Department of Medical Biochemistry and Biophysics (MBB)
Biomedicine programme (candidate)
General and Organic Chemistry (AOK)
HT13
SEMINAR QUESTIONS
(Seminar 2-19)
KAROLINSKA INSTITUTET
Department of Medical Biochemistry & Biophysics
Biomedical program (Candidate): General and organic chemistry
SEMINAR 2
Lab procedures
1. What do you need to keep in mind when you choose glassware for your synthesis?
2. A student performs a vacuum distillation using a water aspirator (strålpump) to create the
vacuum. A sudden drop in water pressure leads to back-splashing of water - the experiment is
ruined and the student has to start from the beginning. He suddenly realizes that he forgot to
incorporate a piece of equipment in the apparatus that could have prevented the disaster.
What is it?
3. How does one recrystallize the raw product from a synthesis?
4. Why does one sometimes need to perform a vacuum distillation?
What boiling point does a substance have at 10 mm HG when it boils at 250 °C at normal air
pressure?
5. What is the purpose of a TLC and how does it work?
When is it performed?
How is the mobile phase chosen?
How is the result interpreted?
6. When does one use desiccator grease (vakuumfett)? When is it not appropriate to use it?
7. Why are anti-bumping granules used?
How do they work?
Does a magnetic stirrer work equally well?
8. How do you measure up 10 g of a liquid?
Useful literatur:
Labkompendium pages 21-30, 93-95, 112-119
Norin “Elementär kemisk laboratorieteknik”
KAROLINSKA INSTITUTET
Department of Medical Biochemistry & Biophysics
Biomedical program (Candidate): General and organic chemistry
SEMINAR 3
Atom structure and chemical bonds
F&F 1.1, 1.2, 1.4, 1.13, 2.9, 2.24
1.
Which of the following molecules are dipoles: chlorine gas, hydrogen chloride,
chloroform (trichloromethane), carbon tetrachloride (tetrachloromethane)? Explain
your answer.
2.
Which of the following molecules has a dipole moment? Indicate the direction of
each.
OH
HO
OH
OH
HO
3.
H2 forms a stable diatomic molecule but He2 does not. Why is that? Explain with the
help of molecular orbitals!
4.
Why does the electron negativity of the elements increase when one goes up/to the
right in the periodic system?
5.
What kind of hybridization do you expect for each carbon atom in: A) vitamin C
(ascorbic acid), B) aspirin (acetylsalicylic acid)?
HO
O
OH
O
HO
O
O
O
HO
OH
A
6.
B
A lab technician accidentally mixed two substances, glucose and stearic acid
(CH3(CH2)16COOH). How can the substances easily be separated again?
KAROLINSKA INSTITUTET
Department of Medical Biochemistry & Biophysics
Biomedical program (Candidate): General and organic chemistry
SEMINAR 4
Structural isomerism, alkanes
F&F 2.16, 2.33, 3.1, 3.5, 3.7, 3.9
1. Name the following compounds!
a)
CH2
C
CH2
CH3
CH
CH3
CH2
CH3
b)
CH3
CH3
c)
CH3
CH3
CH3
CH3
CH
C
CH
CH2
CH3
CH3
d)
C
C
C
CH3
CH3
e)
g)
f)
C
OH
O
H
i)
OH
h)
I
Br
Br
2. Identify the carbon atoms in the following molecule as primary, secondary, tertiary or
quaternary.
CH
CH
3
H3C
C
H
3
H2
C
C
CH3
CH3
3. Draw structural formulas for 4 compounds that have the empirical formula C3H6O!
4. Oxaloacetic acid, an important intermediate in food metabolism, has the formula C4H4O5 and
contains three C=O bonds and two O-H bonds. Propose two possible structures.
5. What does ”trivial name” mean? Give the trivial names for the following compounds: a) 2propanone; b) 2-propen-l-ol; c) propanal; d) propanoic acid; e) 2-propenoic acid; f) ethanoic
acid!
KAROLINSKA INSTITUTET
Department of Medical Biochemistry & Biophysics
Biomedical program (Candidate): General and organic chemistry
SEMINAR 5
Stereo isomerism, conformations
F&F 4.2, 4.3, 4.6, 4.40, 4.47, 4.7, 4.8, 4.9, 4.33
1.
Rank the substituents in each of the following sets according to the Cahn-Ingold-Prelog
rules:
a) –H, -OH, -CH2CH3, -CH2CH2OH
b) –CO2H, -CO2CH3, -CH2OH, -OH
c) –CN, -CH2NH2, -CH2NHCH3, -NH2
2.
Alanine, an amino acid found in proteins, is chiral. Draw the two enantiomers of alanine
using the standard convention of solid, wedged, and dashed lines. Which has Rconfiguration and which has S-configuration?
NH2
Alanine
H3C
C
H
COOH
3.
Build models of (2Z,6Z)-2,6-nonadiene and (2E,6E)-2,6-nonadiene.
Compare the lengths of the molecules – which isomer is longer and why?
4.
Build a model of (2R,3R)-2,3-dihydroxybutyric acid. Indicate the stereo chemistry of the
molecules using the Fischer system!
5.
Build models of (2R,3R)-tartaric acid and (2R,3S)-tartaric acid. Which of the molecules has
a symmetry plane? What is meant with meso-form? How many stereoisomers of tartaric
acid exist?
6.
Build a model of butane. Rotate the bond between C-2 and C-3 and
identify anti, gauche and the two eclipsed conformations!
7.
Build models of cis-1,3-dimethylcyclohexane and trans-1,3-dimethylcyclohexane.
One of the two isomers is more stable than the other. Which? Why? Study the
conformations by turning one chair conformation into the other and looking at the axial and
equatorial bonds. Draw plane formulae, stereo formulae and Newman projections!
