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Lecture Comments (16)

3 answers

Last reply by: Professor Starkey
Mon Feb 1, 2016 11:07 PM

Post by Hajer Rawag on January 31 at 03:53:28 AM

Hello Professor,
For the [ox] general mechanism; my textbook shows that the Hydrogen that is removed from by the base is attached to the LG, not the Hydrogen attached to the carbonyl...are both the mechanisms the same? Thank you for your time!  

1 answer

Last reply by: Professor Starkey
Sun Nov 15, 2015 11:08 AM

Post by Elyse Silverman on November 15, 2015

If you react cyclohexanol with chromic acid (jones reagent) and the temperature is elevated, what product will you get?

2 answers

Last reply by: Professor Starkey
Mon Jun 16, 2014 9:21 PM

Post by monica ortiz on June 16, 2014

at 2:12. How come does i form a carb acid.. if it's a primary and it's reacting with PCC. wouldn't it turn only into an aldehyde??

1 answer

Last reply by: Professor Starkey
Tue Mar 18, 2014 9:39 PM

Post by saima khwaja on March 18, 2014

How is ether different from a methoxide group?

1 answer

Last reply by: Professor Starkey
Sat Jul 30, 2011 12:05 AM

Post by Diane Kurz on July 10, 2011

AT 2:52 one H turns into a carbonyl. What happens to the other H since this is a primary carbon?

2 answers

Last reply by: Professor Starkey
Wed Apr 6, 2011 11:55 PM

Post by Damien Leitner on March 19, 2011

At 15:10, wouldnt the bottom primary alcohol become an aldehyde and not a carboxylic acid, if you're using PCC?

Alcohols, Part II

Draw the product formed from this reaction:
Draw the mechanism and product formed for this reaction:
  • Step 1: The Oxygen atom is protonated to form a good leaving group
  • Step 2: Formation of a carbocation
  • Step 3: Nucelophilic attack
Draw the product formed from this reaction:
Draw the product formed from this reaction:

*These practice questions are only helpful when you work on them offline on a piece of paper and then use the solution steps function to check your answer.


Alcohols, Part II

Lecture Slides are screen-captured images of important points in the lecture. Students can download and print out these lecture slide images to do practice problems as well as take notes while watching the lecture.

  • Intro 0:00
  • Oxidation Reactions 0:08
    • Oxidizing Agents: Jones, PCC, Swern
    • 'Jones' Oxidation
    • Example 1: Predict Oxidation Reactions
    • Example 2: Predict Oxidation Reactions
  • Oxidation Reactions 4:11
    • Selective Oxidizing Agents (PCC and Swern)
    • PCC (Pyridiniym Chlorochromate)
    • Swern Oxidation
  • General [ox] Mechanism 8:32
    • General [ox] Mechanism
  • Oxidation of Alcohols 10:11
    • Example 1: Oxidation of Alcohols
    • Example 2: Oxidation of Alcohols
    • Example 3: Oxidation of Alcohols
  • Example 13:09
    • Predict: PCC Oxidation Reactions
  • Tosylation of Alcohols 15:22
    • Introduction to Tosylation of Alcohols
  • Example 21:08
    • Example: Tosylation of Alcohols
  • Reductions of Alcohols 23:39
    • Reductions of Alcohols via SN2 with Hydride
    • Reductions of Alcohols via Dehydration
  • Conversion of Alcohols to Alkyl Halides 30:12
    • Conversion of Alcohols to Alkyl Halides via Tosylate
  • Conversion of Alcohols to Alkyl Halides 31:17
    • Using HX
    • Mechanism
  • Conversion of Alcohols to Alkyl Halides 35:43
    • Reagents that Provide LG and Nu: in One 'Pot'
  • General Mechanisms 37:44
    • Example 1: General Mechanisms
    • Example 2: General Mechanisms
  • Example 41:04
    • Transformation of Alcohols

Transcription: Alcohols, Part II

Welcome back to Educator.0000

Now that we have had an introduction to alcohols, let's take a look at the reactions that they undergo.0002

One of the reactions that we can have for alcohols is that they can be oxidized; remember an oxidation means that you are increasing the number of C-O bonds.0009

Because alcohols are all starting with one C-O bond, they are very readily oxidized with a variety of oxidizing agents.0020

One of the most common things we are going to be seeing is going from one C-O bond to two C-O bonds which would give a carbonyl.0027

There is going to be three different types of oxidizing agents we are going to be studying: Jones, one is described as a Jones oxidation; PPC and Swern are other oxidizing agents.0034

