Grignards for Commerc=e The Grignprd reaction building showing the Rocky Mountains in the background. Large tank holds process toluene recovered for re-use
DAVID E. GUSHEE, Assistant Editor in collaboration with RICHARD C. WAUGH and THOMAS D. WAUGH, Arapahoe Chemicals, Inc., Boulder, Colo.
IT
WAS in 1900 that French chemist Victor Grignard (4) described the first of the organomagnesium reagents which soon came to bear his name. Since that time, thousands of technical articles have explored the preparation, properties, and reactions of these versatile, reactive compounds. One book on Grignards (6) contains some 10,000 references and does not even consider reactions with other metals such as cadmium or tin. Probably every organic chemist has at one time or another used the Grignard reaction as a direct laboratory route to compounds otherwise difficult to make. But most share a reluctance to think of Grignards as feasible commercial chemicals or to consider them for large scale use-and there are good reasons for this. Most Grignards are dissolved in a flammable ether, usually diethy? ether. They react with water, often violently-even with the water in air. .4nd they also have been considered to be unstable; for best results, many organic chemists have thought, Grignards should be freshly prepared. Most of these objections have now been put to rest, at least for some applications. The hazards of handling diethyl ether are no worse than those for many other commercial organic chemicals-for example, the trialkylaluminums or the boranes. Reactivity of the Grignards poses no unsolvable handling problems. And in most cases. Grignards are definitely stable. Some have been stored for periods of more than five years with no loss of activity (10). As a result, Grignards are now accepted products of commerce. The Grignard reaction during the past decade has become fairly common in chemical
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plants across the country. Silicones, pharmaceuticals, perfumes, and even some agricultural chemicals have been and are being made by it on a commercial scale. Estimates of Grignard manufacture range from $1,000,000 to $10,000,000 per year ( Z ) , mostly by companies which use these reagents in their own processes. But outside sales of Grignards are also growing rapidly, although they are still small in comparison with the value of captive production.
group give rise to the wide applicability of the Grignard process. The various reactions ( 7 7) can be generalized as follows : Reaction with compounds containing active hydrogen
Grignard Chemistry
Reaction with compounds containing unsaturated linkages
The Grignard reaction is known as the most versatile organic reaction. I t is said that almost anything can be made by it if your want is great enough. In general, the reaction has three steps: Make the Grignard reagent RX Mg + RMgX
+
React it with another reactive compound such as a carbonyl R” RMgX
+ R’COR”
+
I I
R’-C-OMgX R
a
+ MX,,
+
RMgX
-+
f HOH
RH
I 1
C=Y
+
R”
(2)
I I
(4)
Reductive reactions RMgX
+ 01
-+
RMgX
HOH (complex) f ROH f Mg(OH)X ( 5 )
+ XI
-+
RX
+ MgXA
(6)
Special Reactions. Most of these involve allylic rearrangements of the Grignard reagent itself, and in some cases the Grignard undergoes 1,4 addition to conjugated systems. Allylic rearrangement
+ %
+ htg(0H)X
a:!
R Varying the organic radical on the Grignard reagent and changing the reactive
INDUSTRIAL AND ENGINEERING CHEMISTRY
+ MgX2
RC-YMgX
\ -CH=CH-CH2MgC1
I
(1)
-+
R R’-&-OH
+ MgXY
RMX,_,. . .R,M f MgXz ( 3 )
-CH=CH-CHIC1
R“
I
+
RMgX f XR’ -+ RR’ RMgX
Hydrolyze and recover the final compound from the solvent system
R’-!+OMgX
+ HY
RMgX
Reaction with halides
1,4 addition
CO 4 HOH
0
0
-CH=CH-
!
