Physical Organic Chemistry-Questions from all problem sets (Finals period)

[Lecture 14. Rate of Reaction]

[1-3] Rate-law of chemical reactions can reveal the stoichiometry of transition-states, but not the
actual structure. Several theories have been put forward to suggest transitional-state structures,
however, each has limitations. Answer the following questions about the theories proposed to explain
transition-states:

1. Please state the main assumption made by the Salem-Klopman equation and its limitation.

① Assumption: transition state much resembles the starting material, so perturbation theory can be
applied
② Limitation: if there is a substantial reorganization in the transition-state, then it will have a
completely different set of orbitals from the starting material and this may not apply

2. Briefly, using your own words, explain the application of configuration mixing model and
Hammond's postulate in the Bell-Evans-Polanyi principle (BEP) (correlates the exo-/endo-thermicity
with transition-state structure).

① Configuration mixing model

+
Consider the acid-base reaction B + HX → BH + X-:

TS is the "avoided crossing" of the diabatic curves linking a) SM-(SM in PDT geometry) and b)
PDT-(PDT in SM geometry)
In this case Course 1 (strong base) is more exothermic than Course 2 (weak base) so TS1 is earlier
than TS2
② Hammond postulate
Two states of similar energy along the same reaction coordinate have similar structures; can be
written as linear free-energy relation, δΔG‡ = αδΔG° (form of linear equation y = αx)
① and ② are basically the same arguments with different wording
3. The Ritchie solvolysis study is an illustrative example of the breakdown of normal
reactivity-selectivity behavior (more reactive reagent, less selective the reaction). The conclusion
from the Ritchie study is that we cannot expect the dependence of rate on electrophilicity to be the
same for two different nucleophiles. But a more fundamental question is why this dependence does
not hold (and thus breakdown of the generality of BEP principal)? The answer is that we cannot
always assume the transition state to be represented by starting material and product structure, due
to the existence of “intrinsic reactivity” of reactants that is not related to the exo-/endo-thermicity
of reaction. For normal reactivity-selectivity behavior to hold, the intrinsic energy barrier must
remain constant for the series of reactions. Several examples were given in the class where
additional factors are involved in the transition-state that, for example, non-perfect synchronization,
Diels-Alder reactions of electronically biased substrates, etc. One scenario within the Ritchie study
is when one nucleophile is reacting at “diffusion control” then normal reactivity-selectivity behavior
must be observed.
(1) Please define “diffusion controlled” reaction.
(2) Please explain why normal reactivity-selectivity behavior is observed.
(3) Please provide “absolute rate” versus electrophilicity graphs for two nucleophiles exhibiting a)
Normal; b) Constant; c) Inverse reactivity-selectivity relationship, ultimately leading to leveling-off
effect at diffusion control.

(1) A reaction where the reactants are so reactive that the reaction rate is solely governed by their
diffusion through the reaction medium
(2) The reaction rate of any nucleophile goes up as the electrophile gets more electrophilic until it
reaches the diffusion rate. Thus, if the reaction rate of one of the nucleophiles used is fixed at the
diffusion rate, the selectivity necessarily decreases with increasing electrophilicity.
(3) See below:
[Lecture 15. Energy and Reactivity]

[1-3] It is often useful to be able to make prediction on the progression of chemical reaction based
on activation energy, reaction temperature, and reaction time. Two models (hard-sphere collision and
transition-state) have been introduced in the class that gives rise to very similar mathematical
derivations (Arrhenius equation and Eyring equation). Answer the following questions about these
models:

1. Please give estimated energy barriers for a chemical reaction at room temperature that can reach
completion in seconds, hour, or day, respectively.

seconds: 10-17 kcal/mol, hour: 14-22 kcal/mol, day: 15-26 kcal/mol

2. Obviously, increasing temperature will speed up chemical reaction. However, the amount of
“speed up” depending on the activation barrier of the reaction and the reaction temperature. Please
briefly explain why the “speed up” is less for reaction with low activation energy and for reaction
at high temperature.

① Low activation energy: reactions with small barriers are fast already and don't get sped up much
by increasing temperature
② High temperature: incrementing low temperature has a bigger effect than incrementing high ones
(∵ inverse-exponential form of Eyring equation, K = κ(kBT/h)exp(-ΔG‡/RT))

3. It is very useful to be able to predict the ratio of two products, transition-states, intermediates,
and substrate-product based on the free energy difference at a particular temperature. Please state
this simple equation, and predict the temperature requirement for two diastereomeric
transition-states with 1.0 kcal/mol energy difference leading to 95% ee of the product.

The equation is Eyring equation. (K = κ(kBT/h)exp(-ΔG‡/RT))

Plugging in the numbers gives exp(1.0/RT) = 39, which solving for T results in T = 137 K.
[Lecture 16. Acidity Concepts]

1. While we are all familiar with the definition and origin of pH in aqueous media, for organic
chemistry where most processes take place in organic solvent we need a different way to interpret
acidity. Please, in your own words, (1) explain the Bordwell method, (2) how it works, (3) its
advantages from an analytical point, and (4) solvent dependence.

