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Have you ever wondered why the gas station has “unleaded fuel” but there isn’t a “leaded” option? The answer has to do with a chemical called tetraethyl lead, which is an organometallic compound, or an organic compound with a carbon-metal bond. In this episode of Crash Course Organic Chemistry, we’ll learn all about organometallic compounds, including what they are and what kind of reactions we see them in. But beware! This class of compounds may be super useful, but also has a dark side.

Episode Sources:
Lowe, D., 2009. Things I Won't Work With: Straight Dimethyl Zinc. [online] In the Pipeline. Available at: https://blogs.sciencemag.org/pipeline/archives/2009/10/23/things_i_wont_work_with_straight_dimethyl_zinc [Accessed 4 November 2020].
Gilman, H., Jones, R.G. and Woods, L.A., 1952. The preparation of methylcopper and some observations on the decomposition of organocopper compounds. The Journal of Organic Chemistry, 17(12), pp.1630-1634, DOI: 10.1021/jo50012a009

Series Sources:
Brown, W. H., Iverson, B. L., Ansyln, E. V., Foote, C., Organic Chemistry; 8th ed.; Cengage Learning, Boston, 2018.
Bruice, P. Y., Organic Chemistry, 7th ed.; Pearson Education, Inc., United States, 2014.
Clayden, J., Greeves, N., Warren., S., Organic Chemistry, 2nd ed.; Oxford University Press, New York, 2012.
Jones Jr., M.; Fleming, S. A., Organic Chemistry, 5th ed.; W. W. Norton & Company, New York, 2014.
Klein., D., Organic Chemistry; 1st ed.; John Wiley & Sons, United States, 2012.
Louden M., Organic Chemistry; 5th ed.; Roberts and Company Publishers, Colorado, 2009.
McMurry, J., Organic Chemistry, 9th ed.; Cengage Learning, Boston, 2016.
Smith, J. G., Organic chemistry; 6th ed.; McGraw-Hill Education, New York, 2020.
Wade., L. G., Organic Chemistry; 8th ed.; Pearson Education, Inc., United States, 2013.

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Hi! I’m Deboki Chakravarti and welcome  to Crash Course Organic Chemistry!

I don't know about you, but I’m in my 30s  and “unleaded” fuel has always perplexed me. Why is it important to categorize a type  of fuel by something it doesn’t contain,   when there's not a “leaded” fuel pump next to it? Well, turns out, not that long ago, tetraethyl  lead was added to automobile fuel to prevent engine knock -- a problem with fuel igniting unevenly, which can cause engine damage.

In a working engine, the four carbon-lead  bonds in tetraethyl lead break,   forming lead and lead oxide, which react with free radical intermediates from the fuel combustion and help prevent engine knock. But, lead is a neurotoxin, and having millions of cars pumping traces of it out of  their exhaust pipes was… quite bad. Lead was accumulating in air and soil,   and long-term exposure can  cause neurological problems.

It’s also really bad for catalytic converters. So "leaded" fuel was banned across the  United States in 1996, in the UK in 2000,   and most other countries  have also stopped using it. And we solved engine knock using other  not-so-neurotoxic chemicals in fuel.

Tetraethyl lead is an example  of an organometallic compound,   which are organic compounds  with a carbon-metal bond. As we'll learn in this episode, they can be  very useful for certain chemical reactions,   but may also have a dark side... [Theme Music]. By this point, we’ve mostly seen carbon  bonded to more electronegative elements,   such as oxygen or halogens, that draw  shared electrons towards themselves.

This gives the carbon a partially positive charge,  so it’s susceptible to attack from nucleophiles,   for example in substitution reactions. But metals are more electropositive than carbon. So in organometallic compounds,  the carbon in the carbon-metal bond pulls on those shared electrons more,   and ends up with a partially negative charge.

In other words, the carbon  can become nucleophilic. In fact, we often end up with a compound  with significant ionic character: the metal has a positive charge, while the carbon has a lone pair and a negative charge -- a carbanion. One of the most important groups of organometallic compounds is the Grignard reagents,  which contain magnesium-carbon bonds.