KAROLINSKA INSTITUTET
Department of Medical Biochemistry & Biophysics
Biomedical program (Candidate): General and organic chemistry
SEMINAR 6
Thermodynamics & kinetics
1. For a reaction at standard conditions, calculate:
a) ΔS°, if ΔH° = 65.1 kJ/mol and ΔG° = 68.7 kJ/mol
b) ΔG°, if ΔH° = -37.3 kJ/mol and ΔS° = -146.6 J/(mol*K)
c) ΔH°, if ΔS° = 156.4 J/(mol*K) and Keq = 0.668
2. During aerobic metabolism in living cells (cell respiration), glucose is broken down to release
energy that then can be used to drive many energy-requiring processes. The energy currency
is called ATP, adenosintriphosphate. In the cell 38 ATP-molecules are formed per degraded
glucose molecule. Theoretically, what is the maximum number of ATP-molecules that could
be formed? How many percent of the energy of a glucose molecule are effectively used by
the cell (energy efficiency of the cell)? What happens with the rest of the energy?
ATP + H2O → Pi
Glucose + 6O2 → 6CO2 + 6H2O
G° = -30,5 kJ/mol
G° = -2840 kJ/mol
3. Calculate, from the free energies for formation (fG), the G for the reaction
CH4(g) + 2 O2(g)  CO2(g) + 2 H2O(l)
fG for H2O = -237,1 kJmol-1
fG for CO2 = -394,4 kJmol-1
fG for CH4 = -50,7 kJmol-1
Is the equilibrium constant K larger or smaller than 1?
How is K affected by an increase in pressure?
4. When pure acetic acid (CH3COOH) is poured into water, the two equilibria 1& 2 shown
below are reached. Assume that the reactions take place at standard conditions.
a) Calculate ΔH, ΔS and ΔG for reaction 1. Will the water become warmer or colder when the
acetic acid is mixed in? Why is it important to poor the acid into the water, and not vice versa
(SIV)? What happens with the entropy during reaction 1 and how can it be explained? Is
reaction 1 spontaneous? What does that mean for the equilibrium?
b) Calculate ΔH, ΔS, ΔG and the equlibrium constant for reaction 2. What happens with the
entropy in this case and why is that so? What is the concentration of H+ if one dissolves a
total of 0.1 mol acetic acid in 1 l water at 25 ºC, 1 atm? (use the formula for second degree
equations or make an approximation). What pH would it correspond to?
1. CH3COOH(l)
2. CH3COOH(aq)
CH3COOH(aq)
CH3COO-(aq) + H+(aq)
Thermodynamic data:
CH3COOH(l)
CH3COOH(aq)
CH3COO-(aq)
H+(aq)
5.
ΔfH0 (kJ/mol)
-484,5
-485,76
-486,01
0
S0 (J/(K*mol))
159,8
178,7
86,6
0
Based on previous knowledge about water (general education) combined with your
knowledge of thermodynamics, what can you say about magnitude and sign of ΔH, ΔS, ΔG
and the equilibrium constant for the reaction
H2O(g)
H2O(l)
at 1 atm and temperatures
a) 25 ºC
b) 100 ºC
c) 150 ºC
Explain also how ΔG can change sign.
6. The equilibrated mix
SO2(g) + NO2(g)
SO3(g) + NO(g)
contains at 500K 0.30 mol SO3, 0.20 mol NO, 0.05 mol NO2 and 0.40 mol SO2.
a) What is the ΔG of the reaction? Is it spontaneous?
b) How many mol NO have to be added to increase the amount of NO2 to 0.10 mol?
Temperature and pressure are constant.
7. a) The rate, kinetics of a reaction is dependent on three factors. Which?
b) Show with an energy diagram how a catalyst, e.g. an enzyme, can change the kinetics of a
reaction without affecting the equilibrium.
8. Look at the following energy diagram of an enzyme-catalyzed reaction:
a) How many steps are involved?
b) Which step is most exergonic?
c) Which step is the slowest?
Energy Reaction progress KAROLINSKA INSTITUTET
Department of Medical Biochemistry & Biophysics
Biomedical program (Candidate): General and organic chemistry
SEMINAR 7
Alkylhalides, substitution & elimination
F&F 5.3, 5.5, 5.6, 5.7, 5.16
1. Fluoxetine, an antidepressant marketed under the name Prozac, can be prepared by a route
that begins with the reaction between a phenol and an alkyl chloride.
a) The rate of the reaction depends on both reactants. Is this an SN1 or an SN2 reaction?
b) The physiologically active enantiomer of fluoxetine has (S) stereochemistry. Draw the
structure of the alkyl halide that you would need to prepare the active enantiomer, showing
the correct stereochemistry.
OH
N
KOH
F3C
Cl
Fluoxetine
DMSO
+
NH
O
O
N
F3C
F3C
2. Draw mechanisms and energy profiles for the following reactions:
a) 2-chloro-2-methylpropane in methanol
b) bromoethane + iodide
What can you say about the structure of the activated complex and about potential
intermediates?
3. Give reaction types and main products for the following reactions:
a) cyclohexyliodomethane + methoxide in methanol
b) benzyliodide (iodomethyl benzene) in methanol
c) 2-chloro-2-methylpropane + methoxide in methanol
d) 2-chloro-2-methylpropane in methanoic acid
4. Explain why l-iodo-2,2-dimethylpropane is very inert/non-reactive in both SN1- and SN2reactions!
5. When (1R)-1-deuterium-1-iodobutane is treated with an excess of KI a product mixture is
obtained without any detectable optical activity. Explain why!
6. A similar observation is made when (2R)-2-chlorobutane is treated with methoxide in
methanol. What happens and what do the products look like?
