(Hive Prodigy)
08-05-02 01:18
No 341378
(Rated as: excellent)
Hi.
I've been getting a few questions lately in private regarding Grignard Reactions. Instead of just answering the questions one by one (which I actually did) I figured I'd relieve some boredom for a bit and write a short document on the subject, just to toss it into the Search Engine, if nothing else.
If anyone is interested in the following as a Word Document file, PM me and I will email it to you. Here follows some bits of information that everybee should know about this very useful, but unforgiving reaction.
Grignard Reagents are organometallic compounds of a class known as organomagnesium halides, and have the structural formula representation of RMgX, where R denotes a carbon-based substructure wherein there is a carbon directly and singly bonded to a magnesium atom; Mg denotes a magnesium atom singly bonded to both a carbon-based substructure, and a halogen; and X denotes a halogen atom specified in Group VIA (7A) of the Periodic Table, singly bonded to a magnesium atom. The R substructure may not contain any structures or substructures that are reactive toward Grignard Reagents, as will be outlined below, due to these structures’ and/or substructures’ inhibition of preliminary Grignard Reagent formation.
(In other words, R can’t have functional groups in it that the Grignard Reagent will react with, because it would self destruct, so to speak. This will prevent the Grignard Reagent from being made in the first place.)
Grignard Reagents are almost never isolated due to their high reactivity and intrinsic instability outside of a solvent cage. They are commonly prepared as a ready-to-use solution, and are used in reactions without their prior isolation or workup, and are most often prepared right before use so as to prevent unwanted decomposition and side products that may interfere with a reaction.
Grignard Reagents are prepared from alkyl halides of the formula RX by introduction of a magnesium moiety. The carbon in the R substructure that is bonded to the halogen (X) may be primary, secondary, or tertiary, and may contain double or triple bonds. The general procedure for the preparation of RMgX involves solvating the alkyl halide in an inert ether, commonly diethyl ether (Et2O) or tetrahydrofuran (THF), usually of a minimum quantity of twice the molar quantity of alkyl halide moieties to be metallated. Addition of magnesium metal to this solution sets the stage for Grignard Reagent formation.
It is important to insure the anhydrous conditions, and purity of reagents, for Grignard formation to proceed. All solvents and reagents must be thoroughly dried, and inert atmospheres must be employed, usually nitrogen or noble gasses are used. Magnesium should preferentially be free of oxide impurities to the greatest extent possible. Grignard Reagents often require extra persuasion beyond these conditions in order to form, and may take awhile to begin doing so.
Addition of a crystal of iodine, the use of ultrasonication baths, employment of specialized catalysts, and minor mechanical agitation, have been employed in the coercion of alkyl halide/ether solutions to form Grignard Reagents. A cosolvent may be employed to aid in solvation of bulky organic groups, and/or to aid in solvating reactants to be combined with the Grignard Reagent to initiate a reaction. Any cosolvent used must be inert to the Grignard Reagent itself. Common cosolvents employed are aromatic liquids such as benzene and toluene. In the scenario of the usage of a cosolvent, the Grignard Reagent RMgX is first prepared in pure ether, and is then diluted slowly with the cosolvent. Cosolvents must also be carefully dried and submitted to the same handling and purity conditions that primary ether solvents are subject to, to ensure successful reactions.
Reactants to be used in conjunction with Grignard Reagents to initiate a reaction are likewise solvated in ether, of a minimum quantity that will fully solvate the reactant. To initiate reaction, the two ether solutions are combined in an inert system and homogenized (stirred or agitated) until completion. Workup of Grignard Reactions commonly involves addition of dilute aqueous or alcoholic acids to neutralize any unreacted Grignard Reagent in solution.
Grignard Reagents are highly versatile building blocks in organic chemistry, and react very predictably with a very large assortment of functional groups readily, giving anticipated products a vast majority of the time. As versatile as the reagents are, they are just as intolerant and indiscriminate toward the presence of these functional groups, and other reactive entities. In other words, if there is but the slightest negligeable quantity of substance reactive to Grignard Reagents present, expect that substance to react fully with the reagents present, possibly interfering with the reaction. Common intrusions are moisture, oxygen, carbon dioxide, acidic protons, and reactive functional groups in other molecules.