They're named after the French  chemist Victor Grignard,   who won a Nobel Prize for his work in 1912. Grignard reagents sound quite simple to make: you add some haloalkane -- say isopropyl bromide  -- to magnesium in a flask containing ether. And voilà!

But… just one thing:. Keep water away from this concoction,  because Grignard reagents react with acidic hydrogens to produce alkanes,  which aren’t the products we want. Oh, and another thing: be careful with the ether, because  that’s extremely flammable and,   since it’s an anesthetic, may also knock  you out while the lab is on fire...

In fact, this whole mixture  is described as pyrophoric,   which means it reacts and burns in air. So, yeah... it's not that simple. Even though the dangers are totally  different from tetraethyl lead,   we have to be really careful about risk  assessment with most organometallics.

You can also make Grignard reagents by swapping  the diethyl ether for a cyclic ether called THF,   or tetrahydrofuran. The lone pairs on the oxygen of THF  are more available to interact with the positively charged metal ion,    and this helps the Grignard reagent form. THF, which has a higher boiling  point than diethyl ether,   is also better for preparing Grignard reagents  from aryl or vinyl halides, which react more slowly than alkyl halides and might need to  be warmed up to get the reaction started.

Other organometallics include  organolithium compounds,   which -- as you might have guessed from  the name -- contain lithium-carbon bonds. They can be made in a similar  way to Grignard reagents: you add a haloalkane to two molar equivalents  of lithium metal, using ether as a solvent. Both Grignard reagents and organolithium  compounds act as strong bases.

They're proton acceptors and can  rip hydrogen atoms off molecules. This can be a problem, and we do need to  watch out for acidic functional groups,   which could react with our  Grignard in an acid–base reaction. But this basicity can also be very useful.

For example, the organolithium compound n-butyllithium is basic enough to deprotonate alkynes and generate an acetylide ion. As we saw in episode 27, acetylides  are powerful nucleophiles which can form new carbon-carbon bonds  -- super useful for chemists! We also use organolithium compounds as our  strong bases when making Wittig reagents,   aka phosphonium ylides, which we  also talked about in episode 27.

First, we need to make a phosphonium salt by  reacting triphenylphosphine with a haloalkane in an SN2 reaction --  head back to episodes  20 and 21 for a refresher on these concepts. Next, we use n-butyllithium to remove a  proton from the newly-formed phosphonium salt. This gives us our Wittig reagent, a molecule that forms a resonance structure with adjacent atoms  with opposite formal charges!

As a quick reminder, these can react with  aldehydes and ketones to form alkenes. And since we mentioned aldehydes and  ketones, we might as well get into how Grignard reagents and organolithium compounds  will react with these carbonyl compounds. Specifically, they undergo addition reactions.

The carbanion in the organometallic compound  attacks the carbonyl carbon, pushing electrons up to that electronegative oxygen so it  has three lone pairs and a negative charge. We’ve formed a new carbon-carbon bond. Nice!

This compound will hang around until we add acid,  and the oxygen grabs a proton to form an alcohol. And our reaction is officially done. Organometallic compounds can react with epoxides,  too, by opening the ring and forming an alcohol.

For example, let's say we  have an organolithium reagent and an epoxide with two electrophilic carbons. Under these basic, aprotic conditions  the carbanion does a backside attack on the epoxide -- targeting the least substituted, less hindered carbon. A classic SN2 reaction!

We can visualize the stereochemistry of this  backside attack using a Newman projection. The bonds in an epoxide are eclipsed, and  the oxygen atom is bridging both carbons. So the nucleophile, our  organometallic reagent carbanion,   swoops in between the two groups, attacks,  and relieves all that ring strain!

Then, like in the carbonyl addition reaction,   we need some acid to form the alcohol in  a second step and finish the reaction. Notice in the carbonyl addition reaction,   the alcohol is directly  attached to the new carbon bond. But in the epoxide SN2 reaction, there’s one carbon in between the alcohol and the new carbon bond.