I
--cH=cH=-+
OMgX I
-
RMgX
__ HOH
Reagents are stored in. drums at the back of. Arapahoe’s . . . . property. Drums with ether are stored under the shed
k Despite the many comments to the contrary in the literature, however, the Grignard reaction is not always, or even usually, cleancut with little side reaction. First, there is the Schlenk and Schlenk equilibrium ( 9 ) 2RMgX
+ RiMg
+ MgXi
(9)
The compound RzMg reacts in the same way that RMgX does, so this equilibrium is important primarily for its effect on storage and shipment of the Grignards. Although there is still some argument as to its validity (72), there is no doubt of the insolubility of magnesium chloride etherate in ether. Therefore, Crignard reagents which undergo this reaction to some extent cannot be stored and shipped in concentrated form as the chloride in diethyl ether; they precipitate a sludge on standing. Because magnesium bromide etherate is more soluble in ether than its chloride counterpart, solutions of the bromides are more stable at higher concentrations. Thus, many Grignards are made as bromides. Another side reaction is coupling: 2RX
+ Mg
+
Rz
+ MgXs
(IO)
At about 3M strength or above, the purity of phenylmagnesium bromide, for example, begins to deteriorate as
biphenyl forms through this reaction. Other major side reactions are reduction, disproportionation, and reactions with active hydrogen, oxygen, and alcohol (often an ether impurity). Perhaps the most important reduction reaction is that with ketones. Using isopropyl Grignard, for example, you get: RCOR ++CH&H=CHz + CHaCHzCHa (1 1)
2( CH8)zCHMgX RCHOHR
-+
But since many compounds can be made by any of several alternative routes through the Grignard reaction, judicious choice of reagents often minimizes or avoids these complicating side reactions. Ethers other than diethyl can also be used as solvent systems. Dibutyl ether, for example, is sometimes used to obtain a higher boiling, less hazardous system. But the Grignards are in general less soluble in these higher ethers. Although a 4M solution of methylmagnesium bromide can be obtained readily in diethyl ether, a solution of like concentration in dibutyl ether is a solid mass. Recently, however, several chemists (7, 8) have found that tetrahydrofuran (THF) is an excellent solvent for preparing Grignards from vinyl and aryl chlorides-chlorides which are rather inert in ethyl ether. Previously, vinyl Gri-
gnards had never been prepared and phenylmagnesium chloride only could be used to make Grignards in an excess of chlorobenzene using an inconvenient procedure. So T H F is now a common solvent for some Grignard reagents. Arapahoe Chemicals, Inc.
Arapahoe Chemicals is, in so far as the authors know, the only chemical company in the country which makes Grignard reagents for commercial use. It was formed in 1946 and its first product, made in January 1947, was the Grignard methylmagnesium bromide. Up to that time, Grignards had never been manufactured for sale on a commercial basis, for reasons presented in this article. Since 1947, Arapahoe has continued to expand both in the number and volume of Grignards produced, until in 1958 the company made for sale a total of about 100,000 pounds. It has nine Grignards in routine production, and can tackle the commercial production of almost any other Grignard reagent upon request. In 1953, production volume became large enough to warrant building a larger plant for Grignard reagent manufacture and for custom Grignard reac-
4 Operator watches solids drop into R-1, where the organic halide (the solid) is dissolved in ether prior to feeding it to R-2 where it will react with magnesium. R-2 is the shiny tank with the tall funnel through which magnesium is added
b Second floor of Grignard reaction building. At the very near right is vessel R-4. The white one i s R-3. Tank with high funnel on it is R-2, in which the Grignards themselves are made. Beyond the operator is the feed vessel, R-1 VOL. 50, NO. 12
DECEMBER 1958
1713
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1714
INDUSTRIAL AND ENGINEERING CHEMISTRY
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i i
STAFF-INDUSTRY REPORT
Operator adjusts rate of feed of methyl bromide to R-2. This is one case where the organic halide is not dissolved first in ether but is fed directly to the magnesium in ether in R-2
tions. That plant is the one to be described here. From its inception, the company has used the same process for Grignard manufacture-basicallv the Drocess described in most organic textbooks such as Fieser (3)and modified only to the extent needed for large scale equipment. So far as is known, other chemical companies which have used the Grignard reaction to make their products, such as silicones, perfumes, and the like, have used a similar process and similar equipment, although other processes have been disclosed (7, 5 ) . In fact, there is nothing unusual in the Arapahoe manufacture and use of Grignards except for the economies inherent in being able to re-use the ether solvent and in running the same sort of reaction every day. The company makes Grignards for two purposes-for sale as is and for use in further processing on a custom basis. In 1958, it split these activities approximately thusly: 40% for making salable Grignards, and 60% in running custom Grignard reactions. Arapahoe also makes many other chemicals for sale by routes other than Grignard. Of its total business, however, about one half lies in Grignards, both in selling them and using them. The plant has the equipment needed to make the Grignard reagent, to react it with the reactive compound, to hydrolyze it to the final product, and to recover most of the solvents used during processing. In all, it has five process vessels (all designed by the company) with auxiliary equipment, such as heat-
The operator regulates flow rate of organic halide from R-1 to R-2. Large motor is to agitator on R-1
ing jackets, condensers, agitators and the like, and tanks for holding solvents and materials in process. That is about the extent of the Grignard equipment.