(1) a method used to determine pKa of a substance in DMSO by reverse titration of dimsyl anion
solution
(2) a three-step process:
① generation of potassium dimsyl solution

② titration of dimsyl solution with indicator and determining [DMSO-]

③ addition of weak acid and monitoring change in color (absorbance)

(3) determines relative instead of absolute acidity, the latter of which is difficult to measure due to
many organic acids being weak
(4) trends in pKa do not vary much from one polar solvent to another (i.e., values in DMSO will also
likely hold in other solvents)

2. Returning to the unique cyclopropane systems, explain why cyclopropylamine are unusually less
basic compared to other aliphatic amines.

C-H σ* antibond in cyclopropylamine is enriched in s-character and is therefore lower in energy and
a better acceptor.
3. Our traditional interpretation of “acid A is more acidic than acid B” is based on the relative
stability of the conjugate base of A and B. Please explain why this interpretation is flawed.

This interpretation implies that recombination of acid A's conjugate base with proton is much less
favorable than the recombination of conjugate base of B and proton, but kinetic measurements show
that the rate of recombination is essentially diffusion-controlled regardless of acidity of the acid in
question.

This explanation Better explanation

4. When comparing the relative acidity between alcohols and carboxylic acids, the stability of the
conjugate bases (alkoxide and carboxylate) are evaluated. Please briefly outline and discuss the
contributing factors behind their stability, and how a set of hypothetical isodesmic reactions can
provide some qualitative insights on their relative contribution.

① inductive argument: resonance stabilizes the product more than it stabilizes the reactant in case
of carboxylate, but no such difference in alkoxide

→ may be misleading in that charge analysis shows that charge delocalization in acetate is not as
pronounced as expected
② electrostatic argument: the carbonyl anion stabilizes full anion better than partial charge

③ isodesmic reactions: reactions where bonds being broken in reactants/being formed in products
are the same and thus allows for comparison / labelling contributions from resonance and
electrostatic effects as x and y respectively, we get...

(the purpose reactions on the right-hand side are to obtain better fits)
then the best fits for x and y are obtained via regression analysis
5. Accessing the contribution of resonance to the observed acidity was exemplified by two examples
in class, namely the phenol vs. acetone enol case and phenol vs phenol vinylogue case. Please, in
your own words, briefly describe these studies and their conclusions.

① Phenol vs. acetone enol

a) KE = kforward/kreverse is determined (kforward - by standard kinetic method,

kreverse - by flash photolysis)
b) Ka(ketone) is already known, so Ka(enol) is determined by Born-Haber cycle shown above
c) result: phenol is more acidic, but only slightly so in water → could be the result of solvation
② Phenol vs. phenol vinylogue
a) compute the gas phase acidities of the three species below:

b) result:
1) conjugated form is significantly more acidic than vinylogue → resonance is actually important
2) vinylogue is similar in acidity with Cy (control) → anisotropic polarization of π-electrons is not
that significant

[6-8] As we have seen in class, interpretation of the relative acidity of substituted carboxylic acids
is not purely based on the intuitive “inductive effect” as you learnt in undergraduate. A complex
interplay between solvent, enthalpy/entropy, polarizability, dipole-dipole interactions all should be
considered. Answer the below questions:

6. In aqueous solution, please account for the relative acidity of α-halogen substituted carboxylic
acids based on enthalpy and entropy arguments.

More electronegative groups -> more acidic

① Enthalpy of deprotonation is relatively unaffected by the substituent, since more electronegative
groups can better stabilize negative charge (increasing acidity) but also reduce the donor capacity of
the anion (decreasing acidity), meaning that the two effects cancel each other out.
② The anion can act as a good hydrogen bond acceptor in water. More electronegative groups will
decrease the hydrogen bond accepting capabilities of anion, meaning a larger net increase in entropy
upon deprotonation.
7. For alkyl-substituted carboxylic acids and alcohols (namely methyl, ethyl, isopropyl, tert-butyl,
and adamantyl, etc.), please describe and rationalize the observed acidity trend in DMSO, aqueous
and gas-phase.

① In DMSO and aqueous phase: methyl > ethyl > isopropyl > tert-butyl > adamantyl.
Reason: In DMSO and water, the anion must be solvated. However, steric hinderance by the alkyl
groups prevent the solvent molecules from assuming many different orientations. This increases the
entropy cost of solvation.
② In gas phase: methyl < ethyl < isopropyl < tert-butyl < adamantyl.
Reason: In gas phase, larger alkyl groups mean greater stabilization of the anion by polarization.

8. Resonance is a major contributing factor in acidity. Therefore, factors that assist or impede
resonance can influence the observed acidity. Please describe and explain the acidity trend for
benzoic acid, 2-hydroxybenzoic acid, 2-methylbenzoic acid, 2,6-dimethylbenzoic acid in aqueous and
gas-phase.

① In aqueous phase: 2-hydroxybenzoic acid > 2,6-dimethylbenzoic acid > 2-methylbenzoic acid >
benzoic acid.
Reason: 2-Hydroxybenzoic acid exhibits intramolecular hydrogen bonding, with anionic oxygen being
a better donor than the carbonyl group. Presence of more methyl groups mean greater stabilization
of the anion by polarization.
② In gas phase: 2,6-dimethylbenzoic acid > 2-hydroxybenzoic acid > 2-methylbenzoic acid >
benzoic acid.
Reason: Polarization effects become more pronounced in gas phase due to lack of solvation. The
presence of two methyl groups adjacent to the anion is better in terms of polarization, which
obviously outweighs the disadvantage of losing some resonance stabilization.