General reactions of Grignard Reagents with various organic compounds, and their corresponding products, are listed below. In these lists, R may denote any all carbon alkyl or aryl or arylalkyl or alkylaryl substructure or combination of substructures that does not contain functional groups reactive toward the Grignard Reagent.
Notes for above table:
1. This method can be useful for stripping a halogen off an alkyl or aryl structure, by formation of the Grignard Reagent, followed by immediate acid hydrolysis. The resultant RX ___> RH is often high yielding. Aryl halides are often more difficult to form Grignard Reagents, however. Bromides and iodides are often used for aryl systems, but chlorides are very slow to react, and fluorides often never react at all, be they aryl or alkyl.
2. Both R and R’ may be Primary, Secondary, or Tertiary carbons. The product is always a single bond between R and R’ to form R-R’.
3. Formaldehyde is used to produce Primary alcohols of a length of one carbon longer than the Grignard Reagent structure.
4. Ethylene oxide is used to produce Primary alcohols of a length of two carbons longer than the Grignard Reagent structure.
5. Aldehydes other than formaldehyde are used to produce Secondary alcohols.
6. 2-substituted ethylene oxides, such as propylene oxide, are used to produce Secondary alcohols in which a carbon is placed between the alcoholic carbon and the Grignard carbon structure. Propylene oxide, for example, produces 1-substituted isopropanols where the substitution is the Grignard carbon structure.
7. Ketones are used to produce Tertiary alcohols. I suspect (but am not certain) that Ketenes can also be reacted with Grignard Reagents, forming enol alcoholates of the magnesium halide half salt. Upon acid hydrolysis of these alcoholates to liberate the alcohol, the acidic environment would cause tautomerization of the enol to produce another ketone. This is only speculation, however.
8. Carbon dioxide is used to produce carboxylic acids of structure in which the COOH function is attached to the Grignard carbon structure. This is a very useful reaction. Grignard Reagents themselves will react with Carboxylic acids and esters unpredictably, but in the formation of these acids, the magnesium entity bound to the carboxyl prevents its further reaction with another Grignard Reagent moiety.
9a. Organic nitriles are used often to form Ketones. This process proceeds by reaction of the Grignard Reagent with the CN function of the nitrile, facilitating C-C bond formation between the nitrile carbon and the Grignard R carbon. The nitrile is reduced to an imine magnesium salt of the formula RCH(=N-MgX)R’. Upon workup with dilute aqueous acid, the salt is reduced to the free imine, and is hydrolyzed to the Ketone.
9b. If the intermediate iminium magnesium salt is not reduced by acid and hydrolyzed, but instead subjected to reducing conditions such as NaBH4 reduction, the imine is reduced to a Primary amine.
10. DMF is dimethylformamide, HCON(CH3)2. Grignard Reagents react with DMF like they react with an Aldehyde or Ketone, causing C-C bond formation at the carbonyl and reduction of the carbonyl to an alcohol. In this case, reduction of the carbonyl in DMF produces an aminal, which decomposes to an Aldehyde and dimethylamine upon workup. The amine used for the formamide must be secondary, so that the amide contains no hydrogen atoms. The Grignard Reagent will react with said hydrogens if they are present, and the reaction will not proceed properly.
11. Aziridines can be used to form ethylamines upon reaction with Grignard Reagents. Ethylene imine will form plain ethylamines, and 2-substituted aziridines will form ethylamines substituted at the amine carbon. N-substituents on the aziridine translate to an N-substituent on the formed amine.
12. Grignard Reagents react with imines to form either Primary or Secondary amines, depending on the nature of the imine. If the imine is of the formula R=NH, the formed amine is Primary after workup. If the imine is of the formula R=NR’ where R’ does not equal H, the formed amine is Secondary after workup. C-C bond formation between the Grignard Reagent and substrate imine occurs at the carbon involved in the imine double bond.
General Mechanics of Grignard Reactions:
The reactivity of Grignard Reagents is derived from their electronic polarization. In an alkyl halide, the halide is more electronegative than the carbon it is bound to, and some polarization occurs, at least on a small scale. The halides take on a weak negative charge, whereas the carbons take on a weak positive charge, due to the electrons occupying the shared orbitals residing more often near the halogen atom than near the carbon atom.
