron density above and below the plane of the molecule
are conjugation and resonance stronger or weaker effects than induction?
conjugation and resonance are stronger effects than induction
defn: enone
+ what type of conjugation is shown in this compound
defn: alpha-beta unsaturated carbonyls
conjugation established with the carbonyl group itself
why are enones so stable? why are they more susceptible to nucleophilic attack?
because the have multiple resonance structures due to the conjugation
this allows for the stabilization of a positive charge once the nucleophile has bonded, making these compounds more susceptible to nucleophilic attack
why are certain lactams and lactones more reactive to hydrolysis?
because they contain more strain
what is an example of a more reactive lactam?
beta-lactams (four-membered cyclic amides that are highly reactive due to significant ring strain)
what 2 types of strain do 4-membered rings have?
- torsional strain from eclipsing interactions
- angle strain from compressing the normal sp3 angle of 109.5
is ring strain and reactivity increase or decreased by fusion to a second ring?
increased
why does the trigonal pyramidal bond geometry on the N atom in the ring of a B-lactam make hydrolysis more likely?
because resonance is reduced
defn: cleavage reaction
splits an anhydride in two
what is the electrophile, nucleophile, and leaving group in a nucleophilic acyl substitution that converts an anhydride to an amide to a carboxylic acid?
electrophile: one of the carbonyl carbons
nucleophile: ammonia
leaving group: a carboxylic acid
what results when alcohols act as nucleophiles toward anhydrides?
the formation of esters and carboxylic acids
what is another way for anhydrides to be converted to carboxylic acids?
what should be true for this reaction to be useful?
by exposing them to water
for this reaction to be useful, the anhydride should be symmetric, othereise, one forms a mixture of products
defn: transesterification
alcohols can act as nucleophiles and displace the esterifying group on an ester
one ester is transformed into another (different alcohol chains are swapped into and out of the esterifying group position)
explain how amides can be hydrolyzed under highly acidic conditions via nucleophilic substitution
- the acidic conditions allow the carbonyl oxygen to become protonated
- this makes the molecule more susceptible to nucleophilic attack by a water molecule
- the product of this reaction is a carboxylic acid and ammonia
- this is the reverse of the condensation reaction by which amides are formed
can hydrolysis of amides occur under basic conditions? explain
yes if the conditions are basic enough
the reaction is similar to an acid-catalyzed reaction, however the carbonyl O is not protonated and the nucleophile is a hydroxide ion
product: deprotonated carboxylate anion
defn + components: amino acids
defn: dipolar molecules that come together through a condensation reaction, forming peptides
contain an amino group and a carboxyl group attached to a single carbon atom (the alpha-C)
the two other substituents of the alpha-C are a H atom an a side chain referred to as the R group
defn: proteins
larger, folded peptide chains
is the alpha-C of an amino acid chiral? why or why not?
yes! it is a chiral (stereogenic) center because it contains 4 different groups
what is the one amino acid that does not have a chiral alpha-C? why?
Glycine
because its R group is a hydrogen atom
Are amino acids optically active? L or D isomers? (S) or (R) configuration?
ALL amino acids in eukaryotes (except for glycine) are OPTICALLY active and are all L-isomers
(S) configurations except for cysteine which is (R) because of the change in priority caused by the sulfur in its R group and glycine because not chiral
what does it mean that amino acids are amphoteric? why are they?
they can act as both acids and bases
because of their acidic carboxyl group and basic amino group –> the amino groups take on a positive charge by being protonated and carboxyl groups take on negative charges by being deprotonated
when is a zwitterion formed? + aka
when an amino acid is put into solution, it will take on both the positive charge on the amino group and the negative charge on the carboxyl group
aka: dipolar ion
explain how an amino acid acts depending on the pH of the environment
in basic solutions: the amino acid can become fully deprotonated
in acidic solutions: it can become fully protonated
other than the zwitterionic properties common to every amino acid, what else determines the properties of an amino acid?
they are defined by its R group, or side chain
what are the 5 categories that we can group the 20 eukaryotic proteogenic amino acids into?