9. In acid-base equilibria where an inorganic base is involved, clearly, the interaction between the
inorganic cation and the conjugate base (of the acid), so-called ion-pairing, will have a subtle yet
important effect on the reaction. Following this logic, please describe the pKa trend with respect to
the size of the cationic inorganic counter-ion, in the case of alkoxide and carbanion (as the
conjugate base).

① Carbanion: delocalized anion → solvent-cation interactions dominate → larger ions are solvated
better, so higher pKa (e.g., Cs+ > K+ > Na+ > Li+)
② Alkoxide: ion pairing is strong (localized anion) → cation-anion interactions dominate → reversed
order (e.g., Cs+ < K+ < Na+ < Li+)
[Lecture 17. Tetrahedral Intermediates]

[1-4] Although a seemingly trivial concept today, the speculation, proposition, experimental detection
and mechanistic study of tetrahedral intermediate is an important advance in organic chemistry and
physical organic chemistry. Answer the below questions regarding tetrahedral intermediates:

1. Please give examples using the A/B(AC/AL)1/2 terminology.

① Acidic ester hydrolysis

AAC2: via tetrahedral intermediate AAC1: via acylium ion

AAL1: sterically hindered esters

② Alkaline ester hydrolysis

BAC2 mechanism BAL2 mechanism

2. Please, in your own words, briefly discuss the proof of tetrahedral intermediate in BAC2 reactions,
its stability, and methods to enable its detection.

① Proof: Consider hydrolysis of a methyl ester with H218O. If the reaction proceeds directly via the
18
transition state, re-isolated starting material should not have O, but such an exchange is observed.
② Stability: Hydrolysis occurs 18.3 times faster than exchange.
③ Detection: via KIE (kinetic isotope effect)
3. We learnt about breakdown of 6-membered tetrahedral intermediate that led to the formation of
6-membered lactone and open-hydroxyester, and the stereoelectronic argument to rationalize the
observed outcome. Please briefly explain this stereoelectronic argument, its flaws, and the correct
interpretation of the reaction outcome.

① Argument: endocyclic cleavage is preferred due to the number of oxygen lone-pairs anti to
endocyclic and exocyclic bonds being 2 and 1 respectively, so oxygen lone-pair to σ*(C-O) antibond
donation is better in the former case

② Flaws: assumes axiality of hydroxyl group (-OH), but the barrier to ring-flipping in this kind of
intermediate is very low and thus selectivity does not hold well
③ Correct interpretation: lactones are essentially esters frozen into a Z-conformation, and thus they
are substantially destabilized (absence of n(O) to σ*(C=O) interaction)

4. Please discuss the basic principal of Weinreb amide.

a) Normal ester: cannot be turned into ketone with organometallic reagent (RM) directly since O-M
bonds are very good donors, leading to regeneration of ketone, wh[Lich reacts again

b) Weinreb amide: the tetrahedral intermediate is stabilized by chelation and bad leaving group
capability of amide → gives ketone on workup
[Lecture 18. Hydroboration]

[1-4] Hydroboration is a valuable tool in organic chemistry, and the corresponding hydroboration
product can undergo a wide variety of transformations leading to structurally and functionally diverse
organic compounds. Answer the below questions about mechanisms and kinetics of hydroboration:

1. Please provide generalized schemes showing associative and dissociative hydroboration

mechanisms.

① Associative mechanism:
i) 1/2(R2BH)2 + THF ⇄ R2BH·THF
ii) R2BH·THF + olefin → product + THF
② Dissociative mechanism:
i) 1/2(R2BH)2 + THF ⇄ R2BH·THF
ii) R2BH·THF ⇄ R2BH + THF
iii) R2BH + olefin → product

2. Please rationalize the effect/strength of donor ligand/solvent in the rate of hydroboration

reactions.

General consensus: dissociative mechanism

i) (9-BBN)2 + S ⇄ 9-BBN·S + 9-BBN
ii) 9-BBN·S ⇄ 9-BBN + S
iii) 9-BBN + olefin → product
① Weak donors (Et2O, 2,5-dimethyl-THF): no effect on rate, step i) remains as RDS
② Medium donors (THF, N-methylpiperidine): ↑ rate, speed up step i)
③ Strong donors (NMe3): ↓ rate, binds tightly to 9-BBN monomer and prevents then from reacting

3. Hydroboration has been studies extensively by computation, where a “dynamic effect” explanation
has been put forward to account for the inadequacy of transition-state theory. To the best of your
ability, briefly explain this “dynamic effect.”