Introduction of a magnesium atom between the carbon and halogen reverses this polarity. Magnesium is less electronegative than carbon, and so the polarity between C-Mg is the reverse of that of C-Br for example. The carbon carries the negative polarity and the magnesium contains a positive polarity. These carbanions are strongly attracted to positive charges and polarities. The C-C bond is very strong, once it has been made, it takes a great deal of energy to break it, and generally in Grignard Reactions, this energy is not present.
The carbanions of Grignard Reagents are attracted to carbocations of traditional alkyl halides and other carbocations such as carbonyl functions, where the polarization strongly favors a negatively polarized oxygen atom and a carbocation counterpart. Conversely, the positively polarized MgX entity is electrically attracted to the negative polarizations found in the vicinity of carbocations. In a traditional Grignard Reaction between RMgX and HCHO to form a primary alcohol, the carbanion of the Grignard Reagent electronically couples with the carbocation of the formaldehyde, retracting its electron from the magnesium, making it (the Mg) positively charged, and the oxygen in the carbonyl retracts an electron, attaining a negative charge. The formation of the C-C bond neutralizes the carbon polarizations, and the positive MgX entity is attracted to the negatively charged oxygen ion, forming a neutral O-Mg-X coordination. This complex is highly reactive toward active hydrogens and moisture, just as Grignard reagents are. When aqueous HX’ is used to quench the reaction upon completion, the MgX attains a second halogen atom, forming a full magnesium salt, MgXX’. The freed oxygen scoops up the remaining proton, forming an alcohol.
The basis for all Grignard Reactions is the reactivity of the Grignard carbanion toward another molecule’s carbocation, or in the case of purposeful reduction, the carbanion’s reactivity toward protons. The reagents are stabilized in ethers due to the nature of the unreactivity of these solvents, and their ability to complex with the Grignard Reagents at the extremely positively polarized magnesium atom, stabilizing it. The lone pair of valence s orbital electrons in the oxygen bridge of an ether molecule stabilize the positive polarity of the magnesium atom by sharing their charge. This effect is essential to Grignard Formation. It should be noted that Grignard Reagents rarely react with aryl halides, however. This is because the aryl ring is sufficiently electronegative so as to not exhibit a positive polarity due to a halogen’s presence. This, combined with the effect of charge distribution throughout the ring, prevents any carbocationic activity, and thus the aryl system is inert to the Grignard Reagent. To use aryl halides, you must make Grignard Reagents of them.
Links to view:
../rhodium /grignar
../rhodium /grignar
Enjoy, and be sure to tell me if I made any incorrect statements, and I'll edit them. Now if I get any more questions about these reactions, I can reply UTFSE!
PrimoPyro
(Chief Bee)
08-05-02 02:53
No 341399
Great post, but don't distribute Word files written on your own computer, the file will include too much personal information about yourself (see the Server forum for a discussion about this).
(Hive Bee)
08-05-02 07:04
No 341482
Hey Rhodium, perhaps notifying PrimoPyro and others of their errors of this nature should be done by PM so as not to draw attention to the error. Then a general statement or warning post can be made elsewhere for all to see. if the personal information is too, well, personal, then have the post deleted and reposted.
(Chief Bee)
08-05-02 12:18
No 341596
I don't believe he ever sent that Word file to anyone. Besides, the information is whatever you typed into the windows and word registration when installing the programs, and noone I know write their real names there anyway.
I found a very interesting image in an old post of mine regarding grignards, see Post 303153 (Rhodium: "grignard", Chemistry Discourse).
(Stoni's sexual toy)
08-05-02 13:48
No 341621
> the information is whatever you typed into the windows
> and word registration when installing the programs, and
> noone I know write their real names there anyway.
There's more in the doc than just the name. Word/Office also saves your computer's GUID, which includes the globally unique serial number of your NIC.
I'm not fat just horizontally disproportionate.
(Old P2P Cook)
08-06-02 02:13
No 341885
Word/Office also saves your computer's GUID, which includes the globally unique serial number of your NIC.
Today I used a Hex editor (UltraEdit32) to look at a Word document and while I found some username info in the file I was not able to find a CPU or NIC ID.