Makingthe ~
~R~~~~~~ i
The Grignard reagent is made by dissolving a n organic halide ih an ether solvent and reacting it with magnesium turnings, also suspended in the same ether solution. Diethyl ether, in spite of its hazards, has proved to be the most satisfactory solvent. It is cheap; commercial grades are sufficiently pure; it is to recover for re-use; and it has solvent power for most Grignar Arapahoe prefers diethyl ether, therefore, to higher boiling ethers, tertiary and hydrocarbons, all of which en recommended as solvents from time. About the only time when ether is not used is when tetrahydrofuran is; these cases arise most often when aryl or vinyl halides are being processed. Arapahoe uses two mild steel vessels eration. R-1 (Figure 1) has a
so in
halide in ether. I t has a workre of 75 p.s.i. and has a double, d agitator driven by a 3-hp. has no provision for heating
or cy gen) is used to transfe from R-1 to reaction vessel R-2. This reactor has a 650-gallon capacity, is also of mild steel, and has the same agitator setup as R-1. I t is jacketed for
~
heating and cooling, has a working pressure of 75 p.s.i., and is equipped with a rupture disk and a 4-inch vent line to the roof to handle any excessive rise in pressure, should a reaction “take off.” An excess of magnesium is used in ~ ~ ~ d each run so that a heel is always left in R-2 to help initiatd the reaction which forms the Grignard. This heel has an etched surface from the previous reaction, and hence, is more reactive. For very stubborn reactants, Arapahoe adds a small amount of the product to be made to aid the reaction mixture through its induction period. In all cases, only a small amount of halide is added until the reaction has definitely begun. Most control is manual. The reaction vessel, R-2, has a thermometer and a pressure gage and the operators watch these to check the progress of the reaction. R-1 is pressured to a few pounds per square inch (ranging from 5 to 20 p.s.i., depending on the reaction). As the reaction proceeds in R-2, pressure in it builds up, also, and this back pressure serves to regulate the flow rate of organic halide to the magnesium. Reaction times vary from about 2 to 6 hours. All reaction temperatures are between ambient and about 50’ C. and held there by cooling water, manually controlled. When all of the feed has been added, the reaction mixture is stirred for another 15 to 30 minutes to ensure complete reaction. To get consistently good yields of Grignard reagents, Arapahoe depends on good agitation and controlled rate 01. 50, NO. 12
DECEMBER 1958
1715
Operator checks progress of Grignard reaction in reactor R-3 through glass plate. Reactor R-2 is in left foreground
of halide addition to minimize local overheating and resultant losses from Wurtz and disproportionation reactions. Yields range from 85% to 9570,depending on the reactants, and they are reproducible. If the Grignard thus prepared is to be sold, it is placed in drums directly from R-2 after appropriate analysis. If it is to be used for a custom Grignard reaction, it is transferred, again by nitrogen pressuye, to reactor R-3, which, except for the disentrainment column and condenser ( 4 E ) added, is a duplicate of R-2. In this way, the magnesium heel, with its etched surface, can be left in R-2 and used to initiate the next Grignard batch.