① Observation: experimental selectivity for anti-Markovnikov product is far lower than what is
expected from computational results
② Explanation: trajectory studies for starting from a) π-complex and b) TS's leading to π-complex
→ high selectivity when began from π-complex, and low selectivity when began from TSs
→ π-complex formation is needed for selectivity, but is too short-lived to impart enough of it to the
product
4. Please draw the catalytic cycle for a rhodium-catalyzed hydroboration, indicate the key steps, and
state which steps are reversible/irreversible.
[Lecture 19. Organolithium aggregates]

[1-3] LiHMDS and LDA are two of the most commonly employed lithium amide bases in synthetic
organic chemistry, however, their characteristic and reactivity is very complex and highly solvent
dependent. Answer the below questions regarding these bases:

1. Organolithium compounds are known to form aggregates, and the degree of aggregation is
intuitively rationalized by the solvent/ligand donor strength. Please discuss the validity of this
statement, and explain the observed experimental results based on steric, enthalpy and entropy
arguments (Please in your own words!).

① Validity of this statement: the statement is not valid, as the two factors have been shown
experimentally to have no correlation i.e., solvents that bind more strongly to lithium may or may
not (de)aggregate the organolithium compounds.
② Steric arguments:
a) ↓ solvent size - ↑ solvent-amide interactions in the dimer, monomer preferred as solvent gets
bulkier
b) ↑ solvent size - ↑ solvent-solvent interactions in the monomer, dimer preferred as solvent gets
bulkier

③ Enthalpy arguments: near-zero enthalpy of aggregation

a) Solvation enthalpy: monomer is more heavily solvated, so deaggregation is better
b) Dimerization enthalpy: a dimer is basically the solvent in monomer exchanged with an amide, so
aggregation is better
c) Effects in a) and b) are cancelled out

④ Entropy arguments:
a) Translation entropy: (dimer + 2 solvents) is favored than (2 monomers) due to 3 particles vs. 2,
so dimer is better
b) Solvation entropy: solvation means taking away freedom from solvent molecules, so dimer is
better
c) Solvent-dependent entropy: dimer is more preferred with acyclic solvents (diethyl ether) than
cyclic solvents (THF) because free solvents lose a lot more freedom upon solvation in the former
2. Please discuss the degree of aggregation between LDA and LiHMDS.

① Trend: LiHMDS is less aggregated than LDA

② Reason: LiHMDS is more electronically stabilized than LDA, since vicinal delocalization of σ(N-Li)
is better when the acceptor is σ*(Si-C) than when it is σ*(C-C) (due to Si being more
electronegative than C)

3. Reactions which proceed through de-aggregated monomeric transition-states are not necessarily
better/faster than dimeric transition-states. Please rationalize.

Suppose that in the absence of an "aggregate disrupting" ligand, S, the dimer is prevalent. If S is
added, it would deaggregate the dimer by selectively solvating the monomer. In this case, the
monomer has to be desolvated to react, meaning that deaggregation leads to ground state
stabilization resulting in slowing down of the reaction.

However, a new pathway in which the solvated monomer reacts faster might also open up. In such
case, deaggregation can also lead to transition state stabilization which accelerates the reaction.

Thus, it is the relative importance of these two factors that determines whether aggregates or
monomers are more reactive.
[Lecture 20. Enamine and Iminium Organocatalysis]

[1-3] Enamine/iminium organocatalysis has definitely made a revolutionary impact to organic

chemistry over the past 10-12 years, both in terms of the originally proposed mode of catalytic
activation to new modes of catalytic concepts. Historically, the first and most recognizable
asymmetric enamine/iminium catalysis dates back to the Hajos-Parrish/Wieland-Miescher ketone
synthesis. This pioneering reaction had instigated extensive mechanistic investigations, at the same
time, the so-obtained products serve as versatile chiral building blocks in a wide-array of synthetic
applications. Please, IN YOUR OWN WORDS, discuss the following:

1. The accepted mechanism in terms of substrate-catalyst stoichiometry (evidence against other

proposals).

① Accepted mechanism:

② Evidence against other proposals:

a) Kinetic studies

"1+" rate law:

Assuming formation of (C·K)' is uncatalyzed, we can substitute K1KI = K1' (< K1)

Then the above expression becomes:

Meanwhile, least-squares fit to experimental results gives

1) Suppose that RDS is C+K ⇄ C·K: then v ∝ [K][C]T
This is 1st order in [K], which does not fit the experimental result

2) Suppose that RDS is C·K + A ⇄ C·K·A: then v ∝

This is little less than inverse-1st order in [H2O] and little less than 1st order in [K], which fits
the experimental result
b) Non-linear effects experiment: no such effect (i.e., catalyst enantiopurity directly translates to
product enantiopurity)
c) Retro-aldol reaction is 1st order in proline, so forward aldol reaction also should be 1st order in
proline ([C]T)
d) Performing reaction in H218O results in 18
O-labeled ketone: further proof of iminium intermediate
2. The transition-state structure to account for the observed stereochemical outcome (Houk-List vs.
Seebach-Eschenmoser models).

① Houk-List ② Seebach-Eschenmoser

3. The unique structural feature of proline that makes this reaction so effective.

① General acid catalysis: -COOH stabilizes forming alkoxide

② Enamine activation: condensation of reacting ketone with catalyst results in an enamine, which is
much more reactive (electrophilic) compared to starting ketone

(approximately two oxygens equal one nitrogen)

[Lecture 22. Intermolecular Forces and Hydrogen Bonding]

[1-4] Weak interactions are important intermolecular forces that implicate a wide variety of
chemical and biological processes. In parallel, the understanding behind weak forces has also
witnessed significant advances with more refined theories. Answer the following questions regarding
such weak chemical interactions:

1. In "London's" view, weak interactions are treated as two isolated systems and gradually "turn-on"
the interaction potential. This interpretation may be acceptable for long-distance (as in the case of
many weak interactions) but has defects in short distances. Please briefly explain this, and discuss
how the NBO approach we learnt provides a better description of the system.

