Basic overview of nucleophilic substitution reactions:
- Nucleophile donates an electron pair to an electrophile to form a new chemical bonds.
- Electrophile accepts an electron pair to form a new chemical bond.
Nucleophilic substitution reaction mechanisms:
- SN1, first order kinetics. Slow step only involves reactant. Ends up with a racemic mixture. (Daughter leaves first, rate depends only on the person leaving the seat)
- SN2: Daughter pushes other daughter off the seat. Second order kinetics, rate depends on both reactants.
- Planar carbocation intermediate, so the size of the substituents on the electrophile don’t matter
- Activation energy of first step is much higher than the second step.
- Slow step is the loss of the leaving group from the electrophile and the formation of the carbocation.
- Nucleophile is not involved in the rate limiting reaction, so it doesn’t matter whether it’s a good nucleophile.
- Stability of the carbocation factors heavily. Resonance stabilization of carbocation makes reaction much faster.
- No intermediate, only one step.
- Single high energy transition state
- Nu must add opposite the LG
- Both reactants are involved in the rate determining step, so increasing the concentration of either speeds up the rate of reaction.
- Back side attack leads to the inversion of stereochemistry (not necessarily R to S and S to R)
- The size of the substituents on the electrophile matter!
What is a nucleophile?
- Atom or functional group with a pair of electrons that could be shared to form a new bond. Similar to bases (bases are often nucleophiles)
- Steric hindrance applies, atoms with more carbons bonded to them make worse nucleophiles.
- Strength of nucleophile matter much more for SN2 than SN1
- For two related groups, charged is better than uncharged. HOWEVER check if the charge is stabilized through resonance, which would make the nucleophile much weaker.
- Generally (in H2O), as electronegativity goes up, the atom becomes better at keeping electron attached, and nucleophilicity decreases. Weaker bases then make better nucleophiles.
- H3N > H2O > H3F
- I > Br> Cl > F
- In biological chemistry, thiols > alcohols
What to consider for nucleophile strength?
- Strength of nucleophile matter much more for sn2 than for sn1
- Negatively charged is better than uncharged
- Positively charged is the worst.
- Higher electronegativity results in lower nucleophilicity
- Steric hindrance (size matters, smaller is better)
What to consider for electrophile strength?
- Steric hindrance: Bulky groups around the electrophile slow down sn2 reactions or make them impossible.
- Steric hindrance and carbocation: Bulky groups around the electrophile stabilize the carbocation, making sn1 reactions likelier. Since carbocation is planar, their bulkiness does not matter.
What do methyl electrophiles undergo?
What do primary electrophiles undergo?
What do tertiary electrophiles undergo?
What do secondary electrophiles undergo?
SN1 or SN2
What to consider for leaving group strength?
- Both SN1 and SN2 have leaving groups in their rate determining step. Hence, better LG speeds up both SN1 and SN2.
- Weaker bases are better leaving groups, as they’re better at stabilizing the negative charge
- Biologically, leaving groups are often made better by protonation or phosphorylation
Water as nucleophile
What are carbonyls?
- C double bonded to O and 2 R.
- Double bond electron pair can be transferred to the O, making it negative and the C positive.
- The C is then electrophilic, so attracted to nucleophiles.
What are the 3 elementary steps in carbonyl addition mechanisms?
- Reversible proton transfer. Leads to two resonance structures: 1) O bonds to an H and becomes positive. 2) O bonds to an H, one of the electron pairs of the double bond to the C goes up to the O, C becomes positively charged.
- Nucleophilic attack on electrophilic carbon: Nucleophile attacks electrophilic carbon, electrons shift onto the O, which becomes negative.
- If one of the Rs is a good leaving group, we can substitute it with the nucleophile by returning the electron group as double bond. LG takes electron pair and leaves.
How do we push reaction to the products?
- Add lots of reagent
- Or remove product
How to identify acetals?
- Look for a C bonded to 2 Os.
- If one of them is OH and the C is bonded to an H, then it is a hemiacetal
- If one of them is OH and the C is not bonded to an H, then it is a hemiketal.
- If both are ORs and the C is bonded to an H, it is an acetal.
- If both are ORs and the C is not bonded to an H, it is a ketal.
In most biological conditions:
Hemiacetals/hemiketals can slowly interconvert with aldehydes/ketones.
In most biological conditions:
Acetals/ketals require enzymatic catalysis to interconvert with aldehydes/ketones, this is because the process requires the creation of a carbocation intermediate.
What is a sugar?
A polyol with an aldehyde or ketone at one end. Every carbon has an oxygen.
What does D for a sugar mean?
Non H substituent on bottom most stereocenter points to the right.
What do we call a 6 membered ring of sugar?
What is an anomeric carbon?
Stereocenter derived from a carbonyl molecule.
- Up (beta) is more stable, lower E
- Down (alpha), less stable, higher E
- Interconversion of alpha and beta forms establishes 63:37 equilibrium ratio.
What are glycoside bonds?
Bonds formed between hemiacetal and hemiketal of a sugar or sugar derivative and a hydroxyl group (OH) of another sugar.
What is mutarotation?
- Interconversion fo alpha beta forms.
- Only possible for hemiacetals and hemiketals.