Ground floor of Grignard building, showing reactors R-1 to R-3 from center rear to front right. The white powder on floor is Celite to take up a Grignard spill
R-3 where it is allowed to react with a carbonyl or other reactive compounds. To illustrate this process, which can take so many forms, let us use the production of dimethylbenzylcarbinol, a perfume ingredient which the company makes in this equipment, as an example. For this reaction, the Grignard is benzylmagnesium chloride, made in R-2 and transferred to R-3 by nitrogen pressure according to the method already described. This is reacted with acetone in a typical carbonyl reaction (reaction 3). Thus, acetone is dissolved in ether in an 80-gallon, carbon-steel feed tank for R-3. From there, it is fed slowly by nitrogen pressure to the Grignard
solution. Reaction temperature is controlled to 50” to 55’ C. either by cooling water manually throttled to the reactor jacket or, if the reactor will not hold the full charge, by boiling, with the distilled ether flowing by gravity from the condenser ( 4 E ) to the recovered ether storage tank (5E). After all the acetone-ether solution has been charged, the reaction mixture is agitated for an extra 10 minutes or so to ensure the reaction is complete. Next step is to transfer the Grignard reaction product from its ether solution into a hydrocarbon such as toluene or xylene. This is done to recover the ether dry so it can be re-used without having to go through the expensive and
Making the Magnesium Complex
When the Grignard reagent is to be used by Arapahoe it is transferred to
Machine at left center is an ice crusher; the hose conveys crushed ice to hydrolyzer, R-4, where it is used to keep reaction cold and to keep corrosion from acid a t a minimum
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INDUSTRIAL AND ENGINEERING CHEMISTRY
looking from behind R-4, the tank’s agitator set-up and operator’s work platform in front of the row of reactors
STAFF-INDUSTRY REPORT
Drummed Grignard reagents are stored under this shed awaiting shipment. Roof keeps direct rays of sun away from drums, and protects ether from expanding. Sun is hot at this altitude, even though temperature may be moderate
Operator checks progress of steam distillation of toluene from product in R-5. Toluene returns to cylindrical tank outside building. Product ends as separate product layer or as water slurry, depending on its properties, This fellow is watching the vapors go up through sight glass at top of picture just to the left of center
difficult process of drying it. Toluene is thus pumped (3E) from its storage tank (6E)outside the building into R-3, as ether distills off. Heat is supplied by steam in the reactor jacket. Reactor contents are not allowed to rise above 90' C Cduring distillation of the ether. This is one of the most ticklish operations in Grignard chemistry as practiced by Arapahoe. Economics of Grignards depend to a considerable extent on the company's being able to re-use its ether which other chemical companies using the Grignard reactions frequently cannot do. But many magnesium complexes are less soluble in the hydrocarbon than in ether, so the transfer must be accomplished carefully to avoid getting a large solid mass in R-3. The company uses extreme care a t this stage, therefore, to prevent the formation of these solid masses. Ether is distilled slowly, and toluene is added approximately as fast as the ether distills to give the complex as much chance as possible to stay in solution. Water and oxygen are excluded by keeping everything at all times under a positive pressure, either by nitrogen or by process conditions. Alternative Processes. For some reactions, it is better to add the Grignard to the carbonyl or other reactive compound rather than in the manner cited in the example. In those cases, Arapahoe dissolves the reactant in R-3 and adds the Grignard slowly from R-2, with all other factors the same as before. In some cases, the Grignard reaction
can proceed in the hydrocarbon faster than it can in ether because the hydrocarbon, with its higher boiling point, provides a higher reaction temperature. I n those cases, the ether is displaced by toluene or other hydrocarbon before the reactant is added (the reactant too, of course, is dissolved in toluene in these cases). But when this is done, some ether cannot be removed by distillation; it is complexed with the Grignard. Thus, it is released as the reaction proceeds and is distilled off and recovered during the course of the reaction. Hydrolysis of Complex