KAROLINSKA INSTITUTET
Department of Medical Biochemistry & Biophysics
Biomedical program (Candidate): General and organic chemistry
SEMINAR 8
Alkohols, ethers & epoxides
F&F
7.2, 7.6, 7.8, 7.9, 7.28, 8.5, 8.6, 8.7
1. Which products are formed from the following reactants?
a)
Na
OH
O
?
NH3
b)
O
?
CH3OH, H+
c)
?
HI
d)
OCH3
e)
OCH3
?
HI
?
2. What is formed when a) ethylenoxide is heated with potassium cyanide in ethanol?
O
KCN
?
b) tetrahydrofuran is treated the same way?
O
KCN
?
3. Paroxetine is an antidepressant drug that inhibits the reuptake of the neurotransmitter serotonin
in the synapses of the central nervous system. The following reagents are used in the synthesis
of paroxetine. Draw the structures of the intermediates A and B.
O
O
OH
SOCl2
pyridin
N
HO
A
B
KAROLINSKA INSTITUTET
Department of Medical Biochemistry & Biophysics
Biomedical program (Candidate): General and organic chemistry
SEMINAR 9
Alkenes, alkynes & addition
F&F 10.8, 10.14, 10.16, 10.17, 10.18, 10.35
1.
Which products are obtained when (Z)-3-heptene is treated with Br2 in water? Indicate the
stereochemistry of the products with stereo formulas or Fischer projections.
2.
What happens during an anti-Markownikoff-addition of HBr to an alkene? How can the
ratio/extent of anti-Markownikoff-addition be increased and decreased?
3.
Predict the major products of the following reactions.
Br2
HBr
A?
B?
1. BH3, THF
C?
2. H2O2, -OH
HO
kolesterol
KAROLINSKA INSTITUTET
Department of Medical Biochemistry & Biophysics
Biomedical program (Candidate): General and organic chemistry
SEMINAR 10
Aldehydes & ketones
F&F
13.10, 13.11
1. Explain the pH-dependence of the reaction rate:
-1
O
H2NOH
+
-2
H3C
CH3
N OH
H3C
-3
CH3
-4
1
2
3
4
5
6
7
8
pH
2. Suggest a mechanism and products for the reaction between the following compound and
water and explain what is needed to catalyze the reaction.
N
3. Many biological reactions, e.g. of the amino acid metabolism, are catalyzed by so-called
pyridoxal-5′-phosphate-dependent enzymes (PLP enzymes). PLP is a derivative of vitamin B6
that is directly involved in these reactions. It is tightly bound to the enzyme via a covalent
bond with a lysine residue, an amino acid carrying an amine group. Give the mechanism for
the reaction of PLP with the enzymes.
2- O PO
3
H
O
N+
H
OH
pyridoxal phosphate (PLP)
enzym
+
H2N
4. Which products are obtained when butanal is allowed to react with the following reagents:
a) sodium cyanide in water
b) methylmagnesium bromide in diethyl ether followed by acidic water
5. How would you synthesize the following compounds:
a) 2-phenyl-2-propanol
b) chloral hydrate (an anaesthetic)
6. Give product and mechanism for the reaction between acetone and ethylene glycol in
presence of acid.
KAROLINSKA INSTITUTET
Department of Medical Biochemistry & Biophysics
Biomedical program (Candidate): General and organic chemistry
SEMINAR 11
Carbohydrates & carboxylic acids
F&F
15.6, 15.16 a,c,d, 15.21, 23.5, 23.9, 24.1
1. Suggest a mechanism for the reaction between the following compound and sodium
hydroxide. What is the name of the compound and which important application/use has the
product?
O
O
O
O
O
O
2. Give the products of the following reactions:
O
SOCl2
OH
N
O
?
?
OH
H+/H2O
O
O
O
?
H2N
O
H2SO4/H2O

?
3. Give a suggestion how the dipeptide shown below can be synthesized from the protected
amino acids N-acetyl-glycine (G) and alanine t-butylester (A).
O
N
H
H
N
O
O
O
O
O
N
H
OH
(G)
H2N
O
(A)
O
protected dipeptide
4. Suggest a mechanism for the reaction between butylamine and benzoic acid anhydride. How
much of the amine must be added to let all benzoic acid anhydride react?
5. Give product and mechanism for the acid-catalyzed reaction between acetic acid and ethanol.
KAROLINSKA INSTITUTET
Department of Medical Biochemistry & Biophysics
Biomedical program (Candidate): General and organic chemistry
SEMINAR 12
Condensation 1
F&F
14.12, 14.13, 17.1, 17.2, 17.7
1. Arrange the following compounds according to increasing reactivity towards a nucleophilic
attack: acetamide, acetyl chloride, sodium acetate, ethyl acetate, acetic acid anhydride.
2. Identify each of the following reactions as a nucleophilic addition, nucleophilic acyl
substitution, an α substitution or a condensation.
O
O
NH3
a)
Cl
NH2
O
b)
NOH
NH2OH
H
c)
H
NaOH
2
O
OH
O
3. Order the following compounds according to increasing acidity:
O
O
O
O
OH
O
O
O
O
O
N
O
O
4. Give complete mechanisms for the following reactions. The decarboxylation step occurs after
heating of the formed β-diacid. Give an example for a compound that is not a diacid but
which allows a corresponding reaction to take place.
Br
O
O
Na+OEt-
A
O
B
H+/H20
C

D
- CO2
O
5. Suggest a synthesis pathway for 2-pentanone with ethyl bromide as starting material.
6. Give the main products for the following reactions:
O
Cl
O- Na+
O
CH3 CH2 CN
OH-/H2O
KAROLINSKA INSTITUTET
Department of Medical Biochemistry & Biophysics
Biomedical program (Candidate): General and organic chemistry
SEMINAR 13
Condensation 2
F&F
17.11, 17.12, 17.13, 17.18
1. Name the products!
H
NaOH/H2O

O
O
O
H3O+
NaOH/H2O
+
O
H
2. The frangrance cis-jasmone can be prepared by an intramolecular aldol condensation of a
diketone.
a) Write the structure of the diketone.
b) What other cyclic aldol condensation product might you expect to be formed in this
reaction?