Explain glycoside bond formation for glucose
- OH attaches to H+, water acts as leaving group, making a resonance stabilized carbocation.
- Nucleophilic O on OH group attacks electrophilic carbocation
- O on H2O takes H on OH group of other sugar, Positive O becomes neutralized.
- An acetal with no mutarotation is formed.
Explain non-biological acid catalyzed acetal formation
- Double bonded O turns into O bonded to the carbon part of the alcohol.
- Add the same O bonded to C part of the alcohol as the 4th group.
- If the alcohol has two OH groups, we bond some kind of a cycle.
What are disaccharides?
2 sugars connected to each other through a glycosidic bond between the anomeric bond of one sugar and an -OH at any position of another sugar.
Glucose + fructose
Galactose + glucose
Glucose + glucose
- Old word for sucrose
- Glucose + fructose
- Module 8
- What is the reaction for plant sucrose production through phosphorylation?
- Glucose + fructose + 2ATP + 1UDP -> sucrose + 2ADP + 1UDP + Pi + PiPi
- The overall reaction thermodynamics favor sucrose formation by coupling to the hydrolysis of ATP + UDP
- Stereospecificity of sucrose formation is enzyme mediated.
What is the phosphorylation mechanism analogous to?
- H in OH replaced by Pi
- H is stolen by a base, O bonds to P, like SN2 both Os bonded to P in the intermediate, then the O without R is the leaving group.
- The P acts as an electrophile.
What is the ending of the enzyme that add phosphates?
Any time you see sugars connected to a nucleophilic atom at the anomeric C, the likely mechanism was:
- Activation by phosphorylation
- Loss of the good leaving group to create a resonance stabilized carbocation
- Attack by a nucleophile (stereochemistry is determined by enzyme)
What is glycosylation?
Covalent addition of sugar moieties to specific amino acids on proteins
What is a tautomer?
Constitutional isomer that only varies in position of Hs.
What is xylose isomerase?
Interconverts aldehydes to ketones in sugars.
What is the keto form?
Ketone or aldehyde form.
What is the enol form?
What is keto-enol tautomerization?
From the keto form (99%) to the enol form (1%)
How to go from glucose to fructose?
Glucose (keto) -> enol -> fructose (keto)
- Most abundant organic compound in the biosphere: a bunch of glucose
- Forms fibrils (threads)
- Anomeric carbons are beta (up)
- Intramolecular forces (H bonds) give it stiffness.
- H bond between O of (icinde olan) glucose and OH next to the glucose
- Amylose (alpha glucose at anomeric carbon) forms 20-30% of starch
- Energy storage in plants
- Broken into glucose
- Amylopectin (amylose + branches) 70-80% of starch, branches occur every 20 to 30 glucose units. Alpha (1-4) links with alpha (1-6) branches
Same as amylopectin, but branches are more frequent and the overall size is much larger.
How to number sugars?
Start from double bonded O in open chain version.
What are carboxylic acid derivatives?
An acyl group bonded to an electronegative atom or substituent that can act as a leaving group in a substitution reaction.
Examples of carboxylic acid derivatives?
- Acid chlorides
- Acyl phosphates
What is acid chloride
R - c = O -Cl
What is nucleophilic acyl substitution
- Acid to ester
- Tetrahedral intermediate
- Tetrahedral intermediate will only kick out the better leaving group
- H+ catalytic
- Notice EQUILIBRIUM
- Double bonded O bonds to an H and becomes +
- As one of the bonds in the double bond goes up to the O (to make it neutral), Nu attacks electrophilic carbon to form the tetrahedral.
- Leaving OH group grabs one of the H from the Nu
- Water leaves as O reforms double bond.
- H initially bonded to O leaves.
What is the general rule for acyl substitutions
- Tetrahedral intermediate will only kick out the better leaving group
- Which means NAS only goes down the hill
Acyl substitution hill
- Esters and acids
- Carboxylates (o-, not electrophilic at all)
What happens if you mix carboxylic acid and amines? (amino acids?)
- Acid base reaction
- NH3 gets H from OH
What is a protein?
- A long chain of amino acids connected by peptide bonds.
- N terminal has the NH3+
- C terminal has the free carboxylate O-
Why do peptide bonds between amino acids not form at physiological pH without enzymes?
Because there is an acid base reaction and the NH3+ is no longer a nucleophile and the O- is no longer an electrophile.
Explain peptide bond formation
- Carboxylate of aa1 is activated with AMP (ATP turns into PiPi). O- acts as a nucleophile and the third P acts as an electrophile. P gets O, and phosphate group’s O that is bonded to the next Pi goes to the next Pi. The mechanism is SN2, so leaving and adding happens at the same time.
- Convert aa1-AMP into aa1-ester connected to tRNA using Nucleophilic acyl substitution.
- In the enzyme, a base deprotonates the amineon aa2 so that it can be a nucleophile and attack ester of aa1. tRNA is recycled.
What is the product of the hydrolysis of an amide?
Why does phosphorylation occur?
- phosphates are better leaving groups
- hydrolysis of ATP is thermodynamically favored, which makes equilibrium favor products
What happens in phosphorylation?
- OH attacks P, double bonded O electrons go up.
- OH loses H and becomes neutral
- Os electrons go down, the Pi bonded on the right and the adenine act as leaving groups.