① Defect: The interaction potential Vint is described as a power series in 1/R, where R denotes the
intermolecular separation between the systems, as in Vint = V1/R + V2/R2 + …. However, this series
only converges when R is large enough; otherwise the potential will violate the Pauli principle.
② Improvement with NBO approach: In NBO approach, a Pauli-compliant overall wavefunction is
arbitrarily split into two subunits, so there's no such issue. The choice can be scrutinized using the
variational theorem.

2. For the hydrogen bond, both the strength and geometry have been studied extensively and two
(not mutually exclusive) factors have been put forward. Please state these two factors and the
anticipated geometry.

① Factors: a) electrostatics b) charge transfer

② Geometry: a) electrostatics – alignment of two dipoles b) CT – alignment of donor-acceptor NBOs
In case of water dimer, a bisected geometry suggestive of charge transfer is observed, although this
does not rule out electrostatics.
3. In connection with Question 2, the relative contribution of these two factors have been studied
theoretically, both classically using the Kitaura-Morokuma scheme and more recently with the
Natural Energy Decomposition Analysis (NEDA). Compare and contrast these two methods, their
“accuracy” (I place “accuracy” in inverted commas since no one can be sure what accurate means!)
and results.

① Similarities: involve decomposing the hydrogen bond into steric, electrostatic, and charge-transfer
factors; both report the hydrogen bond strength of water dimer as stronger (6-7 kcal/mol) than
experimental results (5 kcal/mol), although the NEDA result is closer
② Differences
a) Kitaura-Morkuma scheme: wavefunctions not Pauli-compliant, more balanced representation of
various contributing factors
b) NEDA: wavefunctions Pauli-compliant; contribution of electrostatics may be overrepresented

4. Spectroscopic evidence of hydrogen bonds are widely available. Please state the criticism about
X-ray and neutron diffraction analysis (both infer the position of atoms), and the expected/observed
trend in IR and NMR shifts.

① Criticism about X-ray and neutron diffraction

a) crystal structures do not accurately represent the solution phase
b) just because two things are close in crystals, it does not mean interaction between them exists
② Trend in IR and NMR shifts
a) ↓ IR stretching frequency (∵ O-H bond is weakened)
b) ↑ 1H NMR downfield shift (∵ electron density taken away from hydrogen)

[5-7] In class we visited numerous examples and particularly focused on the molecular geometry to
provide an insight to the contributing factors towards hydrogen bonds. IN YOUR OWN WORDS,
please discuss the following cases:

5. HF-dimer.

Dipoles are not aligned in equilibrium geometry → this reflects that

① donor-acceptor interaction (rather than Coulombic interaction) is the main player and
② fluorine is sp2 hybridized, indicating that H-bond is strong enough to influence its hybridization
6. Acetone-MeOH vs acetone-LA (Lewis acid) complex (we studied this before!).

① Acetone-MeOH:
a) Hydrogen bond somewhat alters hybridization of (normally orthogonal) acetone lone pairs, but is
not strong enough to make them equivalent
b) Global minimum of energy is not well-defined

② Acetone-LA:
a) Much stronger acid-base interaction (↑ covalent character) → renders lone pairs sp2 hybridized
b) Global minimum of energy is well-defined
7. Urea-formaldehyde.

① Ideal geometry: formaldehyde located right between the N-H antibonds (since both s- and p-lone
pairs can donate to them)

② Little penalty for out-of-plane placement, since s-rich lone pair is spherical
→ accessible zone for formaldehyde can be defined as a "half-sphere"

[8-9] Intuitively, charged species can participate better as hydrogen bond donors and acceptors.
Answer the following questions regarding this phenomenon:

8. In connection, hydrogen bond interaction in formamide dimer is stronger than in

formaldehyde-ammonia, and cyclic formamide dimer is even stronger. Please rationalize.

① Formamide dimer: n(N) to π*(CO) resonance enhances both donor and acceptor properties of
formamide

② Cyclic formamide dimer: cooperative effect between each hydrogen bond (RAHB)
9. In analogy with the stabilization trend in benzene, conjugated polyene and cross-conjugate
polyene, chains of HF molecules also exhibit a similar behavior, and this appears to provide more
support for one of the two contributing factors in hydrogen bonding. Please rationalize.

① Open chains: ↑ H-bond strength with ↑ HF molecules participating (⇔ polyene)

② Cyclic complex: even more stable than 5-membered open chain due to the additional hydrogen
present resulting in cooperative effect (⇔ benzene)

③ Bifurcated complex: less stable than open trimer due to anti-cooperative effect
(⇔ cross-conjugate polyene)

10. Formyl hydrogen bond championed by Professor E. J. Corey have received fair share of
appraisal and criticism. Explain this concept.