- nonpolar nonaromatic
- aromatic
- polar
- negatively charged (acidic)
- positively charged (basic)
what are the 7 nonpolar nonaromatic amino acids?
what types of side chains do they tend to have?
- alanine
- valine
- leucine
- isoleucine
(tend to have side chains that are saturated hydrocarbons) - glycine
- proline (cyclic with secondary amine)
- methionine (contains sulfur)
what are the 3 aromatic amino acids?
- tryptophan
- phenylalanine
- tyrosine
what are 2 characteristics of nonpolar amino acids (both nonaromatic and aromatic)?
- hydrophobic
- tend to be sequestered in the interior of proteins
what are the 5 polar amino acids?
what types of side chains do they tend to have?
tend to have terminal groups containing oxygen, nitrogen, or sulfur
- serine
- threonine
- asparagine
- glutamine
- cysteine
what are the 2 negatively charged (acidic) amino acids?
what types of side chains do they have?
- aspartic acid
- glutamic acid
have terminal carboxylate anions in their R groups
what are the 3 positively charged (basic) amino acids?
what types of side chains do they have?
- arginine
- lysine
- histidine
have a protonated amino group in their R groups
what are 2 common characteristics of polar, acidic, and basic amino acids?
- hydrophilic
- tend to form hydrogen bonds with water in aqueous solution
what bonds and molecules form when amino acids undergo condensation reactions?
amino acids undergo condensation reactions to form PEPTIDE BONDS which form POLYPEPTIDES which are the base unit of pROTEINS
what is the reverse reaction of the condensation of amino acids to form peptide bonds? what is this reaction catalyzed by?
hydrolysis of the peptide bond
catalyzed by a strong acid or base
explain the effect of the amide bond having two resonance structures
the true structure of the amide bond is therefore a hybrid of these two structures with partial double bond character between the nitrogen atom and the carbonyl carbon
explain the rigidity or freedom of the bonds in and near a peptide bond
the partial double-bond character of the amide bond limits rotation about the C-N bond, which adds to the rigidity and stability of the backbone of proteins
the single bond on either side of the peptide bond, permit free rotation
what are the 2 types of amino acid synthesis?
- Strecker synthesis
- Gabriel synthesis
process (5) + summary: Strecker synthesis Step 1
summary: an aminonitrile is generated from an aldehyde or ketone
- start with an aldehyde, ammonium chloride (NH4Cl) and potassium cyanide (KCN)
- the carbonyl O is protonated, increasing the electrophilicity of the carbonyl C
- ammonia can attack the carbonyl C, forming an imine
- the imine carbon is also susceptible to nucleophilic addition reactions, thus, the CN- atom from the KCN attacks, forming a nitrile group
- the final molecule at the end of Step 1 is an aminonitrile
defn: nitrile
have a triple bond between N and C
defn: aminonitrile
a compound containing an amino group (-NH2) and a nitrile group (N triple bond C)
process (4) + summary: Strecker synthesis Step 2
summary: an amino acid is generated from the aminonitrile
- the nitrile N is protonated, increasing the electrophilicity of the nitrile C
- a water molecule attacks, leading to the creation of a molecule with both imine and hydroxyl moieties on the same C
- this imine is attacked by another equivalent of water
- a carbonyl is formed, kicking off amonia and creating the carboxylic acid functionality
what conditions are true for strecker synthesis step 2?
