Chem 232 D. J. Wardrop

wardropd@uic.edu

Problem Set 4 Answers

Does the nucleophilic substitution of substrate X proceed via an SN2 or SN1 mechanism? is a perennialquestion in Organic Chemistry. Use the table below as a guide to the likelihood of each mechanismtaking place for a given substrate.

Table. Substrate Types and the Choice of SN1 of SN2

Type of electrophiliccarbon atom

SN1 mechanism? SN2 mechanism?

methyl (CH3-X) no very good

primary alkyl (RCH2-X) no good

secondary alkyl (R2CH-X) yes yes

tertiary alkyl (R3C-X) very good no

allylic (CH2=CH-CH2-X) yes good

benzylic (ArCH2-X) yes good

Question 1.

a. An aqueous solution containing 10 g of optically pure (2S,3R)-2-chloro-5-hexyne-3-ol was diluted to 5 dL with CHCl3 and placed in a polarimeter tube 5 cm long. The measured rotation was –5.50º. Using the equation below, determine the specific rotation ([α]D). Hint: all values have been given withthe correct units for use in the equation below.

[α]D = -55 [(100 X -5.5 °)/(2 g/dL x 5 cm)]

b. The solution above was mixed with 5 dL of a solution containing 20 g of racemic 2-chloro-5-hexyne-3-ol. Calculate the enantiomeric excess (ee) of this solution.

The quantity of solvent in this question is a red herring. The enantiomeric excess of a givenmixture of enantiomers is independant of the volume of solvent in which they find themselvesdissolved in.

Enantiomeric excess in this case = 33.3%

[(20 grams of (2S,3R) - 10 grams of (2R,3S)]/[(30 grams of (2S,3R) and (2R,3S)] x 100 = 33.

c. Draw the structural formula for (2S,3R)-2-chloro-5-hexyne-3-ol.

(2S,3R)-2-chloro-5-hexyne-3-ol

OH

Cl

d. What is the stereochemical relationship between (2S,3R)-2-chloro-5-hexyne-3-ol and (2R,3R)-2-chloro-5-hexyne-3-ol?

(2S,3R)-2-chloro-5-hexyne-3-ol

OH

Cl

(2R,3R)-2-chloro-5-hexyne-3-ol

OH

Cl

Diastereomers(any stereoisomers not related as object and mirror image

Question 2.

Upon heated in a solution of sodium ethoxide in ethanol, compound 1 (C7H15Br) underwent reaction toyield a mixture of alkenes 2 and 3, which both have the molecular formula C7H14. Catalytichydrogenation of both 2 and 3 gave only 3-ethylpentane. Suggest structures for compounds 1, 2 and 3consistent with these observations.

C7H15Br C7H14 (alkene)

2C7H14 (alkene)

3

EtONa

3-ethylpentane3

1

Br

Question 3.

The following sequence of reactions form part of a total synthesis of the powerful anticancer agent fumagillol (4).

OHOH

MeO HHO

1

TsCl, Et3N

pyridine, CH2Cl2r.t., 12 h

2(C21H30O6S)

t-BuOK

t-BuOH, r.t.88%, 2 steps MeO H

HO

3

O

MeO HHO

4

O

O

OHO

MeO HHO

SO

OMe OH

O

H

Ts

a. Draw the structure of intermediate 2.

b. Draw a reasonable arrow-pushing mechanism for the conversion of 2 to epoxide 3.

e. Using the Cahn–Ingold–Prelog (CIP) priority rules, determine the absolute configuration and assignan R or S descriptor to each chirality center in 4.

MeO HHO

O

OS

R

RRRS

(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-ol

Question 4.

Two common tests for alkyl chlorides used in undergraduate laboratories is to treat them with a solutionof silver nitrite (AgNO3) in ethanol or a solution of NaI in acetone. The reactions give an alkyl nitrate andan alkyl iodide, respectively. Both inorganic products, AgCl and NaCl precipitate out of their respectivesolvents, thereby providing a visual confirmation that an alkyl chloride reacted. Tertiary, secondary andprimary alkyl chlorides can be distinguished from one another by the relative rates of precipitation. Therate of precipitation of AgCl in ethanol is fastest for tertiary alkyl chlorides; primary alkyl chlorides do notreact at all. This trend is reversed for the NaI test. Here, primary alkyl chlorides react fastest; tertiaryalkyl chlorides do not react at all. Answer the questions below based on these observations.

R Cl + AgNO3 R ONO2 + AgCl(s)

R Cl + NaI R I + NaCl(s)

solvent = ethanol

solvent = acetone

SN1

SN2

a. Write the mechanistic descriptor (SN1, SN2, E1, E2, or AdE) for each reaction in the box above thereaction arrows.

see answer above

b. Provide a detailed explanation that accounts for the observed trend in precipitation rate when alkylhalides react with AgNO3 in ethanol. Use complete sentences.

As you may recall from descriptions of gravimetric analysis, silver(I) ions have a very highaffinity for halide anions, with which they form salts with high lattices enthalpies (NaCl = -787kJ/mol; KCl = -718 kJ/mol; AgCl = -916 kJ/mol). In Organic Chemistry, this behavior can beused to promote the solvolysis of alkyl halides, which undergo reaction with Ag(I) ions to formcarbocations (see mechanism below). For a given series of substrates with the same halide

leaving group, the rate at which this process occurs will depend largely on the stability of thecarbocation formed upon departure of the halide (Hammond's postulate). Capture of thecarbocation by the nitrate counter ion generates the observed alkyl nitrate products.

