Exp't 13
Phase-Transfer-Catalyzed Alkylation of Diethyl Malonate
(Adapted by Modi, Monarch, Perriello, Pohland, Minard and Walton (PSU '91-'92) from D Thompson and P. Reeves, "Phase-transfer-catalyzed Alkylation of Ethyl Acetoacetate
and Diethyl Malonate", J. Chem. Ed., 62, 1985, 907-908.) Revised 10/5/00
Introduction:
Practical synthetic methods for the construction of molecules through carbon-carbon bond formation are of obvious
importance. Of the somewhat limited number of methods available, the alkylation of an enolate anion with an alkyl
halide is used quite often. In the past, the formation of the enolate anion required using a strong base such as sodium
ethoxide (made by reacting sodium metal with ethanol) to remove a proton a to the carbonyl group.
O
O
O
O
C2H 5O
H (strong
CH2X
base)
R
enolate anion
CH2R
+
X
(1)
new C-C bond
There are several problems with this method: 1) the handling of highly reactive sodium metal; 2) the necessity of
preparing absolutely anhydrous ethanol; 3) the large amount of E2 elimination of the alkyl halide.
While carbonate anion (CO32- )is not a very strong base in aqueous medium (pKa=8.5), in an organic medium it is basic
enough to remove a proton from an active methylene compound. Active methylene compounds contain two electron
withdrawing groups, such as carbonyl groups, adjacent to a C-H bond, making the hydrogen relatively acidic. (The
pKa =13 for the active methylene compound, diethyl malonate, shown below1).
O
O
CH3CH2
O
O
CH
H
B-
CH3CH2
O
CH2CH3
Base
C 2H5O- in C2H5OH
2acidic hydrogen or CO3 in organic phase
Diethyl malonate
O
O
-
O
CH2CH3
(2)
-O
CH3CH2
O
CH
O
CH
O
CH2CH3
Unfortunately, one cannot normally dissolve a carbonate salt, for example potassium carbonate, in organic solvents.
However, the addition of a phase transfer catalyst such as
O
O
O
O
O
CH3
+
N
Cl-
O
18-crown-6, a cyclic polyether
tricaprylmethylammonium chloride
a cyclic polyether or a tetraalkylammonium salts will allow dissolution of carbonates in organic solvents. A liquidsolid two phase system using anhydrous K 2CO3 or Na2CO3 has the added advantage of absorbing the water formed in
the reaction, thus minimizing ester hydrolysis. Since diethylmalonate has two acidic a hydrogens, it can be dialkylated
(a minor product of this reaction) by reaction with two equivalents of an alkyl halide. This double alkylation can be
cleverly used to prepare cycloalkanecarboxylic acids starting with the appropriate alkyl dihalide. An example is the
malonic ester synthesis of cyclopentanoic acid from 1,4-dibromobutane.
Exp't 13
O
CH3CH2
O
O
CH2
O
CH2CH3
+
BrCH2C H2C H2C H2B r
base
O
C H3C H2
O
O
O
C
CH2
C H2C H3
CH2
CH2 CH2
O
N a+ -O
NaOH
O
CH2
CH2
(3)
O - N a+
C
CH2
CH2
H+, -CO2
O
H
C
C H2
OH
C H2
C H2 C H2
In this experiment solid K2 CO3 is used as the base and the cyclic polyether, 18-crown-6, is used as the phase transfer
catalyst to prepare 2-(n-butyl)-diethyl malonate from diethyl malonate and 1-bromobutane (syn: n-bromobutane or n-butyl
bromide):
O
O
K2 CO3
O
O
CH3CH2
CH2CH3
CH3CH2
CH2CH3 + CH3CH2CH2CH2-Br
O CH O
O CH2 O
18-crown-6
Diethyl malonate
CH3CH2CH2CH2
(4)
Prelaboratory Exercise:
1. The use of phase transfer catalysts with hydroxide instead of carbonate as a base works with 2,4-pentanedione
(acetylacetone), but not with diethyl malonate. What side reaction occurs with hydroxide and the ester to subvert the
desired reaction?
2. When carbonate is used as a base (reaction 4 above), water and CO 2 are formed. Using an equation or equations,
explain why.
Cautions:
The cyclic polyether 18-crown-6 ether is toxic and induces sterility in male rats at high oral doses. Wear gloves
when handling. 1-Bromobutane, like all alkylating reagents is toxic and a potential carcinogen because it can react
with physiological nucleophiles in the body. Wear gloves when handling with care and work in a hood.
Synthesis:
In a 5-mL long-necked round-bottom flask, place about 0.4 g of anhydrous potassium carbonate, 0.30 mL of 1bromobutane (0.38 g, 2.8 mmol), 0.38 mL of diethyl malonate (0.40 g, 2.5 mmol) and 0.25 mL of 18-crown-6 phase
transfer catalyst solution (5% in acetonitrile). Add a 1/2-inch magnetic stir bar and cap the flask with a rubber septum
and needle. Gently heat the mixture on the top of a shallow sand bath for 2 hr with constant vigorous stirring.
Isolation and Purification:
Remove the 1/2-inch stir bar by drawing it up and out magnetically with your 1-inch stir bar held on the outside.