We will start with Jones; Jones oxidation refers to either using a dichromate with acid or CrO3 plus acid.0044

What is going to happen is when we combine these, the chromium species is going to get protonated and we are going to form chromic acid.0053

This is something that is formed in situ; so sometimes this is just described as a chromic acid oxidation.0061

What happens is we take this carbon which contains the one C-O bond, that is the carbon that is going to be oxidized.0068

What is going to happen is we are going to replace one of the CHs with a CO which would give this product; this would give an aldehyde.0075

But this is not our final product because this aldehyde still has a single hydrogen on this carbon which still can be traded for an oxygen; this can still be oxidized.0090

In these oxidation conditions, the sodium dichromate oxidation conditions, the oxidation continues so that we replace the second C-H bond with another C-O bond.0106

When we start with a primary alcohol like this, a primary alcohol has two hydrogens on the carbon this bearing the OH; both of those will get replaced with carbon-oxygen bonds.0119

The product we are going to get is a carboxylic acid; in other words, we get complete oxidation as much as we possibly can with Jones conditions.0128

These are fairly harsh strong reaction conditions; we are dealing with strongly acidic conditions, aqueous conditions; this is a very extreme oxidation.0140

Let's try and predict a few products; we have this alcohol and we see sodium dichromate and H2SO4; this looks like Jones conditions, chromic acid oxidation.0150

We find the carbon bearing the OH and we oxidize that as much as we can; we are going to take that carbon and turn it into a carboxylic acid.0161

We are going to turn the CH2 into a carbonyl instead; we get a carboxylic acid product.0173

How about the next one?--we find the carbon that is subject to oxidation; right there, this carbon is the one that already has one C-O bond.0181

When we increase the two C-O bonds, let's try and look at the pattern we have had so far; how about turning this into a carboxylic acid?0189

Something looks strange with this product, doesn't it?--this is impossible of course because you can't have five bonds to carbon.0201

We find in this case, because this is a secondary alcohol, that is why we are going to see a difference in the product because it is a secondary alcohol.0208

This only has one C-H bond to lose; our product is going to just increase from one C-O bond to two C-O bonds; and our oxidation is complete.0218

This carbon can no longer be oxidized because it doesn't have any hydrogen bonds; remember oxidation is an increase in C-O bonds while we decrease the number of C-H bonds.0230

This is what we are going to be seeing for alcohols; if we have a secondary alcohol and we oxidize it with chromic acid, we are going to get a ketone product.0240

Let's take a look at a few other oxidizing agents; one is called PCC; one is called Swern; these are more selective; these have milder reaction conditions.0252

Because they are less reactive, they are going to be able to stop and do just a partial oxidation; they will be able to stop at the aldehyde stage.0261

If I take my primary alcohol, again this is the carbon that is going to be oxidized, if I use either PCC or Swern conditions, I am going to oxidize, go from one C-O bond to two C-O bonds.0269

Then I am going to stop here; it will give the aldehyde product from a primary alcohol; just a little reminder here that there is no over-oxidation with these reagents.0282

There is no over-oxidation; in other words, we don't go all the way to the carboxylic acid here.0296

This is going to be a big difference for chromic acid oxidation, Jones conditions, versus PCC and Swern; for primary, we would stop here at the aldehyde.0301

What do PCC and Swern represent?--PCC stands for pyridinium chlorochromate; this is the structure of that reagent.0311

This is a pyridine ring when you have a benzene ring with a nitrogen replacing one of the carbons; we call that pyridine; because it is protonated, we call this the pyridinium ion.0322

Here we have chlorochromate; you can still see the oxidizing agent here; we still have the CrO3 component.0332

But rather than mixing it with a strong acid like H2SO4, we are going to mix it with this pyridine salt.0338

It is going to change the reactivity and make it be able to stop at the aldehyde; you should get used to it; if you see this reagent, you would recognize that as an oxidizing agent.0344

But very often you will see it just written as PCC; it is very commonly just written as that because that is how it is known; it is an abbreviation for the reagent in itself.0356

Swern oxidation however is one of our name reactions where it is named after the chemist who developed it.0367

You can't go up to the stockroom and say I need some Swern reagent; there is no such thing; instead it is a combination of reagents; here is what it looks like.0374

It is going to be a two-step process; the first step involves treatment of the alcohol with dimethyl sulfoxide, also called DMSO; this reagent is called oxalyl chloride.0384

Step one, we mix DMSO and oxalyl chloride; then step two, we add in a base like triethylamine.0397

