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The Molecular Modeling Workbook for Organic Chemistry - Hehre J.W.

Hehre J.W., Shusterman J.A. The Molecular Modeling Workbook for Organic Chemistry - Wavefunction, 1998. - 307 p.
Download (direct link): molecularmodelingworkbook1998.djvu
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each reagent (this is the LUMO or lowest-unoccupied molecular orbital),
and identify the best electron acceptor site in each. (Hint: Display the
molecule as a space-filling model to see LUMO sites that are most
available for intermolecular attack.) Is the LUMO bonding or antibonding
with regard to the sulfur-chlorine (phosphorus-chlorine) bond? What
bonding changes should accompany alcohol attack? Base your answer on the
LUMO shape.
Alcohol attack generates an unstable intermediate that undergoes
nucleophilic attack by Cl- at carbon. Compare electrostatic potential
maps of methanol, thionyl chloride intermediate, and phosphorus
trichloride intermediate. What features of these maps are consistent with
an electrophilic reactive intermediate?

Electrostatic potential map for phosphorus trichloride shows negatively-
charged regions (in red) and positively-charged regions (in blue).

LUMO of thionyl chloride reveals the best electron-acceptor sites.
Chapter 8 Alcohols and Ethers 125
Activating Oxygen as a Leaving Group
E(tert-BuOH) = -230.8738 au E(OH ) = -74.8686 au
Neutral alcohols, ROH, and ethers, ROR, do not undergo either
substitution or elimination reactions, presumably because OH (OR-) is a
poor leaving group. Acids can "activate" OH (OR) by converting it into a
better leaving group.
The simplest way to assess "leaving group ability" is to calculate the
energetics of dissociation leading to a carbocation (the first step in an
SN1 substitution), relative to that of a "standard", e.g., dissociation
of tert- butyl alcohol to 2-methyl-2-propyl cation and hydroxide anion.
Consider as substrates protonated tert-butyl alcohol, tert-butyl methyl
ether,protonated tert-butyl methyl ether, tert-butyl acetate and tert-
butyl tosylate (leading to water, methoxide anion, methanol, acetate
anion and tosylate anion as leaving groups). Calculate dissociation
energies relative to tert-butyl alcohol, i.e., substrate + hydroxide ->
tert-butyl alcohol + leaving group. (Energies for hydroxide and tert-
butyl alcohol are provided at left.) Are these results consistent with
the observation that neutral alcohols and ethers are relatively
unreactive? Are all of the other groups good leaving groups, or are some
much better than others?
It is frequently said that "a good leaving group is the conjugate base of
a strong acid." Look up pKa values for the conjugate acids of the leaving
groups. To what extent can you use pKa values to predict leaving group
126 Chapt er 8 Alcohols and Ethers
Cleavage of an Unsymmetric Ether
Unsymmetric ethers, ROR', react with HI by a protonation-substitution
mechanism that can lead to two different product combinations.
Interestingly, some unsymmetric ethers undergo selective cleavage and
give only one of the two possible product combinations.
Consider the reaction of ethyl propyl ether with HI. Write the two
different possible product combinations. Compare the energies of the two
products {1-propanol and ethyl iodide; ethanol and 1-propyl iodide).
Which is the lower-energy combination? Is the energy difference
significant (>.002 au or 1 kcal/mol)? Based on thermochemistry alone, is
this reaction likely to be selective? Explain.
Selective ether cleavage comes about during the substitution step, which
obeys an SN2 mechanism. Therefore, selective cleavage requires selective
attack by A on one of the electrophilic carbons in the protonated ether.
Determine if selective attack is likely by examining the shape of the
lowest-unoccupied molecular orbital (LUMO) in protonated ethyl propyl
ether. Is this orbital larger near one carbon than the other? If so, what
product combination will result? What other atom(s) contribute to the
LUMO? What would happen if 1" attacked this atom(s)?
Repeat this analysis for the reaction of phenyl methyl ether with HI
leading to phenol and methyl iodide or methanol and phenyl iodide and
involving protonated phenyl methyl ether as an intermediate. (Note: In
this case, the appropriate empty molecular orbital is LUMO+2; the LUMO is
concentrated primarily on the CO bond.) Which reaction, with ethyl propyl
ether or phenyl methyl ether, appears to be more likely to give selective
ether cleavage?
LUMO of protonated ethyl propyl ether reveals likely site of nucleophilic
LUMO+2 of protonated phenyl methyl ether reveals likely site of
nucleophilic attack.
Chapter 8 Alcohols and Ethers 127
Electrostatic potential map for 2,3-dimethyl-3-hydroxy-2-butyl cation
show most positively-charged regions (in blue) and less positively-
charged regions (in red).
E(H20) = - 75.5860 au
The Pinacol Rearrangement
The pinacol rearrangement is a dehydration reaction that converts a 1,2-
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