Add one mL of CH 2 Cl2 and 2 mL of distilled water. Mix vigorously with pipet mixing to effect extraction into the
organic layer. Remove the CH2Cl2 layer with a pipet, placing it into a reaction tube, and repeat the extraction with
another 1 mL of CH2 Cl2 , combining the organic layers. Wash the CH 2 Cl2 extracts with 2 mL sat'd. aqueous NaCl, and
dry over anhydrous Na2SO4 , adding the drying agent until it no longer clumps together and then letting the solution
stand for about 10 minutes. Remove the CH2 Cl2 to a clean, dry, pre-weighed 10-mL Erlenmeyer flask and let the bulk
of the CH2 Cl2 evaporate in your locker. In the next lab period, remove the last traces of CH2 Cl2 until a constant
product weigh is obtained by aspirating the flask in a bell jar. The product is a viscous yellow liquid (typical yield is
approx. 400 mg). Check product purity and identity by gas chromatography, followed by GC-MS if your GC results
are equivocal.
* If you are unsure about which layer is which, carefully add extra ether and note which layer becomes larger.
Cleaning-up:
The aqueous layer contains crown ether and should be placed in the non-halogenated solvents container. The sat.
NaCl used for washing can be flushed down the sink. Place the dried Na2SO4 in the non-hazardous solid waste
container.
Analysis:
Inject 1 mL of a CH2 Cl2 solution (see the Lab Guide, Chap. 11) of your product into the GC, determine the
retention times, peak identities and peak areas. If gas chromatogram is reasonable, (i.e. has more than 30% product, by
peak areas) reanalyze by GC-MS.
Final Report:
Label chromatographic peaks corresponding to C-alkylated, C-dialkylated, starting materials, solvents, and Oalkylated products (if any),. Calculate the approx. percentage yield of butylated products based on peak areas from the
GC analysis printout. Make a table of the major peaks, their retention times, areas, and assignments.
Questions:
1.
Why do 2° and 3° alkyl halides give low/no yields in this and similar carbanion (enolate) alkylations? What is
the predominant product? Do you expect benzyl bromide to be reactive toward enolate anions?
2.
Why might someone running this experiment detect, by GC-MS analysis, a product with a molecular weight of
272? Draw a structure for this product.
3.
Use resonance structures to explain why diethylmalonate may be easily deprotonated.
References:
1.
2.
3.
4.
5.
6.
Thompson Douglas L.; Reeves Perry C. Phase-Transfer-Catalyzed Alkylation of Ethyl
Acetoacetate and Diethyl Malonate Journal of Chemical Education, volume 62, number 10, 1985.
pp907-8.
Williamson Kenneth L. Macroscale and Microscale Organic Experiments D. C. Heath and Co.
Mass, 1989. pg. 533.
Mackay, K. M.; Mackay R. A. Introduction to Modern Inorganic Chemistry 4th ed. Prentice Hall,
Englewood cliffs, NJ 1989. pp 157-62.
Miller, James M. Chromatography Concepts and Contrasts: John Wiley and sons, New York,
1988, pp. 109-153.
McMurry, John Organic Chemistry Brooks/Cole Co. 1984 pp. 832-7, 617-18.
Brandstrom, Arne; Junggren, Ulf Tetrahedron Letters no. 6, pp 473-474, 1972.
Synthetic Experiment PreLab Grading Sheet
Name(s):
TA:
Date:
PreLab For Exp't # 13
Phase-Transfer-Catalyzed Alkylation of Diethyl Malonate
Possible
Points
Date, Name, Desk #, Experiment # & Title(abbreviated after 1st pg), Section &
TA Name
4
Summary
8
Goals
8
Reactions, structures, conditions, diagrams
14
Completeness of Chemical Data Table(s)
14
Chromatographic Behavior Comparison
16
Spectral Features Comparison
12
Work-up - Explanation of the product isolation and purification process
12
PreLab Questions
12
TOTAL FOR PRELAB
100
Missed
Points
Date Handed in:
General Comments:
Total Points:
Synthetic Experiment Final Report Grading Sheet
Name:
TA:
Date:
Final Report For Exp't # 13
Phase-Transfer-Catalyzed Alkylation of Diethyl Malonate
Possible
Points
Name, Date, Experiment Title (abbreviated after 1st page) and every page
numbered
4
OBSERVATIONS and DATA - Overall organization, readability, completeness
8
Data: Weighing data, molecular weights, moles, density, volumes, refractive
index,
Product analysis conditions i.e. gas chromatographic analysis conditions sheet
for GC and/or GC-MS, weight of sample and KBr for IR; solvent and field
strength for NMR; ionization mode for MS;
12
Yield: Show % yield calculations with limiting reagent clearly stated.
Indicators of product purity such as gas chromatograms or TLC, boiling point
or refractive index.
12
RESULTS AND DISCUSSION - Overall organization, readability, completeness
Results; Achievement of goals
Missed
Points
8
16
Product Analysis Data: Quality and Interpretation – Structures assigned to all
gas chromatogram peaks and structures written on the corresponding mass
spectra from GC-MS. Structure(s) drawn and interpreted on the product
spectrum. Calculate relative %’s of isomers, by-products or starting materials
from GC peak areas.
Interpret major MS or IR peaks or all NMR peaks (including impurities).
Explain how spectra confirm product identity.
See Lab Guide Chapter 3, Section 3.4 for guidelines in annotating spectra and
Ch 11 for help with interpretation.
24
POSTLAB QUESTIONS
16
TOTAL POINTS
100
Date Handed in:
General Comments:
Total Points: