Chapter 8
Dimethylcarbonate as a Green Reagent 1
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Pietro Tundo , Maurizio Selva , and Sofia Memoli Downloaded by NORTH CAROLINA STATE UNIV on September 20, 2012 | http://pubs.acs.org Publication Date: August 15, 2000 | doi: 10.1021/bk-2000-0767.ch008
1
Department of Environmental Science, Cà Foscari University, Dorsoduro 2137, Venice 30123, Italy Interuniversity Consortium "Chemistry for the Environment", Via della Libertá 5/12, 30175 Marghera, Venice, Italy
2
Dimethylcarbonate (DMC) is an environmentally friendly substitute for dimethylsulfate (DMS) and methyl halides in methylation reactions. It is also a very selective reagent. The reactions of DMC with methylene-active compounds produce monomethylated derivatives with a selectivity not previously observed. The batchwise monomethylation of arylacetonitriles, arylacetoesters, aroxyacetonitriles, methyl aroxyacetates, benzylarylsulfones and alkylarylsulfones with DMC achieve >99% selectivity at 180-220°C in the presence of K CO3. Mono-N-methylation of primary aromatic amines at 120-150 °C in the presence of Y- and X-type zeolites, achieved selectivities up to 97%. At high temperature (200°C) and in the presence of potassium carbonate as the catalyst, DMC splits benzylic and aliphatic ketones into two methyl esters; in contrast, DMC converts ketone oximes bearing a methylene group to 3-methyl-4,5disubstituted-4-oxazolin-2-ones. Dibenzylcarbonate (DBzlC) exhibits similar reactivity, selectively monobenzylating methylene-active compounds. 2
Dimethylcarbonate (DMC) is a non-toxic, environmentally safe reagent that can be used in organic synthesis as a "green" substitute for toxic intermediates such as phosgene in carbonylation reactions, and dimethylsulphate (DMS) and methyl chloride in methylation reactions (/). However, the limit for the use of DMC in industrial practice was in its preparation, far from eco-friendly, that involved the reaction of methanol with phosgene. Among the alternative phosgene-free routes to DMC considered in the last two decades, the most attractive is the metal ion-catalyzed oxidative carbonylation of methanol, set up by EniChem in 1983 (2). This technology is now currently used in the industry for the production of DMC. © 2000 American Chemical Society In Green Chemical Syntheses and Processes; Anastas, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2000.
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88 The ever increasing numbers of industrial applications of DMC include its use as a solvent for removing asphalt and metalsfromthe residue of crude oil distillation, as a lubricant, as a component of oxygenated gasoline and as an expanding system for polyurethane foams. As far as its use in organic synthesis is concerned, the carbonyl group and the methyl group of DMC represent the two reactive centers at which a nucleophile may react. Under batch conditions and in the presence of a weak bases (e.g. an alkaline carbonate), DMC may act as a methylating agent (Eq. 1), in the place of DMS and methylchloride (5), or as a carbomethoxylating agent (Eq. 2) and a phosgene substitute (3).
The reactivity of DMC can be influenced by experimental parameters. Methylation reactions (Eq. 1) occur at high temperatures (T>180 °C) when a nucleophilic anion attacks the methyl group (instead of the acyl carbon) of the organic carbonate. The leaving group (methoxycarbonate anion, CH OCOO") is not stable and decomposes rapidly into C 0 and methoxide, which is converted into methanol by reaction with the substrate. In this way, catalytic amounts of the alkaline carbonate are sufficient to initiate the reaction. At lower temperatures, the attack of the nucleophile on the acyl group of DMC gives the transesterification product (Eq. 2). The reactivity of DMC toward nucleophilic compounds is somewhat lower than that observed when analogous reactions are performed with phosgene and DMS. However, both carboxylation with phosgene and methylation with DMS generate stoichiometric quantities of inorganic salt as a byproduct because a base must be used as a reagent. The corresponding processes with DMC do not involve disposal problems since no salts are produced and the co-product methanol can be easily recycled in the DMC production plant (4). DMC can be used profitably to carry out methylation reactions under both continuous-flow and batch conditions. When performed under Gas-Liquid Phase3
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In Green Chemical Syntheses and Processes; Anastas, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2000.