O
cis-jasmone
3. Give reagent and reaction mechanism for the following conversion:
O
O
O
O
O
O
O
4. Name the following reactions and give products A-C.
A
CH3CH2I
CH2 -
H 3C
O
O
H
H 3C
B
CH2
O-
O
O
C
5. Present a mechanism for the enolization of ethyl acetate and ethyl acetoacetate under basic
conditions (don’t forget to show resonance structures).
6. Give mechanism and product of the ester condensation that occurs with ethyl ethanoate in
presence of sodium ethoxide. Why is the equilibrium shifted towards the product and how is
the reaction completed?
KAROLINSKA INSTITUTET
Department of Medical Biochemistry & Biophysics
Biomedical program (Candidate): General and organic chemistry
SEMINAR 14
Aromatic compounds
F&F
11.8, 11.11, 11.14, 11.20, 11.27
1. Draw the energy diagram for the bromination of benzene Br2 and FeBr3.
2. Give the main products of the following reactions.
O
CH 3
O
C
CH 3
Br 2
a)
HNO 3
b)
FeBr 3
H 3C
CH
H 2 SO 4
CH 3
H 3C
H NO 3
c)
CH 2
d)
AlCl 3
H 2 SO 4
O
Br
H 3C
e)
Cl
C
Cl
AlC l 3
3. Draw the mechanism for bromination of phenol and give the resonance structures for the
carbocation intermediates for binding of bromine to the ortho-, meta- and para-positions in
phenol. Explain the regioselectivity.
4. Which compounds are aromatic and which are not? Explain!
O
O
KAROLINSKA INSTITUTET
Department of Medical Biochemistry & Biophysics
Biomedical program (Candidate): General and organic chemistry
SEMINAR 15
Articles
Go through the articles to see how they are partitioned. Answer the following general questions
as well as the specific questions for each article. Do that beforehand. This is especially important
for the tasks which require computers having internet connection and SciFinder.
What is the question/intention?
What was known before? Where can one read about that?
What was done? How can information about the procedure be obtained?
Are some steps or substances especially risky or crucial/sensitive?
What of the result/outcome is completely new?
How is the outcome explained?
How can the outcome be used/applied in another context?
Are there any unexpected results?
A. ”Reaction of ,-unsaturated ketones with LiAlH4 under oxygen: synthesis of 1,3-diols”,
Aurelio G. Csákÿ, Natalia Máximo, Joaquín Plumet and Ainhoa Rámila (Tetrahedron Lett.
(1999) 40, 6485-6487)
1. How was revealed what the first step of the reaction is?
2. For the conversion of 1 to 2 both a reducing and an oxidizing agent was used. Is the conversion
of 1 to 2 a reduction, an oxidation or none of the above? Give the oxidation numbers for the
drawn in carbon atoms in 1 and 2!
3. Describe how 1f can be synthesized by using the method described in reference 3. Which
aldehyde and which methyl ketone should be used? Give the reaction mechanism including all
steps and resonance structures. What is this type of reaction called?
4. Give a complete name and structures for the isomers of product 2a. Which of them are
optically active when pure?
5. Use the SciFinder to find out whether there exist other methods to convert 1a to 2a!
6. Use e.g. SciFinder to find out how 2f can be synthesized from acetophenone!
B. “A New Method for the Synthesis of ,-Difluoro--hydroxy Esters through the
Enolization of S-tert-Butyl Difluoroethanethioate”, John A. Weigel (J. Org. Chem. (1997), 62,
6108-6109)
Abbreviations: LDA = lithium diisopropylamide ((CH3)2CH)2N- Li; LHMDS = lithium
hexamethyldisilazide, ((CH3)3Si)2NLi. Both are strong bases that are sterically hindered and
therefore do not react with carbonyl groups.
1. Give the complete reaction formula for reaction (1).
2. How do the two fluor atoms in 2 affect the tendency to form an enolate, compared to the
compound that would have them replaced by hydrogen atoms?
3. Would reaction (1) be equally successful if NaOH would be used instead of LHMDS? Explain!
4. Give the complete mechanism for the synthesis of 9 in Table 1.
5. Which products are formed when 13 is treated with acid in water? Explain!
6. Is there a description how 3 can be synthesized with oxygen instead of sulphur? Search e.g.
with SciFinder!
TETRAHEDRON
LE'ITERS
Tetrahedron Letters 40 (1999) 6485--6487
Pergamon
Reaction of a,13-unsaturated ketones with LiA1H4 under oxygen:
synthesis of 1,3-diols
Aurelio G. Cs;ik~,* Natalia M~tximo, Joaqufn Plumet * and A i n h o a RAmila
Departamento de Qulmica Orgdnica I, Facultad de Qldmica, Universidad Complutense, 28040 MadriK Spain
Received 10 June 1999; accepted 29 June 1999
Abstract
1,3-Diols have been obtained by the reaction of a,[3-unsaturated ketones with LiAIH4 in THF under a dry oxygen
atmosphere. © 1999 Elsevier Science Ltd. All fights reserved.
Keywords: diols;ketones;oxygenation;reduction.
1,3-Diols have attracted considerable attention in recent times due to the ubiquitous presence of this
moiety in macrolide antibiotics.l Consequently, a wide variety of synthetic methods have been developed
for these targets. 2 However, most of these procedures require several steps for the preparation of the
starting materials, which poses an inherent difficulty from the large-scale synthesis standpoint. We wish
to report herein a new procedure for the synthesis of 1,3-diols based on the reaction of the easy-to-prepare
a,[~-unsaturated ketones3 1 with LiAIH4.