The Grignard complex made in R-3 is next hydrolyzed to the desired product in R-4, an 1100-gallon vessel of mild steel and atmospheric pressure with a conical bottom and flat top and equipped with a two-bladed propeller agitator driven by a 5-hp. motor. I t is charged with the requisite amount of sulfuric. acid, water, and ice to bring its initial temperature to -20' to -30' C. and the final temperature after hydrolysis to near 0' C. The magnesium complex in hydrocarbon (toluene when dimethylbenzylcarbinol is being made) is then pumped (9E) from R-3 into R-4, while the latter is kept vigorously agitated to ensure intimate contact between complex and acid. Final temperature is kept below 5 O C. ; the final pH is adjusted to 2 with more acid if needed. Then the aqueous and organic layers are allowed to separate,
the aqueous layer being discarded. (In a few cases, the product of hydrolysis is water-soluble and organic-insoluble, in which case the water layer is retained and treated.) Because the acid is always kept cold in the tank, it does not corrode the mild steel. After five vears of acid use, in fact, corrosive attack is hardly noticeable except above the liquid level where acid has occasionally splashed. Dimethylbenzylcarbinol, unlike most of the products made in this plant, is vacuum stripped in separate, standard equipment to remove the solvents. Most of the products are nonvolatile and water-insoluble. In these cases the organic layer is filtered (8E) to remove residual magnesium salts, and finally transferred to R-5, a 300-gallon steam still (7E), equipped with a steam sparger, disentrainment space, and condenser (4E). The solvent is steam-distilled out and the product is then recovered either by decanting if it is a liquid or by filtration if it is a solid. Further purification is carried out by conventional means in conventional equipment if needed. Safety
Most of the hazards of Grignard manufacture and processing are those of ether. Thus, all floors and all equipment are grounded. Sparkproof tools are used in the processing area. All motors and fixtures are Class I, Group D or Class 11, Group G. The building has four 30-lb. dry chemical fire extinguishers (7E) spotted in several easy-to-reach places in the building and a 150-lb. wheel mounted dry chemical extinguisher (2E) outside in a small shed. Floors are kept washed clean from all spills and this also serves to reduce the problem of static sparks-a problem which one would expect to be great in
-
-VOL.40, NO. 12
DECEMBER 1958
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I
Grignard reaction building showing how it is set apart from everything to minimize effects of a fire, should one break out
the dry air of the Rockies. There are two 10,000-cubic-feet-per-minute blowers continually changing the air inside the building. Elephant trunks (large diameter, flexible hoses) provide extra, local exhaust capacity where needed. Spills are absorbed in Celite. And when Grignards are being transferred, the floors are kept dry to minimize the effects of any spill. Operators wear rubber gloves, hard hats, and safety glasses with side shields. They put on face shields when handling the Grignards. They wear safety shoes with the steel-covered toes also. Bzcause of the nature of the solvents used, these last only an average of two months per pair; no pair has ever been resoled ; the uppers go as fast as the soles. The operating area has a soundpowered telephone connecting with the office several hundred feet away. Solvents, ether, and drums of Grignard reagents are spaced around the plant, with all ether-containing drums placed under shelter to protect them from the heat of direct sunlight. Small lots in bottles are stored in a separate shelter by themselves. Future Prospects
Arapahoe is the only chemical company in the country which, to the authors’ knowledge, makes Grignard reagents for sale. I t is one of only a few which use the Grignard reaction on a large scale for commercial production of other chemicals. In 12 years, the company has seen its reagent business reach a lOO,OOO-lb.-per-year level, and it is still apparently on the rise. The market is expected to continue to grow gradually, despite the high cost and hazards of Grignard reagents. There are several situations in which it is feasible for a chemical company to purchase Grignards, rather than to make them itself, Also, in some cases, a Grignard expert, such as Arapahoe, can make them
