chem 232 problem set 4 key - chemistry | university of...
TRANSCRIPT
Chem 232 D. J. Wardrop
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.
!