Portionwise addition of solid LiAII% (6.0 mol) to a 0.2 M solution of compounds 1 (1.0 mol) in THF
under dry oxygen (0°C, 1.5 h) and hydrolysis (H20) resulted in the isolation of the 1,3-diols 2 (Scheme 1,
Table 1).
R ~ , ~ , R a LiAIH~
O
OH OH
1
2
Scheme 1.
Additional experiments carried out with compound la put forward that the unsaturated alcohol 3a
and the saturated alcohol 4a can be isolated by carrying out the reaction under an argon atmosphere and
quenching with water prior to bubbling oxygen into the reaction mixture. Furthermore, 1,3-diol 2a was
also isolated from the reaction of 3a 4 with LiAIIG under the same reaction conditions (vide supra). On the
other hand, when the reaction was carried out with less than 6.0 equiv, of LiAlI-h, longer reaction times
were required to ensue full conversion, and only 3a (95% yield) was isolated when 1.0 equiv, of LiAlI-h
* Corresponding authors.
0040-4039/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)01270-8
6486
Table 1
Reaction of the a,f~-unsaturatedketones I with LiAIH4
~try
1
R'
R~
1
1Ph
Ph
2
lb
2-Furyl
2-Furyl
3
le
Ph
2-Furyl
4
ld
2-Fmyl
Ph
5
le
2-Thienyl
2-Furyl
6
If
Ph
CH3
(a) Isolatedyieldafire-silica-gelchromato~'~hy~ O A c )
2(%)"
2a (90)
2b (85)
2e (85)
2d (80)
2e (85)
2f(80)
was used. These observations allowed the proposal of a reaction course (Scheme 2) based on an initial
1,2-reduction of the carbonyl group of compounds 1 followed by an intermolecular hydroalumination
process of the C--C bond of the intermediate allylic alkoxides. 5
1
2
"
1
~
:--
3
OH
~R 1
O'AI"
I
R2
OH 2 OH
R
J
R2 H20 R
AI
/\
O.AI.I
R=
4
OH
Scheme 2.
Compounds 2 were obtained as an equimolecular mixture of syn and ant/ diastereomers, which
were separated by crystallization in hexane-ethyl acetate (2a-e) or chromatography (2f, silica gel,
hexane:ethy! acetate 80:20). Compounds 2 can be deracemized by means of known procedures. 6,7
In summary, the herein reported procedure constitutes the one-pot transformation of an a,[3unsaturated ketone into a 1,3-diol, which is without precedent in the literature consulted.
Acknowledgements
D G Y C T (project PB-960641) is gratefully ackowledged for financial support.
References
1. (a) Macrolide Antibiotics: Chemistry, Biology, and Practice; Omura, S., Ed.; Academic Press: New York, 1984. Co)
Rychnovsky, S. D. Chem. Rev. 1995, 95, 2021-2040.
2. See for instance: (a) Oishi, T.; Nakata, T. Synthesis 1990, 635--645. Co)Enders, D.; Hundertmark, T.; Lampe, C.; Jegelka,
U.; Scharfbillig, I. Fur. J. Chem. 1998, 2839-2849 and references cited therein.
3. Compounds lbl-e were prepared by the addition of the corresponding aldehyde (10 retool) at 0°C to a solution of the
corresponding methylketune (10 retool) in a mixture of EtOH (50 mL) and H20 (30 mL) containing NaOH (3 retool).
The solution was stirred from 0°C to rt for 24 h. Compounds lb--e precipitated out of the solution upon addition of water
6487
4.
5.
6.
7.
(20 mL) and cooling the mixture at 0*C. This procedure can be easily scaled to the multi-gram synthesis of these starting
materials.
Prepared by the reaction of la with 1.0 equiv, of LiAIH4 in THF at 0°C under As (3 h) followed by addition of water and
extraction with Et20.
For the hydroalurnination of C=C bonds, see: Eisch, J. J In Comprehensive Organic Synthesis; Trost, B. M.; Fleming,
I., Eds.; Pergamon Press: New York, 1991; Vol. 8, Chapter 3.11. See also: (a) Snyder, E. I. J. Org. Chem. 1967, 32,
3531-3534. (b) Borden, W. T. J. Am. Chem. Soc. 1968, 90, 2197-2198.
For a deracemization procedure of 1,3-diols, see: Harada, 1".; Shintani, T.; Oku, A. J. Am. Chem. Soc. 1995, 117,
12346-12347.
For the spontaneous resolution of racemic 1,3-diphenylpropane-l,3-diol, see: Dale, J. Chem. Soc. 1961, 910-922.