① Definition: nO to π*HC interaction (or nF to π*HC), where the carbon is sp2 hybridized
② Example: can be invoked to explain the stereoselectivity in oxazaborolidine-catalyzed Diels-Alder
reaction between methacrolein and butadiene systems
[Lecture 23. π-π Stacking and Cation-π Interactions]

[1-10] Continuing our discussion on weak interaction, π-π interactions and cation-π interactions are
equally important as hydrogen bonds, once again with significant relevance in both chemical and
biological systems. Answer the following questions regarding such classes of interactions:

1. Similar to hydrogen-bonds, the key contributing factors responsible for π-π interactions have
been put-forward together with theoretical and experimental supports. Please state these factors.

a) quadrupole-quadrupole interaction b) London dispersion

2. In connection with the van der Waals radius in contrast with hydrogen bonds, please state the
key difference in the contribution towards these weak interactions.

π-π interactions occur outside of van der Waals radii of carbon atoms, so higher-order interactions
must be envoked to interpret them, which are very challenging to model using computations.

3. In connection with Question 1, the preferred conformation (both computationally and

experimentally) have been suggested and rationalized. Please illustrate these conformations and the
corresponding rationale.

① Conformations:
a) Parallel-displaced conformation b) T-shaped conformation

② Rationale: based on benzene's quadrupole moment, with the (+) charge at the edge of the ring
and (-) charge on the faces of the ring:
4. Substituent effects also played a key role in establishing the key π-π interactions. Please state
the substituent trend for substituted benzene vs benzene and substituted benzene vs
hexafluorobenzene, and the model to rationalize these trends.

① Substituted benzene vs benzene: ↑ EWG ⇒ ↑ interaction

② Substituted benzene vs. hexafluorobenzene: ↑ EWG ⇒ ↓ interaction
③ Model: The partial (+) charge of the EWG placed on the benzene will interact with the face of
the other ring → good for benzene (-+-) but not good for hexafluorobenzene (+-+)

5. A clear correlation between π-π interactions and HX-π interactions has been established. Please
explain the significance of this correlation.

This correlation emphasizes that the substituent itself, and not the effect of the substituent on the
benzene ring, is important in determining the effect of the substituent in the interaction energy of
benzene-substituted benzene complexes.
6. Probing weak interaction is an extremely scientifically and intellectually challenging exercise, and
several contrived models were synthesized and studied. Please pick two models and discuss their
rationale and flaws.

① 1,8-Diaryl naphthalene (1992):

a) Rationale: barrier to rotation due to loss of π-π stacking in the TS; higher barrier if X=EWG
b) Flaws: merely seems to be measuring the difference between sandwich and T-shaped orientations
(not the strength of π-π stacking itself)
② Molecular torsion balance (1994):

a) Rationale: folded/unfolded ratio can be measured by NMR, can reflect π-π stacking itself
b) Flaws: the ratio will be affected (decreased) due to competition with NMR solvent; can be offset
by placing EWG on edge ring or EDG on face ring

7. In contrast with hydrogen-bonds and π-π interactions, factor(s) contributing to cation-π interaction
are intuitively easier to conceive and rationalize both theoretically and experimentally. State these
factor(s), and once again state the significance with regards to the distance of these interactions and
the van der Waals radius.

① Factors: a) ion-quadrupole interaction b) NBO charge transfer

② Relation with vdW radius: cation-π interactions occur within the vdW radii of relevant species, so
there is no need to invoke higher-order interactions
8. Substituent effect in cation-π interaction can also be easily rationalized based on the interaction
model proposed. Please state the substituent trend and the interaction model.

① Substituent trend: ↑ EDG → ↑ interaction

② Interaction model: the substituent superimposes an ion-dipole interaction along with the existing
ion-quadrupole interaction, and has no additional effect on the ring

9. Once again, a clear correlation between cation-π interactions and cation-HX interactions has been
established. Please explain the significance of this correlation.

This supports the idea that the substituent itself, not the combination of the substituent and the ring,
is important in determining the impact of the ring substituent in cation-π interactions.

10. Cation-π interaction is not limited to benzene and substituted benzene rings, particularly in
biological system where many heteroaromatics are present. Please state and explain the trend of
these heteroaromatics-cation interactions.
[Lecture 24. First-Order Kinetics]

1. In the multi-step reaction shown below, draw an energy diagram to explain the reaction process
and find the rate-determining step/zone for each case where (1) A and B are in pre-equilibrium, and
(2) B is in a steady state. Also, for each case give a rough sketch of the plot that describes the
change in [A], [B], and [C] over time.

(1) Pre-equilibrium: e.g., when [A]0 = 1.0 M, k1 = 10, k-1 = 100, and k2 = 0.1.
In this case, we can treat the first step as an equilibrium where K = k1/k-1.
Thus the rate is v = k2[B] = k1K[A]; in this case following a brief induction period where B builds
up, [A]:[B] ≈ 9:1 is maintained at all times, with the product C accumulating slowly.
The rate-determining zone is between the resting state (B) and the highest-energy TS after it.

(2) B in steady state: e.g., when [A]0 = 1.0 M, k1 = 1, k-1 = 0.01, and k2 = 100.
In this case, B is used up as fast as it is formed, so we can use steady-state approximation:

Since k1 ≪ k-1 +k2, the rate of product formation should equal that of starting-material consumption.