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A large dry-cheniical, wheel-mounted fire extinguisher ( 2 € )i s housed in a separate shed about 50 feet away from the Grignard processing building so a fire fighter can approach a fire from outside the building. There are also four smaller extinguishers of the same type ( I € ) inside the building
more cheaply, particularly where the customer is a small scale user. I n still others, the chemical company prefers to put its capital investment into equipment for its primary product, rather than into Grignards, which someone else is willing to make for it. The custom Grignard reaction business, too, is expected to grow as new pharmaceuticals, such as synthetic hormones and vitamins, go into commercial production. An exact estimate of the growth pattern, however, is difficult indeed, although some general rules can be laid down. Reaction of a Grignard with a carboxylic ester illustrates some of the economic factors involved : 2RMgX
+ RCORRaCOH + 2Mg(OH)X -+
I n this case, for each 1-pound mole of useful product obtained, 2-pmnd moles of basic magnesium halide are formpd. Unless the operation is very large, it is not economical to recover this material. even though it contains magnesium worth about $25 and, in reactions using the bromide, $40 worth of bromine. It is obvious that few compounds with raw materials costs of less than $1.00 per pound can be produced by this reaction. Most of those now made, in fact, run closer to $3.00 or more a pound. Therefore, the commercial use of the reaction is restricted to expensive chemicals such as perfumes, pharmaceuticals, silicones, and a few agricultural chemicals. Indeed, since most of the products now made fit into these categories, the future will probably bring mostly “more of the same.” literature Cited il’i Bohrd. \-, ~ - - C. E.. Henne. A. L.. Green‘ K. ’W.. Pkrilstein,’ W. L.; Derfer, IC.,~ e .~J. M., IND.E.NC.. - CHF.M. -..- 41, 609 (1949). (2) Chem. Eng. iVews 36, 50 (July 28, 1958).
(3) Fieser, L. F., “Experiments in Organic Chemistry,” pp. 403-10, Heath, New York, 1941.
INDUSTRIAL AND ENGINEERING CHEMISTRY
(4) Grignard, V., Compt. rend. 130, 1322 (1900). (5) Hill, J. S. (to Cincinnati Milling Machine Co.), U. s. Patent 2,522,676 (May 1951). (6) Kharasch, M. S., Reinmuth, O., “Grignard Reactions of Nonmetallic Substances,” Prentice-Hall, New York, 1954. (7) Nprmant, H., Compt. rend. 239, 1510 (1934). (8) Ramsden, H . H., Belint, A. E., Whitford, W. R., Rosenberg, s. D., Waliburn, J. ,J., Leebrick, J. R., Coerr, R., J. O r g X h e m . 2 2 , 1202; 1602 (1957); 23, 935 (1958). (9) Schlenk, W., Schlenk, W., .Jr., Ber. 62B, 920 (1929). (IO) .Waugh, R. C., Waugh, T. D., Division of Industrial and Engineering Chemistry, p. L-10, 131st Meeting, ACS, Miami, Fla., April 1957. (11) W’augh, T. D., “Grignard Reactions,” in “Encyclopedia of Chemical Technology” (Kirk, R. E., Othmer, D. F., ed.), vol. 7, p. 314, Interscience, Kew York, 1951. (12) Wotiz, J. H., Simon, A. W., Hollingsworth, C. A,: Division of Organic Chemistry, p. N-7, 133rd Meeting, ACS, San Francisco, Calif., April 1938. Processing Equipment
(1E) Ansul Chemical Co., Marinette, Wis., fire extinguisher, 30-lb. dry chemical. (2E) 16id., fire extinguisher, 150-lb. wheel mounted dry chemical. (3E) Fairbanks. Morse and Co., Chicago, Ill., centrifugal pump, 1 X 1, 20 gal. per min. (4E) Graham Manufacturing Co., New York 17, N. Y., 30 X S18L HeliFlo condenser, 49 sq. feet of heat transfer surface. (5E) Longera Boiler & Sheet Iron Works, Denver. Colo.. storage vessel, 750-gal. pressure and 50-p.s.i.-working pressGre. (6E) Longera Boiler & Sheet Iron Works, Denver, Colo., storage vessel, 1000-gal. atm. pressure. (7E) Pepper Tank Co., Denver, Colo., steam still with steam sparger, 300 gallon. (8E) T. Shriver & Co., Harrison, N. J., plate-and-frame filter press, 24-inch cast iron, 14-plate. (9E) U. S. Government, Navy surplus bronze gear pump, 20 gal. per min. (10E) Worthington Corp., Harrison, N. J., positive displacement pumps, 10 gal. per min.