6108
J. Org. Chem. 1997, 62, 6108-6109
A New Method for the Synthesis of
r,r-Difluoro-β-hydroxy Esters through the
Enolization of S-tert-Butyl
Difluoroethanethioate
John A. Weigel
Chemical Process Development, Lilly Research Laboratories,
Eli Lilly and Company, P.O. Box 685,
Lafayette, Indiana 47902
Received June 25, 1997
The need for dependable methods to introduce fluorine
atoms into organic molecules has grown tremendously
as the medicinal chemistry community searches for
unique biological activity through substitution of hydrogen atoms with fluorine.1 For example, 2-deoxy-2,2difluorocytidine (gemcitabine, 1), a novel anticancer agent
which possesses a geminal difluoromethylene group, has
been synthesized through construction of an R,R-difluoroβ-hydroxy ester, which provides the carbohydrate portion
of the nucleoside.2 The geminal difluoromethylene moiety may be obtained via several methods, which include
Reformatsky reaction of halodifluoroacetate esters,3 gemdifluoroallylation,4 difluorovinyl anion additions,5 intramolecular trapping of gem-difluoroalkyl radicals,6
difluoroketene silyl acetal condensations,7 and direct
fluorination.8 In the original synthesis of gemcitabine
achieved by Hertel and co-workers, a Reformatsky reaction utilizing ethyl bromodifluoroacetate and 2,3-Oisopropylidene-D-glyceraldehyde provided the desired
difluororibonic ester as a mixture of diastereomers.2
We set out to develop a general synthesis of R,Rdifluoro-β-hydroxy esters which does not rely upon
expensive halodifluoroacetate esters as the fluorine
source and which avoids formation of a stoichiometric
amount of zinc waste. An aldol condensation utilizing
the lithium enolate of ethyl difluoroacetate would meet
these criteria, and indeed Easdon has investigated the
synthesis of this enolate (eq 1).9 Unfortunately, this
(1) Taylor, N. F., Ed. Fluorinated Carbohydrates, Chemical and
Biochemical Aspects, ACS Symposium Series 374; American Chemical
Society: Washington, DC, 1988.
(2) Hertel, L. W.; Kroin, J. S.; Misner, J. W.; Tustin, J. M. J. Org.
Chem. 1988, 53, 2406.
(3) (a) Hallinan, E. A.; Fried, J. Tetrahedron Lett. 1984, 25, 2301.
(b) Burton, D. J.; Easdon, J. C. J. Fluorine Chem. 1988, 38, 125. (c)
Shen, Y.; Qi, Y. J. Fluorine Chem. 1994, 67, 229. (d) Hanzwa, Y.;
Inazawa, K.; Kon, A.; Aoki, H.; Kobayashi, Y. Tetrahedron Lett. 1987,
28, 659. (e) Lang, R. W.; Schaub, B. Tetrahedron Lett. 1988, 29, 2943.
(4) (a) Yang, Z.-Y.; Burton, D. J. J. Org. Chem. 1991, 56, 1037. (b)
Seyferth, D.; Simon, R. M.; Sepeiak, D. J.; Klein, H. J. Am. Chem. Soc.
1983, 105, 4634. (c) Hiyama, T.; Obayashi, M.; Sawahata, M. Tetrahedron Lett. 1983, 24, 4113.
(5) (a) Percy, J. Tetrahedron Lett. 1990, 31, 3931. (b) Bennett, A.
J.; Percy, J.; Rock, M. H. Synlett 1992, 483. (c) Ichikawa, J.; Minami,
T. Tetrahedron Lett. 1992, 33, 3779. (d) Ichikawa, J.; Hamada, S.;
Sonoda, T.; Kobayashi, H. Tetrahedron Lett. 1992, 33, 337.
(6) (a) Arnone, A.; Bravo, P.; Frigerio, M.; Viani, F.; Cavicchio, G.;
Crucianelli, M. J. Org. Chem. 1994, 59, 3459. (b) Morikawa, T.; Uejina,
M.; Kobayaski, Y.; Taguchi, T. J. Flourine Chem. 1993, 65, 79. (c) Yang,
Z.-Y.; Burton, D. J. J. Org. Chem. 1992, 57, 4676. (d) Okano, T.;
Takakura, N.; Nakano, Y.; Eguchi, S. Tetrahedron Lett. 1992, 33, 3491.
S0022-3263(97)01159-6 CCC: $14.00
species is not stable and results in formation of a β-keto
ester via a self-condensation reaction. In an attempt to
form the difluoroketene silyl acetal from the enolate in
the presence of chlorotrimethylsilane, carbon silylation
was observed along with defluorination of the ester.
Given the known differences in electronic structure,
acidity, and reactivity of thiolesters versus esters,10 we
decided to investigate the enolization of S-tert-butyl
difluoroethanethioate (2) and its subsequent reaction
with electrophiles. We also explored the formation and
reactivity of difluoroketene O,S-acetals.
As a means to test the stability and reactivity of the
lithium enolate of 2, its reaction with benzaldehyde was
investigated. Accordingly, the desired R,R-difluoro-βhydroxy ester 3 was obtained in 70% isolated yield by
the addition of LDA (1.1 equiv) to a solution of 2 (0.1 M
in toluene) at -78 °C followed by addition of benzaldehyde (1.1 equiv) and warming to 25 °C (eq 2). The major
byproducts, as determined by 19F NMR spectroscopy of
the reaction mixture, were unreacted 2 (5%) and the selfcondensation product HF2CC(O)CF2C(O)S-t-Bu (10%).
In order to explore the scope of this reaction, several
other electrophiles were screened to afford condensation
products 3-12 in moderate to good yield (Table 1).
Anisaldehyde, hexanal, isobutyraldehyde, and pivalaldehyde gave rise to the expected secondary alcohols 4-7,
while acetophenone yielded tertiary alcohol 8. The
double addition product 9 was obtained from benzoyl
chloride, presumably through formation of an intermediate ketone upon chloride displacement. Additionally,
cyclohex-2-en-1-one reacted via 1,2-addition to form 10.
An intermediate suitable for the synthesis of gemcitabine was obtained by aldol condensation of 2 with 2,3O-(3-pentylidene)-D-glyceraldehyde (13), which afforded
compounds 11 and 12 as an 85/15 mixture of diastereomers. The erythro isomer 11 is the major compound, as
predicted by the Felkin-Ahn model of asymmetric induction.11 The relative stereochemistry was assigned by
(7) (a) Greuter, H.; Lang, R. W.; Romann, A. Tetrahedron Lett. 1988,
29, 3291. (b) Kitagawa, O.; Taguchi, T.; Kobayashi, Y. Tetrahedron
Lett. 1988, 29, 1803. (c) Taguchi, T.; Kitagawa, O.; Suda, Y.; Ohkawa,
S.; Hashimoto, A.; Iitaka, Y.; Kobayashi, Y. Tetrahderon Lett. 1988,
29, 5291. (d) Matsumura, Y.; Fujii, H.; Nakayama, T.; Morizawa, Y.;
Yasuda, A. J. Fluorine Chem. 1992, 57, 203.
