Chem 232

Problem Set 4 Answers

D. J. Wardrop wardropd@uic.edu

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

Table. Substrate Types and the Choice of SN1 of SN2

Type of electrophilic carbon atom methyl (CH3-X) primary alkyl (RCH2-X) secondary alkyl (R2CH-X) tertiary alkyl (R3C-X) allylic (CH2=CH-CH2-X) benzylic (ArCH2-X) SN1 mechanism? no no yes very good yes yes SN2 mechanism? very good good yes no good 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 5.50. Using the equation below, determine the specic rotation ([]D). Hint: all values have been given with the correct units for use in the equation below. []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-5hexyne-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 given mixture of enantiomers is independant of the volume of solvent in which they nd themselves dissolved 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)-2chloro-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 to yield a mixture of alkenes 2 and 3, which both have the molecular formula C7H14. Catalytic hydrogenation of both 2 and 3 gave only 3-ethylpentane. Suggest structures for compounds 1, 2 and 3 consistent with these observations.
Br EtONa 1 C7H15Br 2 C7H14 (alkene) 3 C7H14 (alkene)

3 3-ethylpentane

Question 3.

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

OH OH HO MeO H 1 O t-BuOK t-BuOH, r.t. 88%, 2 steps HO MeO 3 H TsCl, Et3N pyridine, CH2Cl2 r.t., 12 h HO MeO

OH

O O S O

Me 2 (C21H30O6S)

OH O Ts H

HO MeO

H 4

a. b.

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

e.

Using the CahnIngoldPrelog (CIP) priority rules, determine the absolute conguration and assign an R or S descriptor to each chirality center in 4.
O
R R S R

HO S H MeO

O
R

(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 solution of silver nitrite (AgNO3) in ethanol or a solution of NaI in acetone. The reactions give an alkyl nitrate and an alkyl iodide, respectively. Both inorganic products, AgCl and NaCl precipitate out of their respective solvents, thereby providing a visual conrmation that an alkyl chloride reacted. Tertiary, secondary and primary alkyl chlorides can be distinguished from one another by the relative rates of precipitation. The rate of precipitation of AgCl in ethanol is fastest for tertiary alkyl chlorides; primary alkyl chlorides do not react at all. This trend is reversed for the NaI test. Here, primary alkyl chlorides react fastest; tertiary alkyl chlorides do not react at all. Answer the questions below based on these observations.

SN1 R Cl + AgNO3 solvent = ethanol R ONO2 + AgCl(s)

SN2 R Cl + NaI solvent = acetone R I + NaCl(s)

a.

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

b.

Provide a detailed explanation that accounts for the observed trend in precipitation rate when alkyl halides react with AgNO3 in ethanol. Use complete sentences. As you may recall from descriptions of gravimetric analysis, silver(I) ions have a very high afnity for halide anions, with which they form salts with high lattices enthalpies (NaCl = -787 kJ/mol; KCl = -718 kJ/mol; AgCl = -916 kJ/mol). In Organic Chemistry, this behavior can be used to promote the solvolysis of alkyl halides, which undergo reaction with Ag(I) ions to form carbocations (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 the carbocation formed upon departure of the halide (Hammond's postulate). Capture of the carbocation 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 with Ag(I) ions followed by secondary substrates. Primary alkyl chloride do not react since even with the encouragement of Ag(I) ions, the resulting primary cations are just too unstable to be formed at an appreciable rate.
c.

Provide a detailed explanation that accounts for the observed trend in precipitation rate when alkyl chlorides 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 to the corresponding alkyl iodide through bimolecular nucleophilic substitution (SN2) with an iodide anion. The qualitative test can identify the degree to which the alkyl chloride is substituted since SN2 reactions are highly sensitive to steric effects at the electrophilic carbon at (remember the TS has ve groups surrounding a single carbon atom). Primary (1 ) alkyl chlorides react fastest with iodide, followed by secondary (2), with tertiary alkyl chlorides not reacting at all.

Question 4.

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

syn-elimination is less favored than anti process H

Br not observed Br Br 2. t-BuOK

1. Br2, CH2Cl2

Br H

OH

1. HBr

Br

2. t-BuOK 3. H2, Pd-C

O HN O N Me OH 1. MsCl, pyridine HN O

O OMs N Me 2. t-BuOK HN O

N Me

1. HBr, H2O2

Br 2. NaCN, DMF

CN

TsO
S

OTs
R

Na2S
R S

(S2- anion)

S C9H18S

Me

NaOMe MeOH

Me

Cl

AcOH

Me

Me O

OTs O O OBn NaCN DMF O O

CN OBn

Question 5. a.

Rank each compound/anion in order of increasing nucleophilicity (1 = least nucleophilic; 5 = most nucleophilic).
O H3 C ONa NaSH CH3OH NaBr H3 C O OH

4
b.

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

Br

Br

H3C

Br

Br

Br

3
c.

Rank each carbocation in order of increasing stability (1 = least stable; 4 = most stable).
H H3 C C H CH3 H3 C C H CH3 CH3 C CH3 CH3

1
d.

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

O H3 C OH H3C OH ( = 33) H O H

O H OH ( = 58)

( = 6)

( = 78)

e.

Rank in order of increasing leaving group ability (1 = poorest leaving group; 5 = best leaving group).
O H3 C S O O O O F3 C S O O

Br

Question 6.

Salacinol (4) was isolated by Muraoka and co-workers in 1997 from the dried roots and stems of Salacia reticulata (Kotala himbutu in Singhalese), a large climbing plant found throughout the forests of Southern India 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 II diabetes. Shown below is a total synthesis of this natural product.
Ph Ph O BnO BnO 1 S OBn O O S 2 OH OH O S O BnO BnO 5 O OBn O O O acetone (solvent) 75 C, 12 h BnO 3 (33%) BnO +S O O OBn O S O O O

HO HO

+S

O O OH

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 are employed to active hydroxyl groups to nucleophilic substitution. The reaction of 1 with 2 proceeds through an SN2 mechanism at the less sterically hindered, primary carbon. What really distinguishes this process from the nucleophilic substitutions discussed in class is that the leaving group is still bonded to the substrate after it leaves - in this case, it's fortuitous since the 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): ve carbon and one sulfur-based center. Sulfonium ions (but not thioethers) are potentially chiral since it is possible (unlike thioethers) to have four distinct ligands, including one lone pair, attached to the sulfur atom.

c.

Using the CahnIngoldPrelog (CIP) priority rules, determine the absolute conguration 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.
Ph
R S

O
S

O HO R HO

OH
S

OH O S O

BnO

R S S

+S
S

O
S O

O O

O O 2

BnO

R O S S

BnO 1

OBn

OH 4

BnO 5

OBn

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 are higher 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.
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