As with the solvolysis of alcohols in aqueous acids, tertiary alkyl chlorides react fastest withAg(I) ions followed by secondary substrates. Primary alkyl chloride do not react since even withthe encouragement of Ag(I) ions, the resulting primary cations are just too unstable to beformed at an appreciable rate.

c. Provide a detailed explanation that accounts for the observed trend in precipitation rate when alkylchlorides react with NaI in acetone. Use complete sentences.

The basis of the NaI text is the Finkelstein reaction, in which an alkyl chloride is converted tothe corresponding alkyl iodide through bimolecular nucleophilic substitution (SN2) with an iodideanion. The qualitative test can identify the degree to which the alkyl chloride is substitutedsince SN2 reactions are highly sensitive to steric effects at the electrophilic carbon at(remember the TS has five groups surrounding a single carbon atom). Primary (1 °) alkylchlorides react fastest with iodide, followed by secondary (2°), with tertiary alkyl chlorides notreacting at all.

Question 4.

Draw the major organic product for each of the reaction schemes below. Where appropriate, ensure thatyou include the stereochemistry of the product.

1. Br2, CH2Cl2

2. t-BuOK

Br

Br

H

H

Br

H

syn-elimination isless favored than

anti process

Br

not observed

1. HBrOH2. t-BuOK

3. H2, Pd-C

Br

HN

N

O

O

OH

Me

1. MsCl, pyridine

2. t-BuOK

HN

N

O

O

OMs

Me

HN

N

O

OMe

1. HBr, H2O2

2. NaCN, DMFBr CN

Na2S

(S2- anion)

TsO OTs

C9H18SS

S R

SR

ClMeNaOMe

MeOH

AcOH OMe Me

O

Me

OTs

OO

OBnNaCN

DMF

CN

OO

OBn

Question 5.

a. Rank each compound/anion in order of increasing nucleophilicity (1 = least nucleophilic; 5 = most nucleophilic).

H3C ONa

O

NaSH CH3OH NaBr H3C OH

O

5 12 34

b. Rank in order of increasing rate of SN2 substitution (1 = slowest rate; 5 = fastest rate).

Br Br H3CBr

Br Br

12543

c. Rank each carbocation in order of increasing stability (1 = least stable; 4 = most stable).

H3C CH3

CH H

C CH3H3C H

C CH3

CH3

C CH3

421 3

d. Rank the rate of SN1 substitution in each of the solvents below. (1 = slowest rate; 4 = fastest rate).

(ε = 6) (ε = 33) (ε = 78) (ε = 58)

O

H3C OH H3C OH H O HO

H OH

421 3

e. Rank in order of increasing leaving group ability (1 = poorest leaving group; 5 = best leaving group).

S OO

OH3C F H O H Br

S OO

OF3C

1 324 5

Question 6.

Salacinol (4) was isolated by Muraoka and co-workers in 1997 from the dried roots and stems of Salaciareticulata (Kotala himbutu in Singhalese), a large climbing plant found throughout the forests of SouthernIndia and Sri Lanka. Extracts of this herb, prepared by soaking the bark and roots in water overnight,have long been employed in traditional Indian, or Ayurvedic, medicine for the treatment of type IIdiabetes. Shown below is a total synthesis of this natural product.

SBnO

OBnBnO

S

OBnBnO

BnOO

OO

Ph

OO

OS

O

O O

Ph

SO

O O+

S

OHHO

HOO

OHOH

SO

O O

1 2 3 (33%)

4

acetone(solvent)

75 °C, 12 h

OBnO

OBnBnO5

+

a. Write reasonable arrow-pushing mechanism for the reaction of 1 and 2 to form sulfonium-sulfate salt 3.

Despite having an unfamiliar look, cyclic sulfates behave entirely like alkyl sulfonates and areemployed to active hydroxyl groups to nucleophilic substitution. The reaction of 1 with 2proceeds through an SN2 mechanism at the less sterically hindered, primary carbon. What reallydistinguishes this process from the nucleophilic substitutions discussed in class is that theleaving group is still bonded to the substrate after it leaves - in this case, it's fortuitous sincethe natural product has a sulfate group!

b. Indicate how many stereogenic (chiral) centers are present in salacinol (4), noting that the sulfonium ion center (R3S+) is itself a stereogenic center.

There are six chiral, or stereogenic, centers in salicinol (4): five carbon and one sulfur-basedcenter. Sulfonium ions (but not thioethers) are potentially chiral since it is possible (unlikethioethers) to have four distinct ligands, including one lone pair, attached to the sulfur atom.

c. Using the Cahn–Ingold–Prelog (CIP) priority rules, determine the absolute configuration and assign an R or S descriptor to each chirality center in 1, 2, 4 and 5. Note that under the CIPS rule, lone pairs(:) are assigned a lower priority than hydrogen atoms.

SBnO

OBnBnO

OO

OS

O

O O

Ph

1 2

S

OHHO

HOO

OHOH

SO

O O

4

+ OBnO

OBnBnO

5

R

S S

SR

S S

R S S

R

S S

d. Provide a simple explanation as to why cyclic sulfate 2 undergoes nucleophilic substitution with thioether 1, but is inert to cyclic ether 5.

Thioethers are more nucleophilic than ethers because the non-bonding electrons on sulfur arehigher in energy and thus more easily donated to the carbon electrophile.

Sulfur is a better nucleophile than oxygen since it is a less electronegative element.

!