What is nice about this is when you take a look at these oxidation conditions, you see that now we have some set of reagents that no longer contain chromium, unlike the Jones and the PCC.0405

Chromium is a toxic element; handling that is going to be hazardous; disposing of that waste is going to be expensive and hazardous.0415

Chemists are continuously developing new methods that are going to be cheaper, that are going to be safer, that are going to be easier to run, easier reaction conditions, more selective, that sort of thing.0427

This is a really nice illustration of that; Swern oxidation has a nice mechanism too that is worth looking into but we are not going to get into it.0438

At this point, we are just going to be looking at it as a set of reaction conditions to use anytime we want to do one of these selective oxidations.0446

Just a little trick, if you want to look at these reaction conditions, if I see those, how am I ever supposed to remember that these strange set of reagents represents a Swern oxidation?0455

If you look at it very very carefully, if you take a look at that DMSO and you emphasize the sulfur in the DMSO, that might help you think of the reaction--that is a Swern oxidation.0466

Even with the oxalyl chloride, if you write it in just the right form where you tip in the carbonyls and spit out the chlorines, now maybe you can see the -w of S-w-e-r-n.0482

Look, even in the triethylamine, we have a nitrogen for triethyl amine; when you look very closely, if you are a little bit creative, you can actually see the word S-w-e-r-n if you imagine a little ?e-r here.0493

You can kind of see the word Swern buried in those reagents; hopefully that is maybe a little trick that might help you recognize it when you see it.0504

We typically don't get into too much detail with the oxidation reaction mechanisms; but just to give you some idea so it is not a complete mystery what is going on.0514

What is happening in every single one of these is whatever oxidizing agent you have is going to be reacting first with the oxygen of the alcohol and attaching some kind of leaving group to that alcohol.0522

It is either chromium-based in the case of Jones or PCC or sulfur-based in the case of the Swern oxidation; but we have some kind of leaving group on the oxygen.0534

Which means that a base can come in and grab this hydrogen, move the electrons over to be a π bond because there is a leaving group on the oxygen that can get kicked off.0544

As a result, we go from a C-O single bond to a carbonyl; this is where the electrons come from; this is how a carbonyl can be generated.0559

What it also points out is that this hydrogen is necessary for an oxidation reaction to occur; without that hydrogen, we would not be able to form that new C-O bond.0568

Again if you think about an oxidation as replacing a C-H bond with a C-O bond, it helps to reinforce the fact that you can't create a new C-O bond if there is no other bond that you can lose.0586

Most of our oxidation reactions are losing hydrogen bonds, especially all the alcohol oxidation reactions; we go from an alcohol functional group to some kind of carbonyl containing functional group.0598

Let's summarize what we know about these oxidizing reagents; the trickiest one is going to be our primary alcohol because there is two possible products we can have for that.0613

It has two hydrogens here on this carbon; an oxidation reaction can replace just one of those C-H bonds or it can replace both of those C-H bonds.0622

That is why we have a choice of two products we can draw; it is very important to choose our oxidizing agent wisely in that case.0632

If we were to choose PCC or Swern conditions, we would take that primary alcohol and we would oxidize it partially to the aldehyde.0640

But instead if we were to use the harsher reaction conditions, the aqueous acid and chromium, the dichromic conditions, these are our Jones conditions, our Jones oxidation.0654

We take that carbon and we oxidize it completely; in other words, we replace both C-H bonds with C-O bonds and we get the carboxylic acid; a primary alcohol can give two possible oxidation products.0666

A secondary alcohol on the other hand has just a single C-H bond that can be lost; any oxidizing agent, PCC or Swern conditions or Jones reaction conditions, will oxidize it up to the carbonyl.0681

There is no further oxidation that can take place; a secondary alcohol is going to give a ketone product regardless of which oxidizing agent we choose.0697

Let's take a look at a tertiary alcohol; if we wanted to do an oxidation of a tertiary alcohol, again PCC, Swern, Jones, whatever conditions that we had, any oxidizing agent.0707

On this carbon, if we want to increase the number of C-O bonds, we can maybe turn that OH into a carbonyl; that would be a possible oxidation; but what is another problem here?0718

This is another case where we are trying to form a new C-O bond, but there is no bond that we can break; this would form a carbon with five bonds.0732

What is going to here?--no reaction happens; there is no reaction because, when we look at the carbon that we are trying to oxidize, we see that there is no hydrogen.0739

There is no C-H bond that we can lose; there is no hydrogen that can be replaced; therefore it is no reaction.0750