(8) (a) Frogier, P. R. T.; Tran, T. T.; Viani, S.; Condom, R.; Guedj,
R. Antivirial Chem. Chemother. 1994, 5, 372. (b) York, C.; Prakash,
G. K. S.; Wang, Q.; Olah, G. A. Synlett 1994, 425. (c) Kornilov, A. M.;
Sorochinsky, A. E.; Kukhar, V. P. Tetrahedron: Asymmetry 1994, 5,
1015. (d) Xu, Z.-Q.; DesMarteau, D. D.; Gotoh, Y. J. Fluorine Chem.
1992, 58, 71. (e) Wilkinson, J. A. Chem. Rev. 1992, 92, 505.
(9) Easdon, J. C. Ph.D. Thesis, The University of Iowa, Iowa City,
IO, 1987.
(10) Suckling, K. E.; Suckling, C. J. Biological Chemisty: The
Molecular Approach to Biological Systems; Cambridge University
Press: Cambridge, England, 1980; pp 76-79. (b) Douglas, K. T. Acc.
Chem. Res. 1986, 19, 186 and references therein.
(11) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199. (b) Ahn, N. T.; Eissenstein, O. Nouv. J. Chim. 1977, 1, 61.
(12) Chou, T. S.; Heath, P. C.; Patterson, L. E.; Poteet, L. M.; Lakin,
R. E.; Hunt, A.H. Synthesis 1992, 565.
© 1997 American Chemical Society
Communications
Table 1. Reactions of the Lithium Enolate of 2 with
Various Electrophiles
J. Org. Chem., Vol. 62, No. 18, 1997 6109
contrast with the behavior observed by Easdon for
difluoroesters (vide supra).
Acetal 15 reacted with aldehyde 13 in the presence of
BF3‚OEt2 at low temperature to afford 11 and 12 in 74%
isolated yield (95/5, erythro/threo). The alcohols were
presumably formed as the TMS ethers and were desilylated on workup. The diastereoselectivity observed upon
condensation with 13 increased from 85/15 (lithium
enolate) to 95/5 (ketene silyl O,S-acetal); this trend
parallels that observed by Kobayashi for condensations
between 2,3-O-isopropylidene-D-glyceraldehyde and methyl iododifluoroacetate: 65/35 (Reformatsky reaction); 90/
10 (ketene silyl acetal).13 We ascribe the greater erythro
selectivity of the thiolester enolate and acetal to lower
reaction temperatures and the steric bulk of the S-tertbutyl versus methyl ester.
In a search for alternate routes to difluoroketene silyl
O,S-acetals, we investigated the reduction of S-phenyl
chlorodifluoroethanethioate (16) in the presence of
TMSCl. Ester 16 was reacted with zinc dust and TMSCl
in CH3CN at 40 °C to yield a single product, which was
identified as difluoroketene silyl O,S-acetal (17) by 19F
NMR spectroscopy and MS data (eq 4).15 Acetal 17 could
be isolated but is extremely hydrolytically sensitive and
decomposed over several days at room temperature.
Halodifluoro thiolester 16 proved to be a superior precursor to difluoroketene silyl acetals, when compared with
halodifluoroesters, due to the absence of side reactions
and its ease of reduction. For example, compound 16
undergoes rapid zinc reduction in CH3CN, while halodifluoroesters require use of the less available and more
expensive bromo or iodo derivatives to afford reaction.2,6
hydrolysis, cyclization, and benzoylation of 11 to give the
known gemcitabine intermediate, 2-deoxy-2,2-difluoroD-erythro-pentofuranos-1-ulose 3,5-dibenzoate (14).12
Difluoroketene silyl acetal additions to glyceraldehyde
derivatives have been reported to proceed with high
diastereoselectivities, in contrast to their Reformatsky
counterparts.13 Therefore we desired to synthesize a
difluoroketene O,S-acetal and investigate its reaction
with aldehyde 13. To this end, thiolester 2 was enolized
with LDA in the presence of TMSCl at -78 °C (eq 3).
Upon examination of the reaction mixture by 19F NMR
spectroscopy, only one product was observed, which has
been assigned as acetal 15.14 No evidence of carbon
silylation or Claisen reaction was detected, which is in
(13) Kitagawa, O.; Taguchi, T.; Kobayashi, Y. Tetrahedron Lett.
1988, 29, 1803.
In summary, we have reported a new synthesis of R,Rdifluoro-β-hydroxy esters which is operationally simple
and does not produce heavy metal waste. For instance,
the lithium enolate of 2 adds to aldehyde 13 with good
diastereoselectivity, which could be enhanced by use of
the difluoroketene silyl O,S-acetal 15 to provide an
intermediate in the synthesis of the anticancer agent
gemcitabine. Although alcohols 3-8 and 10 were produced as racemates, we note the possibility of enantioselectivity utilizing the work of Mukaiyama and others.16 We have also demonstrated the synthesis of
difluoroketene silyl O,S-acetal 17 through reduction of
a chlorodifluoroethanethioate ester.
Acknowledgment. The author gratefully acknowledges the contributions of Mr. Ross Johnson for analyzing the NMR spectral data.
Supporting Information Available: Experimental procedures and physical data (1H NMR spectra) for compounds
2-12 and 16-17 (19 pages).
JO9711596
(14) 19F NMR (C6D6) δ -97.1 (d, J ) 47 Hz), -108.6 (d, J ) 47 Hz).