89 Transfer Catalysis (GL-PTC) conditions (/), the reactions of DMC with methyleneactive compounds produce monomethylated derivatives, with a selectivity not previously observed. It is worth noting that industrial monomethylation reactions of methylene-active compounds are not a one-step process because the usual methylating agents produce a significant quantity of dimethyl derivatives.
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Methylation Reactions Selective Monomethylations of Arylacetonitriles and Arylacetoesters The monomethylation reactions of arylacetonitriles and arylacetoesters start from readily available intermediates and produce 2-arylpropionic acid (antiinflamatory drugs, e.g. ketoprofen, naproxen, etc.). Using a 10-30 molar excess DMC, either under GL-PTC (5) or batch conditions (6), it is possible to synthesize 2-arylpropionic acid derivatives with >99% purity in monomethyl derivatives (Eq. 3). K C0 > ArCH(CH )X + CH OH + C 0 X = CN, COOCH 2
ArCH X -f- DMC 2
3
3
3
(3)
2
3
Experimental evidence (detection of ArCH(COOCH )X and ArC(CH )(COOCH )X as reaction intermediates) strongly supports the hypothesis that the high monomethyl selectivity is not due to the S 2 displacement of the nucleophile ArCH(')X on DMC. Instead, DMC acts first as a carboxymethylating agent (B 2 mechanism), which allows the protection of the methylene-active derivatives and permits nucleophilic displacement (B j2) to occur with another molecule of DMC. The proposed mechanism is reported in Scheme 1. This pattern shows the peculiar action of the methoxycarbonyl group, which plays a two-fold role in 1) increasing the acidity of ArCH(COOCH )X, favoring the formation of the corresponding anion, and 2) acting as a protecting group, preventing further methylation. The key step is the attack of the anion ArC(")(COOCH )X onto the DMC molecule. Kinetic studies (7) on the DMC-mediated methylation of phenylacetonitrile at 140°C showed that k > k _ and, since reaction 5 is the only nonequilibrium reaction, the formation of PhC(CH )(COOCH )CN is the driving force of the process. Reaction of [K( )PhCO(COOCH )CN], the potassium salt of 2carboxymethylphenylacetonitrile, with DMC yields PhC(CH )(COOCH )CN as the sole product. For this reaction, the activation energy evaluated using the Arrhenius equation was found to be 23.4 kcal mol ; this is higher, as expected, than the value observed performing the reaction with other usual methylating agents. 3
3
3
N
Ac
A
3
3
5
2
3
3
+
3
3
3
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In Green Chemical Syntheses and Processes; Anastas, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2000.
90 kl PhCH CN + B
-
2
PhC^HCN + BH
k-1
+
1
k2 PhC^HCN + (CH 0) CO 3
^
2
PhCH(COOCH )CN + CH 0" 3
2
3
k-2 k3 +
BH + CH 0"
-
Downloaded by NORTH CAROLINA STATE UNIV on September 20, 2012 | http://pubs.acs.org Publication Date: August 15, 2000 | doi: 10.1021/bk-2000-0767.ch008
3 3
B+ CH OH
3
3
k-3 k4 ^
PhCH(COOCH )CN + B
()
-
3
PhC (COOCH )CN + BH
+
4
3
k-4 ÇOOCH
3
()
PhC (COOCH )CN + (CH 0) CO 3
3
+
2
P h
—
-CN I CH
C
+ C0 + CH CX 2
3
5
3
COOCH3
Ph
Ç
+ CH 0
-
3
-
()
PhC (CH )CN + (CH 0) CO 3
3
6
2
CH kl ^ w
PhC (CH )CN + BH
+
3
-
PhCH(CH )CN + B 3
k-7
total reaction PhCH CN + (CH 0) CO 2
3
•
2
PhCH(CH )CN + C0 + CH OH 3
2
3
Scheme 1. Proposed mechanism for the reaction of DMC with phenylacetonitrile.
Selective Monomethylation of Aroxyacetonitriles and Methyl Aroxyacetates Similar to the mechanism reported in Scheme 1, the methylation ο aroxyacetonitriles and methyl aroxyacetates proceeds with a selectivity up to 99%. The monomethyl derivatives (