Our oxidation reactions and reagents are going to, in those predict-the-product type problems, are going to depend on not only what oxidizing agents we use.0759

But whether our alcohol is a primary or secondary or tertiary; remember the way we describe a primary alcohol means that the carbon bearing the OH is attached to just one other carbon.0767

Because this is a primary carbon, we call this a primary alcohol; because this is a secondary carbon, we call this a secondary alcohol.0778

Here we have a tertiary carbon; that is why this is described as a tertiary alcohol; let's do one last example.0785

How about if we were to take this poly-functional structure and treat it with PCC?--we recognize that as an oxidizing agent.0793

Again three new reagents would be a good time for some new flashcards so you could sort three reagents out and learn to recognize them.0804

We look for alcohols that we can oxidize; here is one alcohol; this is a carbon that we can oxidize.0813

How would you describe that alcohol?--the carbon is attached to two other carbons; this is a secondary alcohol.0823

How about this alcohol down here?--how would you describe this carbon?--this has one, two, three carbon groups; this is a tertiary alcohol.0831

What is going to happen at this site with our oxidizing agent?--this is going to be no reaction; no change at this position.0842

How about this carbon?--how would you describe this alcohol?--it has just one carbon group attached; this is an example of a primary alcohol; in other words, a CH2OH.0849

What about this guy?--how would you describe this functional group when you have an oxygen with a carbon on either side?--this is called an ether.0860

That is another important thing to keep in mind--is when we are learning new reagents, we always have to keep in mind which functional groups they react with.0871

PCC, Jones, and Swern are conditions that we are seeing react with alcohols; so an ether is something that is also going to be no reaction.0878

We are going to be talking later about ethers and their reactions; we will find that they are quite unreactive; this is an example of that.0887

What we have then is our top carbon will be oxidized; we go from the alcohol to the carbonyl; it will make a ketone up here.0896

This bottom carbon is still going to have an OH, an alcohol, because it is tertiary; this carbon down here, this CH2, is now going to get turned into a carboxylic acid.0903

Our methoxy group, our ether group, is just along for the ride--has no involvement in this oxidation reaction.0914

What else can we do to alcohols?--another very useful reaction that we will employ is called the tosylation of alcohols.0924

Let me show you an example of how this is going to look; then we will look at the details of the structures.0933

If you take an alcohol and you treat it with TsCl--that stands for tosyl chloride; what is going to happen is you are going to replace the OH group with an OTs group.0938

This OTs group is a good leaving group; once we have a good leaving group, we can do all sorts of interesting reactions just like we had a halide there.0952

For example, we could react this with a nucleophile; a nucleophile could attack the carbon, kick off the leaving group, and we could do a substitution reaction; we could do an Sn2 here.0962

What if we tried to take this alcohol and treat it with a nucleophile?--could we do an Sn2 reaction on just the alcohol?--no, because this OH is not a leaving group.0973

This is not a leaving group; it will not undergo Sn2 or Sn1 conditions or E1 or E2 conditions; as a neutral alcohol, it is a very poor leaving group; this would be no reaction.0987

If we wanted to do a substitution reaction with an alcohol starting material, what we would do is--this is one of the strategies--is we can convert it to a tosylate.1000

Then we would be able to do a substitution; what does this tosyl group look like?--for this first reaction, the mechanism is a little beyond our scope.1008

But you can imagine essentially the oxygen is displacing the chloride; it is not a simple Sn2; but it is a substitution reaction.1018

We are also going to lose the proton on this alcohol--we are losing HCl in this tosylation reaction.1029

That explains why we need the presence of some kind of base like pyridine around--is that is going to react with the HCl as it is formed.1036

What does this OTs group look like?--what we have here is an oxygen; then there is a sulfur with two double bonds to oxygen and a benzene ring with a methyl here.1044

This part from here to here represents the Ts group, the tosyl group; that stands for para-toluenesulfonyl.1065

Sulfonyl, this is a sulfonyl group; this phenyl group with a methyl is called toluene so this is called a toluol group; para represents this relationship between the methyl and the sulfur.1084

So this is called para-toluenesulfonyl or tosyl for short; this OTs group, this is OTs, this is our great leaving group.1096

Meaning if a nucleophile were to see this molecule, it could attack the carbon and kick off this whole group; that oxygen along with the tosyl group is what gets displaced.1107

Let's take a look at this structure then of the leaving group after it leaves; what does this tosylate look like?--this is called tosylate when it leaves; the OTs is called tosylate.1120

This is a good leaving group; let's examine that for a moment and make sure we understand why this is a good leaving group.1135

