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Lecture Comments (32)

1 answer

Last reply by: Professor Starkey
Mon Apr 4, 2016 2:12 PM

Post by Jordan Arciniega on April 3, 2016

Hello Dr. Starkey,

During the acetal mechanism, the first step is protonation of the carbonyl oxygen. This results in the formal charge of the oxygen to be plus one.

But why exactly does this result in the carbon of the carbonyl group to be more electrophilic? Is it because the plus charge on the oxygen changes its electronegativity such that it pulls electron density even more to itself (inductive effect), leaving the carbon more positively charged? Or is it because the oxygen with the positive charge now favors the resonance form of a plus charge on the carbon (to make oxygen more happy)?

I guess in general, I would like to know if plus charges on atoms change the electronegativity of that atom. So if an atom becomes a plus 1 charge, will it attract more electron density towards itself compared to its neutral form?

Thanks in advance, and like always, I highly appreciate these extremely helpful lectures!

1 answer

Last reply by: Professor Starkey
Wed Mar 30, 2016 3:15 PM

Post by Jonathan Ibera on March 29, 2016

Thanks, your lecture are very clear.
For the clemmensen reduction of ketones and aldehydes all the way to alkane, can this reduction method reduce alcohol as well? I know this is kind of gray area as the mechanism of clemmensen reduction might not be clear to me.

1 answer

Last reply by: Professor Starkey
Thu Feb 25, 2016 12:46 PM

Post by Milki Hussen on February 25, 2016

Is it possible to use to use methanal + a 4 carbon grignard reagent to get the propanol on on retrosynthesis ( 28 minutes)?

1 answer

Last reply by: Professor Starkey
Tue Jan 26, 2016 9:27 PM

Post by Jason Smith on January 26, 2016

Hi professor. In the formation of acetals, the reason why the acid acts first is because it's faster? Thank you.

1 answer

Last reply by: Professor Starkey
Sun Dec 14, 2014 8:31 PM

Post by bea v on December 14, 2014

if an C=O bond is flaked by an oxygen on both side is it still more reactive than a C=C ?

1 answer

Last reply by: Professor Starkey
Wed Mar 19, 2014 9:13 PM

Post by Jude Nawlo on March 19, 2014

Hi Dr. Starkey,

Do the same concepts that apply in Wittig apply for Horner-Wadsworth Emmons reactions?

3 answers

Last reply by: Professor Starkey
Mon Mar 3, 2014 10:23 PM

Post by Florel Fraser on March 1, 2014

I am having problems with the portion of the video on Wittig Reagent.  As soon as Dr. Starkey starts the mechanism the video stops and goes back to the beginning of the lesson.

2 answers

Last reply by: Professor Starkey
Wed Jul 19, 2017 11:01 AM

Post by Victor Ye on May 27, 2013

I've really enjoyed your lessons, Prof. Starkey!! They're VERY helpful, and they're the best chemistry video lectures I've found!

I also second Nawaphan's comment about possibly covering biological molecules in your lessons. Educator has a biochemistry section, but I think lessons with a chemistry perspective would very useful for us. My OChem class covers these biological molecules, and the last three chapters of my textbook concern these topics. Thank you!

2 answers

Last reply by: Professor Starkey
Wed Jul 19, 2017 10:59 AM

Post by Nawaphan Jedjomnongkit on May 3, 2013

You are great teacher and this is the first time that I enjoy every ORG Chem lesson!! Now I can remember CTI because it's always come with sound ding ding ding!!!!! lol Thank you so much!! Is it possible to add some lessons about biological molecules like proteins, amino acids, carbohydrates and lipids?

1 answer

Last reply by: Professor Starkey
Sun May 20, 2012 10:13 AM

Post by Mark Deming on May 17, 2012

Wouldn't the grignard add twice so you should use lithium for first addition. That way you won't get two isopropyl groups?

0 answers

Post by Jason Jarduck on March 3, 2012

Hi Dr. Starkey,

Another great lecture. I have been taking notes and using your lectures for studying for tests and exams.

Thank You


1 answer

Last reply by: Professor Starkey
Wed Nov 30, 2011 11:13 PM

Post by ochemstarkey on November 30, 2011

Thank you so much Dr Starkey, the best OCHM teacher ever!!!

