Grignard Reagent Master Organic Chemistry
Ceasar Doyle
Another thing to keep in mind is stereochemistry of the epoxide.Consistent with an SN2 reaction, if the reaction occurs at a secondary carbon, we will observe inversion of configuration:
Here are some examples of reactions of Grignards with aldehydes and ketones. Note that in each case we are forming a new bond between the carbonyl carbon (labelled A) and the carbon bound to magnesium (labelled B), and we are breaking the C-O pi bond in the process.
Esters are close relatives of aldehydes and ketones: they consist of a carbonyl group directly attached to an OR group. As you might expect, they react with Grignards in a similar fashion to aldehydes and ketones: with formation of a new C-C bond and breakage of a C-O (pi bond).
Elimination does not occur in addition to aldehydes and ketones because the leaving group would have to be the extremely strong bases H(-) or R(-). It is reasonably favorable for esters because the leaving group RO(-) is of comparable basicity to the negatively charged oxygen of the tetrahedral intermediate. [Note 1]
Note 3. Alas, no. Using 1 equivalent of Grignard will result in 0.5 equivalents of a tertiary alcohol and 0.5 equivalents of the starting ester. The reason why is that Step 2 [elimination] is quite fast!
Once elimination occurs, we will have ketone in the presence of an ester. For interesting reasons [see Note 2] ketones are more reactive than esters toward Grignard reagents, which means they will be consumed more quickly.
The reagent can get protonated in cases where the Grignard or the ketone are sterically hindered. One complication of acidity of the alpha position of aldehydes or ketones is that the alpha C-H bond must be aligned with the C=O bond in order for it to be acidic; otherwise the resulting carbanion would not be resonance stabilized. There is no such barrier to addition to the carbonyl.
I was wondering about the reactivity of different grignards reagents, with the same R group. Meaning I, Cl, Br. If I where to have two methyl halogens in the solution, which one would be more readily to form the grignard?
Grignard reagents also add to carbon dioxide (CO2) to form carboxylates, in a reaction similar to their reactions with ketones and aldehydes. The carboxylates are converted to carboxylic acids after addition of acid (such as our trusty H3O(+) ).
This can also be used to convert alkyl halides to alkanes. First you treat it with magnesium, and then you treat the Grignard with a strong acid. This gives you the alkane. You can also use this to introduce deuterium (D) into molecules! The first step is to make the Grignard reagent. The second is to treat that Grignard with a deuterated acid such as D2O. This gives you the deuterated alkane!
I have a doubt
As the Grignard reagent is a very strong base, why will it not react with the acidic alpha hydrogen of the carbonyl compound (which has pka value around 20),and as acid base reactions are must faster than nucleophilic addition reactions why would addition occur?
Hello,
I was just thinking that the reaction to make a grignard is exothermic and reacts spontaneously. Furthermore, oxido/ reduction reactions are thermodynamic reactions (Delta G = -nF(delta)E). Hence, can I conclude that the reaction to make a grignard is under thermodynamic control ?
This feels counter intuitive since the formed organometallic compound is much more reactive and much more unstable then the halogenated one.
I hope you will be able to enlighten me in where I am going wrong.
Thanks for all your great work.
Thermodynamic control is when you can choose the product distribution of an equilibrium mixture by changing the temperature. There is no equilibrium between the Grignard product and the starting materials.
They deprotonate carboxylic acids, but do not react further. The resulting O(-) is a very strong pi donor to the carbonyl carbon, which greatly reduces its electrophilicity. Organolithium reagents do add to carboxylic acids however.
The short answer is no. The electons in a C-C pi bond in an alkene are shared relatively equally between the carbons, with the result that neither carbon has any significant partial positive charge. Alkenes are unreactive. Contrast that to a C=O bond, where carbon is partially positive and oxygen is partially negative; Grignard reagents are much more reactive in that situation.
Great question. It tends to initiate electron-transfer type reactions that end up leading to cleavage of the R-X (X being halogen) bond. Grignards tend to be clusters in solution and so they are more sterically hindered than they might appear. The solution is to make them into organocuprates (Gilman reagents) by using CuBr or the like. Then SN2 reactions work well (particularly on primary substrates). James
If you were trying to synthesize a product using Grignard chemistry, and the Grignard reactant (R-MgBr) also contained an ester and the other reactant were an aldehyde, would the Grignard reactant possibly react with itself before it reacted with the aldehyde?