We just said hydroxide is a very poor leaving group; that is because it is a very strong base; it is very reactive having an O-.1145

Yet here is another structure with an O-; we say this is a fine leaving group; what is the difference between tosylate and hydroxide?1153

Why is it okay for this structure to be kicked off and be on its own?--the key to being a good leaving group is that you are stable once you leave.1160

There is something about this tosylate group that makes it very very stable; is there any way we can stabilize that negative charge?1168

The fact that I have this S-O double bond right next door means this negative charge, this lone pair, is allylic; I can bring this down and move this up.1178

That would put the negative charge up on this top oxygen; what do we call this when we can move electrons around--lone pairs and π bonds?--we call this resonance.1187

In fact we have resonance delocalization of the oxygen up to the top oxygen; it can go down to the bottom oxygen, et cetera.1207

In fact this negative charge is totally delocalized equally over all three oxygen; it is incredibly stable; this is resonance stabilized... it is resonance stabilized.1215

The negative charge is delocalized, highly delocalized; that is a good thing; that is what makes it a good leaving group; that also makes it a weak base.1231

The same sorts of things when we talk about leaving group ability, it has to do with stability; that also will parallel basicity; so being a great leaving group and being a weak base are synonymous.1246

That is what the tosylate looks like; it is going to be very useful to us when we want to turn the OH into a good leaving group; let's try an example here.1259

What if I had this alcohol and I wanted to convert it to this nitrile?--I see that this is our new bond that is being bond formed here.1272

Because we had one, two, three carbons to start; those carbons are still here; I need to form this carbon-carbon bond.1282

Let's just talk briefly about our strategy here; one of those carbons must have been a nucleophile and one of those must have been an electrophile in order for that bond to be formed.1290

Have we have ever seen cyanide, the CN group, as a reagent?--we have actually seen it as cyanide anion; this is something we should recognize as being a good nucleophile.1300

This guy was my nucleophile; that means this carbon was my electrophile; it was my electrophile; somehow we have to make it electrophilic.1316

Can I just add sodium cyanide here and expect the substitution to occur?--is this carbon, carbon number 3, appropriately electrophilic so that we can get a substitution to occur?1329

We have the same problem we just were talking about on the last screen--is that there is no reaction here because hydroxide is a very poor leaving group.1343

It is unstable; it is a strong base; it is never going to be substituted, replaced in an Sn2 mechanism; how do we handle this problem?1354

This is exactly where we would use... it would be a great application using this tosylate strategy; rather than having an OH, I want an OTs.1363

Once I have the OTs, now I can add in sodium cyanide and I could expect the Sn2 reaction to take place; we have a nice primary leaving group; this would be a great Sn2.1374

Then all we need to remember--what the reagents are for tosylation; we need to the tosyl group; there is a chlorine on that; tosyl chloride is what we use.1387

That is what the oxygen is going to be replacing on the sulfur; we always do need a base in here as well to get rid of that proton; you could just write base; but most often we use pyridine.1398

So that is nice to be familiar with those reagents and be able to see them being used in tandem; that is probably how you will be seeing it down the line.1410

We have already talked about oxidations of alcohols, how could we increase the number of C-O bonds?--we can also do reductions of alcohols.1423

A reduction means we are going to decrease the number of C-O bonds while increasing the number of C-H bonds; that is the opposite of an oxidation.1430

An alcohol has just one C-O bond; in order to reduce it, you would be going to replace with a hydrogen; you would be going from an alcohol to an alkane.1445

We would describe that as a reduction of an alcohol; there is a few strategies we can do for this.1458

One of them is via an Sn2 mechanism with hydride; hydride is H-; if we had a source of hydride, then it can do an Sn2 mechanism; but what is the problem with just using the alcohol?1463

The source of hydride we had that was nucleophilic was something like lithium aluminum hydride; lithium aluminum hydride, LiAlH4; that was a source of hydride.1484

What would happen if I mixed an alcohol and lithium aluminum hydride?--I wouldn't expect to do an Sn2 mechanism because once again my OH is a poor leaving group.1501

But in this case it is not that there is no reaction because the hydride, just like the Grignard, is an extremely strong base.1513

And the alcohols, remember, have a very acidic proton; that is one of the properties of alcohols; so in fact this would react to give an O-.1521

It would deprotonate; you would get some hydrogen gas being formed; you would form the lithium salt here, or the aluminum salt of the O-, of the oxygen.1531

This is fine if you want to deprotonate; you could use LAH to deprotonate an alcohol; but you couldn't use it to do a substitution.1543