2 answers

Last reply by: Professor Starkey
Sat Nov 5, 2011 3:15 PM

Post by Clint Rapp on October 29, 2011

this is a Ketal because a ketone was the starting material? What is up with that?

1 answer

Last reply by: Professor Starkey
Sat Oct 8, 2011 3:01 PM

Post by Gayk Gevorkyan on October 5, 2011

Wouldn't be able to PASS OCHEM without this......THANK YOU DR.LAURIE!


Draw the major product formed from this reaction:
Draw the major product formed from this reaction:
Draw the major product formed from this reaction:
Draw the major product formed from this reaction:
Draw the major product formed from this reaction:
Draw the major 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.



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.

  1. Intro
    • Aldehydes & Ketones
    • The Carbonyl
    • Preparation/Synthesis of Aldehydes & Ketones
    • Reaction with Hydride Nu:
    • Reaction with Carbon Nu:
    • Reaction with Carbon Nu:
    • Retrosynthesis of Alcohols
    • Example
    • Example
    • Example
    • Example
    • Wittig Reaction
    • Preparation of Wittig Reagent
    • Wittig Retrosynthesis
    • Reaction with Oxygen Nu:
    • Reaction with Oxygen Nu:
    • Example
    • Mechanism for Acetal Formation
    • What is a CTI?
    • Acetals & Cyclic Acetals
    • Hydrolysis of Acetals: Regenerates Carbonyl
    • Reaction with Nitrogen Nu:
    • Mechanism of Imine Formation
    • Oxidation of Aldehydes
    • Reductions of Ketones and Aldehydes
    • Reductions of Ketones and Aldehydes
    • Acetals as Protective Groups
    • Example
    • Protective Groups
    • Example
    • Example: Another Route
    • Example
    • Example
    • Example
    • Example
    • Intro 0:00
    • Aldehydes & Ketones 0:11
      • The Carbonyl: Resonance & Inductive
      • Reactivity
    • The Carbonyl 2:35
      • The Carbonyl
      • Carbonyl FG's
    • Preparation/Synthesis of Aldehydes & Ketones 6:18
      • Oxidation of Alcohols
      • Ozonolysis of Alkenes
      • Hydration of Alkynes
    • Reaction with Hydride Nu: 9:00
      • Reaction with Hydride Nu:
    • Reaction with Carbon Nu: 11:29
      • Carbanions: Acetylide
      • Carbanions: Cyanide
    • Reaction with Carbon Nu: 15:32
      • Organometallic Reagents (RMgX, Rli)
    • Retrosynthesis of Alcohols 17:04
      • Retrosynthesis of Alcohols
    • Example 19:30
      • Example: Transform
    • Example 22:57
      • Example: Transform
    • Example 28:19
      • Example: Transform
    • Example 33:36
      • Example: Transform
    • Wittig Reaction 37:39
      • Wittig Reaction: A Resonance-Stabilized Carbanion (Nu:)
      • Wittig Reaction: Mechanism
    • Preparation of Wittig Reagent 41:58
      • Two Steps From RX
      • Example: Predict
    • Wittig Retrosynthesis 46:19
      • Wittig Retrosynthesis
      • Synthesis
    • Reaction with Oxygen Nu: 51:21
      • Addition of H₂O
      • Exception: Formaldehyde is 99% Hydrate in H₂O Solution
      • Exception: Hydrate is Favored if Partial Positive Near Carbonyl
    • Reaction with Oxygen Nu: 57:45
      • Addition of ROH
      • TsOH: Tosic Acid
      • Addition of ROH Cont.
    • Example 1:01:43
      • Predict
      • Mechanism
    • Mechanism for Acetal Formation 1:04:10
      • Mechanism for Acetal Formation
    • What is a CTI? 1:15:04
      • Tetrahedral Intermediate
      • Charged Tetrahedral Intermediate
      • CTI: Acid-cat
      • CTI: Base-cat
    • Acetals & Cyclic Acetals 1:17:49
      • Overall
      • Cyclic Acetals
    • Hydrolysis of Acetals: Regenerates Carbonyl 1:20:01
      • Hydrolysis of Acetals: Regenerates Carbonyl
      • Mechanism
    • Reaction with Nitrogen Nu: 1:30:11
      • Reaction with Nitrogen Nu:
      • Example
    • Mechanism of Imine Formation 1:33:24
      • Mechanism of Imine Formation
    • Oxidation of Aldehydes 1:38:12
      • Oxidation of Aldehydes 1
      • Oxidation of Aldehydes 2
      • Oxidation of Aldehydes 3
    • Reductions of Ketones and Aldehydes 1:40:54
      • Reductions of Ketones and Aldehydes
      • Hydride/ Workup
      • Raney Nickel
    • Reductions of Ketones and Aldehydes 1:43:24
      • Clemmensen Reduction & Wolff-Kishner Reduction
    • Acetals as Protective Groups 1:46:50
      • Acetals as Protective Groups
    • Example 1:50:39
      • Example: Consider the Following Synthesis
    • Protective Groups 1:54:47
      • Protective Groups
    • Example 1:59:02
      • Example: Transform
    • Example: Another Route 2:04:54
      • Example: Transform
    • Example 2:08:50
      • Transform
    • Example 2:11:05
      • Transform
    • Example 2:13:45
      • Transform
    • Example 2:15:43
      • Provide the Missing Starting Material