Now, there's a third common group of  organometallics we haven't mentioned yet: the Gilman reagents, named after  the American chemist Henry Gilman. Gilman reagents contain two copper-carbon  bonds and are also known as organocuprates. Now, plain old organocopper reagents, which have  one copper-carbon bond, can’t easily be made by mixing copper metal and a haloalkane in a solvent, because copper is much more difficult to oxidize.

Or, looking at it the other way, copper is a much  weaker reducing agent than lithium and magnesium. The way around this is to start  with a different organometallic,   like an organolithium or a Grignard. In these substances, the  reduction has already happened.

So if we then add a copper (I) salt, like  copper (I) bromide or copper (I) chloride,   the metals are exchanged in a process called  transmetallation, which gives us our organocopper! Organocopper reagents are less reactive  than the other organometallic reagents we've been talking about,  so we don't have to worry quite as much about intense reactions with air  that will catch our lab bench on fire. But they can also be too  unreactive to be very useful.

That's where Gilman reagents, with  two carbon-copper bonds, come in. To form an organocuprate, we add a copper (I)  halide to 2 molar equivalents of an organolithium. The name has an “ate” which suggests a negative  ion -- think sulfate, carbonate, nitrate.

This “ate” tells us that organocuprate  reagents have a negative charge. Even though organocuprates are  more reactive than organocoppers,   they aren’t as reactive as  Grignards and organolithiums. But Gilman reagents have an  advantage in their not-so-basicness,   because they can get involved  in other types of reactions.

Grignard and organolithium  reagents are super strong bases,   so when they meet alkyl halides, they  tend to cause elimination reactions. However, when Gilman reagents meet alkyl  halides, they do SN2 reactions instead. In fact, Gilman reagents are really  useful for cross coupling reactions,   where two alkyl fragments are joined together.

The mechanism is a bit beyond the scope  of the series, but basically one of the alkyl bits in the Gilman reagent joins up  with the alkyl bit of the alkyl halide. Gilman reagents can also undergo cross  coupling reactions with haloalkenes,   while preserving the  stereochemistry of the double bond. Since we can’t do SN1 or SN2  reactions with these vinyl halides,   this is a pretty handy new reaction!

Also, the carbon-copper bonds in  Gilman reagents are less polarized than carbon-magnesium or carbon-lithium bonds. This makes Gilman reagents less  reactive and therefore more selective. For example, if we mixed a Grignard or  an organolithium with an acetyl chloride,   two molecules of the reactant would add to the  carbonyl carbon eventually forming an alcohol.

However, if we mixed a Gilman  with an acetyl chloride,   the chloride swaps with the alkyl group,  leaving the carbonyl in the final product. So while learning about all these organometallics,  we've talked about the toxicity of tetraethyl lead, and the reactivity of Grignard  reagents, but more stories are out there. For example, in one of his Things  I Won’t Work With articles,   the medicinal chemist Derek Lowe relates the story of The Library of Congress in the U.

S. trying to use diethyl zinc to deacidify old documents in the 1980s and 90s. In theory, diethyl zinc reacts with  the acid in old wood-pulp paper,   lightening the color and making the paper stiffer. Great!

Except… if you don’t make sure that all the diethyl zinc is gone before you re-expose the paper to air, you end up with an extremely expensive bonfire. So always in chemistry, but  especially with these reactions,   remember to check and follow  your safety data sheets! In this episode we’ve learned that:.

Organometallic compounds have polar  carbon-metal bonds that make carbanions. Some well-known examples are Grignard  reagents, organolithiums, and Gilman reagents. And generally, organometallic reagents  are great for forming carbon-carbon bonds,   like in carbonyl addition reactions  and cross-coupling reactions.

In the next episode, we’ll head  back to aldehydes and ketones,   and look at how they react with  oxygen and nitrogen nucleophiles. Until then, thanks for watching this  episode of Crash Course Organic Chemistry. If you want to help keep all Crash  Course free for everybody, forever,   you can join our community on Patreon.