Instead here is another case where if we instead made the tosylate, tosyl chloride in pyridine replaces the OH with an OTs.1550

Now that we have a good leaving group, LAH, lithium aluminum hydride, can do an Sn2; this is a great nucleophile.1565

Remember we put little quotes around it because it is always coordinated with the aluminum; that is the nucleophilic hydride that we have; it will in fact do an Sn2.1574

That would be a way of replacing a leaving group with a hydrogen, in this case, a tosylate with a hydrogen; overall our transformation has been to reduce the alcohol.1585

Just a little note here; another source of hydride we have seen especially with alcohols is sodium hydride; we use this as a base.1596

In general, because this is ionic, because this is more reactive, this prefers to act as a base rather than a nucleophile.1605

When you are think hydride; that is a good distinction to make--is that when you want a nucleophilic hydride, we use sodium borohydride or lithium aluminum hydride.1615

NaH, you should consider just as a base; anytime we want to deprotonate something, NaH would be a good choice there.1626

Another strategy is to think about maybe if we do a retrosynthesis here and we consider what reactions have we ever seen that give alkanes as products?1634

That is a strange reaction because there is no functional groups here; there is nothing left; what if we had an alkene in this position?1646

Have we ever seen the conversion of an alkene to an alkane?--it looks like we have broken the π bond; we have added something to each carbon.1658

What did we add?--we added a hydrogen and of course there is a hydrogen here too; this was a CH2; now it is a CH3.1666

We could do catalytic hydrogenation; if we had an alkene, we could do a catalytic hydrogenation to give an alkane product.1674

What is nice about this is we have also seen alkenes as something that can be prepared from alcohols; what does that reaction look like?--what reagents will cause that transformation?1683

We are doing an elimination; we are eliminating an OH; but we are also eliminating a hydrogen on the neighboring carbon, the β carbon.1694

We are losing a molecule of water; we call that dehydration; what reaction conditions do we need to dehydrate an alcohol?1703

It is going to be some heat and very strong acid; something like H2SO4 and heat, strong concentrated acid is what we need to do a dehydration.1714

This would be a way of forming an alkene; remember dehydration, we can have our alkenes move around; we could have hydride shifts and such to get more stable carbocations.1726

It is possible that our double bond might move around; but that is okay in this case because hydrogenation is going to get rid of the double bond in the end anyways.1738

We don't care so much where the double bond ends up here; but we do want to make sure that our carbocation is not something that can have a carbon chain rearrangement.1746

Because then that is not going to give us the alkane structure that matches the alcohol structure.1754

The dehydration is only going to work if there is no rearrangement of the carbon frame, of the carbon skeleton.1760

If that is the case, then this is another great way to do the transformation--is dehydration followed by reduction.1781

As you can see, reduction is not going to be something... there is no one magic reagent that is going to reduce an OH and replace it with a hydrogen.1790

We have to do some kind of multistep transformation, either turning it into a good leaving group or getting rid of the oxygen first as a molecule of water.1797

Then doing a complete reduction of both of these carbons via catalytic hydrogenation.1806

Another handy thing we can do with alcohols is convert them to alkyl halides.1814

This conversion going from an ROH to an RX looks like another substitution that we are trying to do here; we are trying to substitute an OH with a halogen.1819

But as we have talked about in the last few slides, in order to do a substitution, the key is we need to make the OH a good leaving group; otherwise we can't do a substitution.1830

One strategy that we have already seen is to do the tosylate; that strategy will work here as well.1842

If I wanted to replace the OH with a bromine, I could use tosyl chloride and pyridine to make the tosylate.1849

Then I can use sodium bromide, NaBr, to give me a bromide nucleophile; and we can do an Sn2 here; that would be a great way to do a substitution; that certainly works as a strategy.1861

Another reaction you might recall from back when we were learning about Sn1 and Sn2 substitutions and being introduced to those.1879

We learned another way to make an OH a good leaving group is to use a strong acid, something like HBr or HCl.1887

Sometimes instead of just HCl, you might see some zinc chloride thrown in as a catalyst; HCl is a little less reactive; so we need that to speed things along.1895

But the concept is the same in either case; what we are doing is taking the alcohol and not just treating it with bromide.1903

If we were to try to do this and sodium bromide, that would be no reaction because we don't have a leaving group.1912

But instead if we react with HBr, then that is going to be a source of H+ and Br-; remember this is a very strong acid and we can get a substitution to take place.1918