- performed in aqueous acid
- can be accelerated by the use of heat
what is the starting material for a Strecker synthesis?
a planar carbonyl-containing compound
why is the product of a Strecker synthesis pathway a racemic mixture? what does this result in?
the incoming nucleophiles are equally able to attack from either side of the carbonyl
L and D amino acids can be generated through this process
aka: Gabriel synthesis
malonic-ester synthesis
summary: gabriel synthesis
an amino acid is generated from phthalimide and diethyl bromomalonate, using 2 Sn2 reactions, hydrolysis, and decarboxylation
process (9): gabriel synthesis
- potassium phthalimide is reacted with diethyl bromomalonate
- phthalimide = nucleophile, secondary substrate C = electrophile, bromine = LG –> reaction creates a phthalimidomalonic ester
- in the presence of base, the alpha-C between two carbonyls can be easily deprotonated
- the molecule as a whole (the whole deprotonated phthalimidomalonic ester) can act as a nucleophile, attacking the substrate carbon of a bromoalkane (Sn2) –> LG = bromide anion, electrophile = substrate C
- this molecule is hydrolyzed with strong base and heat
- the phthalimide moiety is removed as phthalic acid (with 2 carboxylic acids)
- the malonic ester is hydrolyzed to a dicarboxylic acid with an amine on the alpha-C
- this dicarboxylic acid, which is a 1,3-dicarbonyl, can be decarboxylated through the addition of acid and heat
- the loss of a molecule of carbon dioxide results in the formation of an amino acid
char: phthalimide (2), diethyl bromomalonate (1)
phthalimide = acidic, exits in solution as a nucleophilic anion
diethyl bromomalonate = contains a secondary C bonded to bromine, a good leaving group
what is a benefit to using such a large nucleophile (phthalimide)?
the bulkiness of the group creates steric hindrance, which prevents the substrate C from undergoing multiple substitutions
why is the product of the gabriel synthesis a racemic mixture, what does this mean?
it starts with a planar molecule, so the product is a racemic mixture of L and D amino acids
why is phosphoric acid so important biochemically?
it forms the high-energy bonds that carry energy in ATP
3 akas: phosphoric acid
- phosphate group
- inorganic phosphate
- Pi
at physiological pH, what 2 types of molecules does inorganic phosphate include?
- hydrogen phosphate (HPO42-)
- dihydrogen phosphate (H2PO4-)
where else is phosphorus found biochemically?
in the backbone of DNA in phosphodiester bonds, linking the sugar moieties of the nucleotides
how is pyrophosphate formed? what is it? how is it denoted? chemical formula?
when a new nucleotide is joined to a growing strand of DNA by a DNA polymerase, it releases an ester dimer of phosphate which is this!
P2O74-
denoted PPi
what is the function of this pyrophosphate being released? what happens to the pyrophosphate after the fact?
the hydrolytic release of this molecule provides the energy for the formation of the new phosphodiester bond
pyrophosphate is unstable in aqueous solution and is hydrolyzed to form two molecules of inorganic phosphate, which can then be recycled to form high-energy bonds in ATP or otherwise
defn + where does the name come from: organic phosphates
nucleotides such as ATP, GTP, and those in DNA
called this due to the presence of the phosphate group bonded to a C-containing molecule
what property of phosphoric acid is unique?
it has 3 acidic hydrogens, each with its own pKa
what does phosphoric acid generally refer to?
the form that predominates in strongly acidic conditions, H3Po4
what happens to phosphoric acid in mildly acidic conditions?
it loses a proton to become dihydrogen phosphate, H2PO4-
what happens to dihydrogen phosphate, H2PO4- in weakly basic solutions?
it will readily lose a second proton to become hydrogen phosphate HPO42-
what is the form of phosphoric acid that exits in strongly basic solutions?
phosphate, PO43-
what is each pKa for the loss of each of the 3 acidic hydrogens in phosphoric acid?
first H = 2.15
2nd H = 7.20
3rd H = 12.32
what form of phosphoric acid is present at a physiologic ppH of 7.4?
dihydrogen phosphate and hydrogen phosphate predominate in nearly equal proportions
why are phosphates good buffers?
the variety of pKa values makes phosphates good buffers because they can pick up or give off protons depending on the pH of the solution
phosphoric acid has 3 H’s with pKa values that span nearly the entire pH scale
why is the energy released when a phosphate or pyrophosphate is cleaved quite high? (2)
- adjacent phosphate groups on a nucleotide triphosphate experience a large amount of repulsion because they are negatively charged
- the ability of phosphate to stabilize up to 3 negative charges by resonance