    Transcription: Ketones

    Welcome back to Educator.0000

    The next functional group we are going to take a look at contains two groups--either the ketone or the aldehyde--are going to have very similar reactivities; let's take a look at both of them.0002

    The ketones and aldehydes are molecules that contain the carbonyl; the C-O double bond is what we call a carbonyl.0013

    We are going to see that the aldehydes and ketones are the first of many carbonyl containing functional groups that we are going to be exploring.0020

    What is very special about the carbonyl is that it has resonance; anytime we have a π bond between two different atoms, we know that we can draw a resonance form.0028

    Where we take the π bond and we move it to the more electronegative atom; every carbonyl has a resonance contributor that has an O- and a C+.0037

    That combined with the inductive effects that we have for a carbon bonded to an oxygen means that overall every carbonyl has a significant δ- charge on the oxygen.0050

    And a significant δ+ on the carbon; that is going to define the reactivity of the carbonyl.0064

    For example, what do we associate with something that is partially positive?--it is going to be electrophilic; carbonyls are electrophilic.0069

    What does it mean to be an electrophile?--nucleophiles attack; nucleophiles add here; we are going to see again and again example after example of nucleophilic attack onto the carbonyl carbon.0076

    The oxygen is exceptionally partially negative, very electron rich, compared to an ordinary oxygen; that makes it basic; what does it mean to be a base?0090

    It means that you can protonate here; many of our mechanisms are going to begin with the carbonyl interacting with an acid and getting protonated on the carbonyl oxygen.0099

    Those are the reactivities we are going to start with in the next several units in looking at carbonyl chemistry.0110

    Eventually we are going to move into some reactivity not of the carbonyl carbon but of the next carbon over; this first carbon attached to the carbonyl is described as the α carbon.0116

    There is an interesting feature of the α carbon--is that the protons that are attached to that α carbon are acidic.0128

    What does it mean to be an acid?--it means you donate a proton; in other words, it can be deprotonated here.0134

    Eventually we are going to start looking at that α carbon and deprotonating in that position and seeing what reactions lead from there.0149

    Because of this resonance, the carbonyl is a very very stable functional group; that is what makes it ubiquitous.0159

    We find it all over the place in a wide variety of functional groups; it is extremely strong; it is extremely stable.0164

    If we take a look at the bond dissociation energy for a C-O single bond, it is 79 kcals per mole, an average of that.0171

    What would expect for a C-O double bond?--typically if you think about alkenes, we compare it to C-C single bond.0178

    When we added a π bond onto that, onto the σ bond, we didn't see a doubling of the bond strength because a π bond is typically weaker than a σ bond.0187

    What we might predict for the bond strength of a carbonyl if you were to try and break through the σ bond and the π bond, we would expect it to be less than maybe 160.0199

    This is about 80; so if we had two single bonds, two σ bonds, we would expect it to be 160; we would expect this to be a little less than this.0209

    It turns out that the carbonyl strength is 173 kcals per mole; it is actually stronger to have a C-O double bond than to have two separate C-O single bonds.0219

    This is extremely unusual; why is it so stable?--it is because it has that resonance energy; it has that resonance energy, resonance stabilization.0230

    Adding that π bond makes that resonance possible; that makes it a very energetically favorable thing and very strong bond.0242

    In fact what we are going to see a lot of times is formation of the carbonyl could be the driving force of the reaction.0250

    That might be something that helps decide whether or not a reaction is going to be favorable.0256