Let's think about a mechanism here; what do we know about HBr or HCl?--either of those, they are very strong acids.1931

The very first step, once you recognize that you have strongly acidic reaction conditions, the first step of your mechanism is going to be to protonate something with that strong acid.1942

Let it donate a proton to anything that can take it; the alcohol can certainly accept a proton here; we can protonate the alcohol; how does that help us move forward in our substitution?1951

Because protonating the alcohol is another way of making a good leaving group; we talked about how the tosylate is such a good leaving group because the O- is resonance stabilized.1968

What would your leaving group be in this case?--it would be water, very stable molecule; now we can have our substitution.1978

The substitution, our mechanism, here let me make a note, can be either Sn1 or Sn2; once we make a good leaving group, now we can either have that leaving group leave to give a carbocation.1988

Or we could have the nucleophile kick out the leaving group with a backside attack; because this is secondary, we probably will get a mixture of both; remember Sn1 or Sn2.2004

In this case, we probably get both happening to some extent because it is secondary and they are both allowed; but we can most definitely do our substitution.2017

The other product here is water; water of course is extremely stable; that makes him both a weak base and a good leaving group.2029

That is what makes this substitution reaction on an alcohol possible--is we protonated it first to enable it to leave as water.2044

A few things about when can we use HBr and HCl to do this substitution?--one thing is that the conditions favor a carbocation; these are acidic conditions, strongly acidic conditions.2053

Those sorts of conditions always favor carbocations; that means the Sn1 is going to be favored; but that also means we can maybe have some elimination reactions, some E1 products.2068

We can most definitely rearrange certain carbocations; tertiary is going to be the best conditions to do this because it gives a stable carbocation; that is going to be a very fast reaction.2078

Using HCl or HBr to make the chloride or the bromide is not going to be suitable in every case of an alcohol.2092

In addition the reagent HBr or HCl can react with other functional groups besides just an alcohol.2103

For example, we have seen reactions where this adds across a π bond; if you had any alkenes in this structure or alkynes, they would certainly react under these conditions.2111

We will see that ethers also react with these haloacids; that might be a problem; and so on.2120

These, although this is reagents that we are familiar with and we have seen before being used, we are going to learn that these are not always the best reagents to use.2127

Next we are going to learn about some reagents that might be a little more suitable to do this transformation.2138

This involves some new reagents for us; what each of these do is they both provide the leaving group and they provide a nucleophile all in one pot.2146

All at once, we add this one reagent and it both makes the good leaving group and it replaces that leaving group.2157

Unlike the tosylation which is a two-step process--you have to make the tosylate and then you displace it.2164

Unlike the HBr or HCl where you have the strongly acidic conditions that do some other side reactions, these reagents simply take what used to be an OH.2171

And if you have SOCl2, it is called thionyl chloride, it is going to replace that OH with a chlorine; there is no chance for rearrangement of carbocations; and so on.2181

To make the bromide, we are going to use PBr3; that is called phosphorus tribromide; that would be a great way to make bromides, alkyl bromines.2194

Then if you want to do the iodine, we do another phosphorus reagent where we just make this in situ; we just combine phosphorus and iodine; it takes the OH and replaces it with the iodide.2204

You could see we have some phosphorus reagents or SOCl2; you might ask is there a chlorine version of this phosphorus?2219

Sure, there is also PCl3, there is PCl5, there are also sorts of reagents that are similar to this; again wide variety.2226

But what we try and do when we are introducing a new subject like this is we try and give one representative compound or reagent.2235

These are the ones that you will probably see most likely in an organic textbook; that is why I stuck with these.2245

Also different texts emphasize or deemphasize the mechanism of these reactions, of these transformations.2252

Because again they are usually a little beyond the scope of an introductory course; but let me just show you some brief information about the mechanisms.2258

SOCl2 has this structure when you react it with the alcohol; again this reaction is also going to be done in the presence of some base because we have to lose HCl.2268

But the oxygen replaces one of the chlorines; we get this kind of intermediate; then what happens is the sulfur actually delivers this chlorine internally to the carbon and kicks the leaving group off.2282

This is a good leaving group; SOCl2, like the tosylate, makes this sulfonyl leaving group; but it also has a chlorine on here which will replace that leaving group as it leaves.2299

It gets an internal delivery; so internal attack of the nucleophile; what actually happens with the stereochemistry is we get retention of stereochemistry.2315

If this was an alcohol... let me put on an R group here so that we can have a chiral center.2336

If this alcohol was a wedge, this sulfonyl intermediate would still be a wedge because all we did is react this oxygen; it turns out that the chlorine is still going to be a wedge.2343