Because fluorine is the smallest element among the halogens and fluorine forms covalent bond with carbon atom which is strong so in order to break such kind of bond vigorous conditions must be apply therefore
Since conjugate bases are made through deprotonation, we might naively think that we could make organolithium species by taking an organic molecule and just adding a super-strong base to rip off the proton.
If you look at the reaction below, and count the electrons carefully, you might note that the product has two more electrons than the starting material. In other words, particularly if you remember the OIL RIG mnemonic, reduction has occurred.
Lithium, having a very low ionization energy (i.e. it loses its electron easily) is a powerful reducing agent. Since lithium only has a single valence electron, however, we must add two equivalents if we are to complete the reduction reaction.
From a practical perspective, one key thing to make sure of when preparing organolithium or Grignard reagents is that the solvent and glassware are completely dry. Water (pKa 14) is death to Grignard and organolithium reagents, which as we said above, act as the equivalent of highly basic alkyl and alkenyl anions.
From my friend Jeff, who regularly used Li metal to make lithium di-tertbutyl diphenylide (LDBB).
Lithium prep:
tweezers
1 pair of needle-nose pliers
Lithium wire (usually with a small % of Na in it) in oil
3 beakers: hexane, THF, and MeOH, and then a 4th with reaction solvent (or just the reaction itself, with an ARGON atmosphere, preferably)
Cut wire into pieces with scissors or pliers and put into hexanes
Use tweezers to fish out a piece of Li and squish with pliers and return to hexanes
Once all the pieces have been pressed, use tweezers and take a piece out of hexanes and dip in THF then MeOH then THF again and then into the reaction solvent/flask.
Repeat with remaining pieces of Li
is there a reason that orgo students learn about both grignard and organolithium reagents if they do the same thing which acts as a strong nucleophile/base? is there a certain advantage one has over the other
Grignard reagents are extremely useful organometallic compounds in the field of organic chemistry. They exhibit strong nucleophilic qualities and also have the ability to form new carbon-carbon bonds. Therefore, they display qualities that are also exhibited by organolithium reagents and the two reagents are considered similar.
When the alkyl group attached to a Grignard reagent is replaced by an amido group, the resulting compound is called a Hauser base. These compounds are even more nucleophilic than their Grignard counterparts.
Grignard reagents (RMgX) are commonly used for organic synthesis. However, these highly reactive compounds are supplied inflammable solvents, which cause extra complexity in their transport. Herein we note that Grignard reagents with linear alkyl chains can be trapped and stabilized by the macrocyclic host pillar arene while retaining their reactivity.
Reactions that form carbon-carbon bonds are among the most beneficial to synthetic organic chemist. In 1912, Victor Grignard was awarded the Nobel Prize in Chemistry for his discovery of a new sequence of reactions resulting in the creation of a carbon-carbon bond. Grignard synthesis involves the preparation of an organomagnesium reagent through the reaction of an alkyl bromide with magnesium metal.
During a reaction involving Grignard reagents, it is necessary to ensure that no water is present which would otherwise cause the reagent to decompose rapidly. Therefore, the majority of Grignard reactions occur in solvents such as anhydrous diethyl ether or tetrahydrofuran because the oxygen in these solvents stabilizes the magnesium reagent.
Grignard reagents are formed by the reaction of magnesium metal with alkyl or alkyl halides. They are wonderful nucleophiles, reacting with electrophiles such as carbonyl compounds (aldehydes, ketones, esters, carbon dioxide, etc.) and epoxides.
Organolithium or Grignard reagents react to alcohol in aldehydes or ketones with the carbonyl group C = O. Carbonyl substituents determine the essence of the alcohol component. The acidic work-up transforms the intermediate metal alkoxide salt into the desired alcohol by means of a simple acid-base reaction.
The bulk of Grignard reactions are conducted in ethereal solvents, in particular diethyl ether and THF. With the chelating diether dioxane, some Grignard reagents undergo a redistribution reaction to produce organomagnesium compounds.
The Organic Chemistry Reaction and Mechanism Guide will help you understand more than 185 of the most common reactions encountered in undergraduate organic chemistry.
Generally I would prefer dialkyl cuprate to dialkyl cadmium for conversion of an alkyl halide to a ketone, but dialkyl cadmium will also work. Both of these reagents will convert acid halides to ketones without addition to ketones. (see JACS 1972 vol 94 8593)
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