In this case, the rate-determining step is clearly k1.

[Extra Questions]

1. Pearson's hard and soft acid-base concept has been used to determine the equilibrium of Lewis
acid-base complexation. Explain what is meant by "hardness" and "softness" in this case, and how
interactions between hard and soft acids/bases are controlled. Also, describe how hardness can be
quantified according to Koopman's picture.

① a) Hardness: small radius / high Zeff or EN / high oxidation state / low polarizability / high LUMO
(for acid) or low HOMO (for base); b) Softness: opposite of hardness
② Typical examples (soft…hard order); I- > Br- > Cl- > F- / CH3- > NH2- > OH- > F- /
R3Sb > R3As > R3P > R3N
③ Hard-hard interactions: electrostatically controlled / soft-soft interactions: orbital (HOMO to
LUMO interaction) controlled
④ Koopman's picture: IP correlate with HOMO energy / EA correlate with LUMO energy, so
(absolute hardness) = EA-IP (larger HOMO-LUMO gaps ⇔ harder reagent)

2. Adonesine triphosphate (ATP) is considered as an "energy currency" in biological systems due to

its ability to efficiently store large amounts of energy in its weak P-O bond.
(1) Explain why the P-O bond in ATP is weak.
(2) The statement often found in biochemistry textbooks which say that "energy is released when
the P-O bond is broken" is actually flawed. Explain.

(1) The bonding is hypervalent (3c2e), and is thus substantially ionic. More ionic bonds tend to be
stronger. In ATP, the (-) charge on oxygen is delocalized into the neighboring oxygen, so there is
less ionic character and the bond is weak. In ADP, there is only one hydrogen, so there is more
negative charge on oxygen. So, the O-P bond in ADP is strong.

(2) Energetics of ATP hydrolysis:

① Breaking of bonds does not release energy.
② The number of O-H and O-P bonds is conserved throughout the reaction.
③ During the reaction, weak O-P bonds in the reactants are replaced by stronger O-P bonds in the
products.
④ Conversely, strong O-H bonds in the reactants are replaced by weaker O-H bonds in the
products.
⑤ Evidently, the benefit of ③ outweighs the cost of ④.
3. What is the energy barrier for an elementary unimolecular reaction that goes to completion within
24 hours at room temperature, 298 K? (Assume this means five half-lives and value of the
transmission coefficient κ = 1).

The relevant equations: Eyring equation & half-life equation for first order reactions

24 hours = 24×60×60 = 86400s, so one half life is 17280s.

Therefore, k = ln2 / (17280s) = 4.01×10-5 s-1, and...

This works out to a barrier of 23.5 kcal/mol.

4. Suppose an elementary unimolecular reaction goes to completion within six hours at 298 K. If the
temperature is raised to 50°C, how long will the reaction take? Again, assume that this means five
half hours and κ = 1.

From Question 3, this corresponds to a barrier of 22.6 kcal/mol. The equation to be solved is:

One finds that the reaction will now take 17 minutes.

5. Answer the following questions about the equilibrium system A ⇄ B:

(1) How much free energy corresponds to a 1:10 ratio of A:B at 298 K?
(2) What ratio of A:B will an energy difference of 1.4 kcal/mol correspond to at 195 K (-78°C)?

(1) ΔG° = -RTlnK = -1.99(298)ln(10) = -1.4 kcal/mol

(2) Assuming standard conditions, -1400 = -1.99(195)ln(x)
This works out to x = 37, so the ratio is 1:37
6. Consider an irreversible conversion from unimolecular reactant A to product B:

(1) Write the rate equation for this reaction.

(2) Derive the integrated rate law, which is an expression for [A] in terms of time.
(3) What is the half life of the reaction in terms of k, the rate constant?

(1) v = d[B]/dt = -d[A]/dt = k[A]

(2) We need to integrate both sides of the answer to part (1):

Here [A]0 is the original concentration of A.

(3) We need to ask what value of t will give a concentration of [A] = [A]0/2:
7. Consider a unimolecular scenario where species A and B can interconvert reversibly:

(1) Assume that k1 = 1 s-1, k-1 = 0.1 s-1, [A]0 = 1.0 M, and [B]0 = 0.001 M. Which of the following
curves most likely describes the change in [A] over time? Choose one option from A-D below.

(2) Explain your choice in part (1).

(1) B
(2) We use the strategy of elimination:
① The equilibrium ratio of [A] and [B] is K = [B]/[A] = k1/k-1 = 1/0.1 = 10.
Since the total mass balance is 1.001 M, the final equilibrium ratio will be about 9% A and 91% B.
So, this rules out options A and D (too little/too much respectively).
② To distinguish between B and C, we need to know how fast equilibrium is approached. In B, this
is done in ~3 s, compared to ~1 s of option C. Intuitively, we expect that the rate of approach to
equilibirum will be slower than the forward rate itself, due to the reverse reaction. This means that
B is a more appropriate choice.
③ Quantitatively, the mass balance is:

At equilibrium, the forward and reverse rates should be the same so,

Since (flux of A) = (ratio of production of A) - (ratio of expenditure of A),

Integrating both sides over time gives, [A]t = [A]eq + ([A]0 - [A]eq)exp(-(k1 + k-1)t).
So, the characteristic "natural rate constant" k1 + k-1 is larger than k1, but the rate of approach to
equilibrium is smaller than the forward rate. Here, this would be 1.1 s-1, which corresponds to a
half-life of 0.63 s. Assuming 5 half lives for full conversion, the expected time to equilibrium is
about 3 seconds.
8. Consider the following catalytic cycle for an enzyme.