Acetal 15 was not isolated due to its great hydrolytic instability and
was generated in situ for subsequent reactions.
(15) 19F NMR (C6D6) δ -96.8 (d, J ) 47 Hz), -109.5 (d, J ) 47 Hz);
APCI MS (positive ion mode, m/z) 261 [M + 1]+.
(16) For leading references, see: Braun, M.; Sacha, H. J. Prakt.
Chem. 1993, 335, 653.
KAROLINSKA INSTITUTET
Department of Medical Biochemistry & Biophysics
Biomedical program (Candidate): General and organic chemistry
SEMINAR 16
NMR
F&F 9.7, 9.10, 9.12, 9.13, 9.15, 9.16, 9.29, 9.32, 9.44
1.
The picture below shows the 1H NMR spectrum of an organic compound.
a) How many signals are there in the spectrum?
b) What is the multiplicity (splitting pattern) for each signal?
c) The molecular formula of the compound is C2H6O. Indicate above the corresponding
number of protons contributing to each signal.
d) What is the structure of the compound?
e) Assign the signals and explain the multiplicity (splitting pattern) for each signal.
2.
The compound below gives rise to three separate signals in the 1H NMR spectrum: Ha at
δ6.10 ppm, Hb at δ5.78 ppm and Hc at δ5.56 ppm. The corresponding coupling constants
are: Jab = 11 Hz, Jac = 18 Hz and Jbc = 2 Hz.
Hb
Ha
C
Br
C
Hc
a) Sketch the 1H NMR spectrum showing the signals of protons Ha, Hb and Hc.
b) What are the relative integrals of the signals?
c) What are the multiplicities (splitting pattern) of the Ha, Hb and Hc signals, respectively?
d) What are the relative intensities of the split peaks within each signal?
e) Indicate for each signal how the separation of the peaks reflects the coupling constants.
KAROLINSKA INSTITUTET
Department of Medical Biochemistry & Biophysics
Biomedical program (Candidate): General and organic chemistry
SEMINAR 17
Oxidation and reduction
F&F 7.17 (calculate the oxidation numbers for the carbons at which they change!)
F&F 7.16, 10.23, 10.38, 10.40 a, b, 13.31
Name the reagents used for the following conversions:
O
O
a)
OH
O
b)
HO
c)
d)
OH
e)
O
OH
KAROLINSKA INSTITUTET
Department of Medical Biochemistry & Biophysics
Biomedical program (Candidate): General and organic chemistry
SEMINAR 18
Masspektra and radioactivity
F&F
22.13, 22.30a, 22.30b
1. Shown in Fig. 1 is the EI mass spectrum of hexan-3-ol.
(a) Calculate its accurate monoisotopic mass.
(b) Account for the peaks at m/z 84, 73, 59 and 55 in the spectrum.
(c) Would you expect these fragment ions to be odd or even electron species?
2. Given the EI spectrum of synthetic product X (Fig. 2), what functional groups do you think
may be present in the compound. The measured accurate monoisotopic mass is 164.020062
Da. What is the chemical formula of X?
3. Explain the origin of the peaks at m/z 43 and 58 in the EI spectrum of 5-methyl-2-hexanone
(Fig. 3).
4. A mass spectrometrist cut himself on the rim of a test tube containing water. He then recorded
an electrospray spectrum of the resultant aqueous solution, this is shown in Fig. 4. Two series
of peaks are observed, corresponding to two proteins.
If the peaks at m/z 2522.0, 2161.8 and 1891.8 correspond to the [M+6]6+, [M+7]7+ and
[M+8]8+ ions of component (a), calculate its molecular weight.
Similarly if peaks at m/z 2267.8, 1984.4 and 1764.0 correspond to [M+7]7+, [M+8]8+ and
[M+9]9+ of component (b), calculate its molecular weight.
Make a guess as to what (a) and (b) are!
5.
32
P-Labelled nucleotides are used extensively to study DNA. The half-life of 32P is 14.3 days.
How much radioactivity (in %) would remain in a closed sample after 3 months (90 days)?
Fig. 1. EI MS of hexan-3-ol.
Fig. 2. EI MS of synthetic product X.
Fig. 3. EI MS of 5-methyl-2-hexanone
Fig. 4. ES MS of proteins in blood.
KAROLINSKA INSTITUTET
Department of Medical Biochemistry & Biophysics
Biomedical program (Candidate): General and organic chemistry
SEMINAR 19
Integration, repetition
1. What are the characteristics of the noble gas configuration?
2. Draw all hydrogen bonds that can occur in an aqueous solution of sodium acetate.
3. To esterify (R)-2-butanol the alcohol is mixed with acetic acid in water, and HCl is added
to make the solution very acidic. The formed ester appears to lack optical activity almost
completely. Explain what happened!
4. Give the dominant product after the treatment of (S)-2-bromopentane with alkali and heat.
5. Describe and name the molecular orbitals in the cyanide ion, and show how they are filled
with electrons!
6. You perform a careful and therefore incomplete oxidation of octadecanole. Explain how
you perform the reaction and how you can isolate the product from all other components of
the mix.
7. Suggest a method for derivatization of glucose for analysis by GC/MS, based on the acyclic
form of the sugar. Give the systematic name of glucose according to the R/S-system.
8. An alcohol is treated with HBr. The obtained product shows the following mass spectrum
after electric ionization, positive ions. What alcohol was it?
9. Give the complete reaction mechanism for the proton-catalyzed reaction between butanal and
1,2-ethanediol.
10. Give a suggestion for how pentanal can be converted to 3-hydroxy-2-propylheptanal.
11. F&F 7.20, 10.40a, 10.40d, 13.23e, 14.15b, 15.25c.
12. F&F 8.21, 12.34.