    Anytime we see a mechanistic step that creates a carbonyl as part of that step, we need to recognize that that is a very favorable step; that is a good step to happen.0260

    Like I said, we are going to start with just aldehydes and ketones; we call it a ketone when the R group on either side of the carbonyl is a carbon; that is called a ketone.0269

    When we have at least one hydrogen attached here, two hydrogens, or one carbon and a hydrogen, that is what we call an aldehyde.0281

    That is what we are going to start with in today's lesson--is looking at carbonyls that have nothing other than carbons or hydrogens attached to the carbonyl.0288

    But there is many other functional groups that contain carbonyls; this for example when we have an OH attached to a carbonyl, this is no longer an alcohol.0297

    The OH is part of this functional group; together the carbonyl and the OH are described as a carboxylic acid functional group; this is a carboxylic acid.0306

    When we have an OR group attached to a carbonyl, again it is no longer an ether; an ether would mean we have an OR attached to just a plain alkyl carbon group.0318

    But when it is attached to a carbonyl, we call these esters; when we have a nitrogen here; it is no longer an amine; we call this an amide; and so on.0328

    There is a variety of these compounds where attached to the carbonyl we have some group that has lone pairs attached to it.0336

    Just like the oxygen has lone pairs, nitrogen has lone pairs, halogens have lone pairs.0349

    Anytime we have this kind of a structure, these are all going to be related to each other; these are called carboxylic acid derivatives.0354

    Of course this first one is a carboxylic acid; all the others are described as carboxylic acid derivatives.0366

    After we are done talking about aldehydes and ketones, then we will move to these other related compounds.0372

    What are some ways that we can synthesize an aldehyde or a ketone; what reactions have we seen that generate C-O double bonds, carbonyls?0380

    One way we could do it is we could start with an alcohol; if we take an alcohol and we treat it with an oxidizing agent.0389

    We can increase our number of C-O bonds and decrease our number of C-H bonds; that is what our oxidation reactions look like.0395

    That would be a great way to form a carbonyl; we could get either an aldehyde or a ketone depending on what kind of alcohol we started with.0406

    We had things like PCC as an oxidizing agent; that could do this; or maybe Jones, sodium dichromate, Cr2O7, H2SO4; we had Swern oxidation.0414

    There are a variety of oxidizing agents we have seen before; certain situations gave us ketones; others gave us aldehydes as products.0427

    Another reaction we saw that has given carbonyl compounds as products is the ozonolysis of alkenes; ozonolysis means we react an alkene with ozone.0437

    It does a lysis; it cleaves the carbon-carbon double bond; what does it replace the carbon-carbon double bond with?--it replaces it with a carbon-oxygen double; it is replaced with a carbonyl.0446

    This is a way of making two carbonyl containing compounds; again it can be a combination of either aldehydes or ketones depending on what kind of alkene we started with here.0458

    I remember this DMS, this dimethyl sulfide, is just a reductive workup; the ozonolysis is always a two-step procedure to cleave the bond and form the carbonyls.0470

    One other reaction we have seen for creating carbonyls was doing hydration of alkynes; remember that if we add water across a π bond.0482

    We add an H and an OH across one of the π bonds, we get an enol; then that enol will tautomerize to a carbonyl, either a ketone or an aldehyde.0491

    We saw that if we were to add with Markovnikov regiochemistry, then the oxygen would go to the inside carbon and the hydrogen would go to the end carbon.0504

    In other words, we could get a ketone product here; or if we did hydroboration-oxidation, remember that was anti-Markovnikov addition of water.0516

    That would give us a product that has the carbonyl on the end carbon; in other words, we could use that to make an aldehyde.0525

    So an alkyne might be a possible starting material we could use that we can convert into a ketone or an aldehyde if we wanted to.0533

    What are some of the reactions that we can have for carbonyls?--the majority of the reactions we are going to be seeing are going to be reactions with the carbonyl carbon.0542

    Which is always always always partially positive which makes it an electrophile; we are going to be reacting it with a variety of nucleophiles.0553

    One such nucleophile is hydride; we have seen lithium aluminum hydride as a source of H-.0561

    We can put that in quotes because that hydride is still attached to the aluminum; but it behaves as if it is an H-; so it is convenient to draw it that way.0569

    What reaction do you expect to have happen when hydride sees a carbonyl?--it is going to do the same thing that every nucleophile does.0580