Again the stereochemistry is usually not a real big issue here; but this is generally the mechanism we are seeing; typically we see a retention of stereochemistry if we have that.2355

If you have a phosphorus type reagent, again the first thing that happens is the phosphorus is going to combine with the oxygen; it is going to react with the oxygen to make a good leaving group.2366

This is another good leaving group; it is also going to be the source of bromide; we displace the bromide from this phosphorus; the bromide is still around.2378

After we make that good leaving group, we are going to get a displacement of the leaving group.2391

This mechanism looks like backside attack because from an external nucleophile, that is what we have here--we have an Sn2.2396

What kind of stereochemistry do we expect in that sort of substitution?--backside attack gives us inversion of stereochemistry.2404

If we adjust this to be again a chiral alcohol and we think about the stereochemistry.2416

If we had this OH group as a wedge, it would still be a wedge here because we haven't had any chemistry at this carbon.2423

But at this point, now if the leaving group was a wedge, the nucleophile would have to come from behind that.2429

Our leaving group, our halide now, the incoming nucleophile, is going to be in the opposite stereochemistry; it is going to be a dash instead.2436

These reagents of SOCl2, PBr3, and phosphorus and iodine are really used more routinely in the conversion of going from an alcohol to an alkyl halide.2445

Because it avoids some of the pitfalls that we see with some of the other options that we have.2457

Let's see an example of a transformation; this is not a transformation we have seen before; but is a reaction of an alcohol; let's see if we can figure out how to go about this.2466

To convert the alcohol to this... this looks like an organolithium; remember we saw these structures, RLi; we have some carbon group with a lithium attached.2480

This is related to the Grignard reagents we have seen; this is an example of an organometallic.2490

Anytime we want to make an organometallic reagent and we do a retrosynthesis and we say what starting material do I need?--what functional group do you have in order to create an organometallic reagent?2496

You need some kind of halide here; in this case, because that halogen gets replaced by the lithium, it doesn't matter what halide you have.2510

With the Grignard, you still see the bromine or the iodine or the chlorine here so you know which halide you need; here it can be any one you want; this could be chlorine or bromine or iodine.2521

We have those; we have seen that transformation, conversion of alcohols to alkyl halides, is definitely something we can accomplish with some kind of synthesis.2533

Let's think about a possibility; how about if we used... let's say we wanted to make the bromide... that is not a benzyl ring.2546

Let's say we wanted to make the bromide... how about I just put this as a phenyl group; that saves us a little time.2557

If I want to make the bromide, how can I do that?--what if I used HBr?--HBr is one option; it will protonate the OH and make it a good leaving group; and the bromide can replace it.2563

Would this be a good substrate to do HBr?--it certainly could work; but because this favors carbocation and because we are right next to a benzylic position which would be a very good carbocation.2577

There is a chance that we could get some rearrangement; there is a chance that we could get some of this bromide mixed in with this bromide; we want to avoid rearrangements anytime we can.2591

Of course I skipped right over the fact, we already pointed out a few times, I can't just use sodium bromide.2605

I can't just try and do an Sn2 right away because that wouldn't work either; I don't have a good leaving group; how do I make the OH a good leaving group?2611

I could make it the tosylate; I could make a tosylate and convert that to the bromide; that is good; what would be my reaction conditions to make the tosylate?2622

It is TsCl and pyridine; then to make the bromide, now I could use sodium bromide, NaBr, because I have a good leaving group here; that two-step procedure would be okay.2639

What is another process I can use?--I can just take my alcohol and just in one-step I can add PBr3; that would do the same transformation.2652

There is no chance of rearrangement there; so that would probably be a better choice in the laboratory although this transformation is acceptable too.2664

Once I have the bromide, either via the tosylate or via PBr3, how do I go from the alkyl halide to the organolithium?2675

The way we make our organometallic reagents is we simply add in the metal; that will react with the halide; in this case we just use lithium metal.2684

You could write Li0 if you want or you could just say Li by itself; it is not the cation; it is just lithium metal.2696

Remember lithium does an exchange, a halogen metal exchange; that would be a way that we could form this organolithium.2702

We have seen a nice overview of the various reactions that alcohols can undergo; a lot of new reagents on this topic.2710

So again keep up with those flashcards so that you can stay on top of the reagents and what kind of product you could expect for those reactions.2717

Also a few mechanisms in this unit; but not quite as much as we have for our new reagents.2725

Thanks for visiting; I hope to see you again soon.2732