(1) Write the rate law under the pre-equilibrium (k2 ≪ k-1) scenario.
(2) Write the rate law under the steady-state approximation (k2 ≫ k-1) scenario.
(3) Explain what happens when [S] is small and large in pre-equilibrium scenario respectively.

(1) Under the pre-equilibrium assumption, K = [ES]/[E][S]

Using this, we can write v = d[P]/dt as

The last substitution is necessary since [E] is not really easy to measure, whereas [S] is.
The mass balance for the enzyme is applied here:
ET = [E] + [ES] = [E] + K[E][S], so [E] = ET/(1+K[S])
(2) Here, we guess that [ES] is constant since enzyme-substrate complex would be broken down as
fast as it is formed:

Now, we can apply the same kind of algebra:

(3) In pre-equilibrium scenario, the numerator indicates the "things that are needed for the reaction"
(enzyme: ET, substrate: [S], pre-equilibrium constant: K, final rate constant: k2). The denominator
indicates "all the states of the enzyme" (free enzyme: 1, enzyme-substrate complex: K[S]).
① When [S] is small, the denominator approximates to 1, so v = k2K[S]ET (1st order in substrate).
② When [S] is large, the K[S] terms will cancel, giving v = k2ET (0th order in substrate).
9. The Heck reaction, one of the most useful tools in aryl coupling chemistry, can be modelled as
the pre-equilibrium system below. Please work out the "1-plus" rate law for this system.

Under the pre-equilibrium assumption, K1 = [CA]/[C][A] and K2 = [CB]/[CA][B]

Using this, we can write v = d[P]/dt as
v = k3[CB]
v = k3K2[CA][B]
v = k3K2K1[C][A][B]
However, CT = [C] + [CA] + [CB] by mass balance so
CT = [C] + K1[C][A] + K2[B][CA]
CT = [C] + K1[C][A] + K2K1[C][A][B]
So the final rate law is

We can also use the "1-plus" mnemonic: the numerator indicates all things that are needed for the
reaction, and the denominator represents the status of the catalyst (free, bound to A, bound to B
respectively).
[10-12] Consider the following model of the Heck reaction:

Assume that A represents the aryl halide, B represents the olefin, and C represents the catalyst.
The first step indicates oxidative addition, and the second step indicates the sequential insertion and
reductive elimination. Below are concentration-time and rate-concentration plots for this reaction:

Now answer the below questions regarding such a reaction progress kinetics experiment.

10. Explain why the second plot has two linear regions with different slopes. Why does the first
region (on the right) have a non-zero intercept?

① pre-equilibrium scenario (k2 ≪ k-1) → "1-plus" rate law holds:

since K1 = k1/k-1 = 100, and [A] = 0.16 so K1[A] ≫ 1 (i.e., catalyst is saturated at early time)
→ rate law can be approximated as 1st order to [B] and [C]T respectively:

② since 1 molecule of B is turned over every time 1 molecule of A is turned over,

[B] - [A] = e ("excess"; a constant)
using this, the rate law can be written as a linear equation with respect to [A]:

the excess of B throughout most of the reaction means the intercept is non-zero
③ as the reaction nears completion, [A] drops, and the catalyst is no longer saturated; in such case
the rate law is approximated as

This is a different linear equation; the curved part is the transition region between the two cases
11. Obviously, the rate-concentration plots of the same reaction with different amounts of [A]0 and
[B]0 but same initial excess ([B]0-[A]0) should show an overlay, as below:

Now consider the cases where deactivation of the catalyst occurs. How would the result of this
"same-excess" experiment in each of the cases below? Make a rough sketch of the plot and explain
why.
(1) Irreversible catalyst deactivation (2) Reversible catalyst deactivation

(1) Overlay will not be observed because, by the time [A] reaches 0.10 M in experiment 1, a
significant portion of catalyst would have been deactivated. In contrast, all catalyst would be intact
at the start of experiment 2, so the rate would be higher. Overall the curve for experiment 1 would
be shifted to the right compared to that for experiment 2:

(2) Overlay will be observed, but the overall rate will be slower than when the inhibitor is absent.

So the lack of overlay only means the lack of "irreversible" catalyst deactivation.
12. Now, let's consider the scenario where deactivation of the catalyst is caused by the product.
What would be the result of the "same-excess" experiment presented below? Make a rough sketch
of the plot and explain why.

No overlay will be observed in this case also. By the time experiment 1 gets to [A] = 0.10 M,
some product would have formed, so [P] = 0.06 M. However, experiment 2 will start from this point
without any product present, so initially deactivation should not occur. Therefore, experiment 2
should show a higher rate at same [A]. The control experiment in this case, thus, is to add the
amount of product corresponding to the stoichiometric excess to experiment 2.