    It is going to attack the carbon, then break the π bond, and move those electrons up onto oxygen.0588

    We will get an O-; we will have an H now bonded to the carbonyl carbon, the formally carbonyl carbon; that is what we get with hydride.0597

    Step two here, what is the purpose of step two?--step two is just our reaction workup; we do an acidic workup so that we can protonate anything that needs protonating.0607

    Of course it is the O- here that we want to protonate; we could just describe HA as coming in and providing a proton; the product we would get then is an alcohol.0616

    We could take a ketone or an aldehyde and we can convert it to an alcohol by hydride reaction; this is described as a reduction reaction; you could describe this as a hydride reduction.0631

    Because what we did was we decreased the number of C-O bonds and we increased the number of C-H bonds; that is the exact opposite of an oxidation reaction.0646

    Just a little reminder here that if we had a carbonyl, we can convert the carbonyl to an alcohol by a reduction reaction, a reducing agent.0660

    Something like LAH that we just saw, lithium aluminum hydride; we also know how to take the alcohol and oxidize it to the carbonyl by using something like PCC.0669

    Alcohols and carbonyls are very readily interconverted by functional group interconversions using either an oxidizing agent or a reducing agent.0679

    How about a carbon nucleophile, some sort of C-?--there is two kinds of carbon nucleophiles we can look at.0692

    One is just a straight out carbanion; what carbon can hold a negative charge and just be a salt with something like a sodium cation?0700

    There is really only a couple examples of this we have seen; we have seen acetylide anions; we have seen cyanide anions.0710

    What makes these special and unique and able to hold a negative charge is because they are sp hybridized; that triple bond allows us to simply deprotonate that carbon and use it as a nucleophile.0717

    For example, if we took acetylene and we react it with NaNH2; who is NaNH2?--that means we have Na+NH2-.0734

    NH2- looks to me like a very very strong base; what happens when a base sees a terminal alkyne or acetylene?--this is an acidic proton; we are going to deprotonate.0744

    Once again the reason I can deprotonate here is completely because it is an sp hybridized carbon; that is what stabilizes the negative charge.0765

    This is a reasonable nucleophile; what nucleophile can it react with?--that is what we are doing in step two is we are reacting with this electrophile.0774

    The nucleophile is going to see this electrophile; again carbonyl, partial positive, always an electrophile; what reaction happens?0785

    Our nucleophile, in this case our C- attacks the carbon, breaks the π bond, same thing every time when a nucleophile attacks.0794

    We will end up with an O-; now we have added a carbon-carbon triple bond here to that carbon.0804

    What do we need to do in step three?--step three, we need to have a workup so that we can protonate our O-; we get another alcohol product.0813

    When a nucleophile attacks a carbonyl, we will get this alcohol; but this is not a simple reduction reaction like we saw before because we are adding this carbon chain.0831

    What is new here is we have created a new carbon-carbon bond; that is a really big deal for synthesis; what is exciting about carbonyls is they are carbon electrophiles.0842

    If we combine it with a carbon nucleophile, we can create an alcohol with a new carbon-carbon bond that is being formed.0854

    Cyanide is another example of a carbanion that exists; we could just use that sodium cyanide anion; we can have as commercially available.0864

    Once again it is going to attack the carbonyl and break the π bond; what is going to happen after workup?0876

    We are going to have an OH where we used to have a carbonyl; now we are going to have a CN attached to the carbon.0883

    In each case, we are seeing... we saw hydride attacking the carbonyl; we can also have an acetylide type anion; or we can have a cyanide type anion; those are all good.0890

    These are called cyanohydrins--this structure where we have a CN and an OH on the same carbon.0900

    This is an interesting reaction because this is the only reaction we have seen so far that is reversible; in other words, this can kick back out that molecule of HCN.0905

    Because cyanide is poisonous, this is something that is dangerous; when we have a structure like this, we should know that that is something that could generate some cyanide.0919

    Another class of carbon nucleophiles are the organometallic reagents; what is great about organometallic reagents like a Grignard reagent or an organolithium reagent.0933

    Remember all of these are like having an R-; what is great about the organometallic is you can have any kind of R- that you can imagine.0943

    Unlike having to have a triple bond for a carbanion, with an organometallic you can have phenyl groups; you can have alkyl groups.0951

    You can have just about anything you can imagine, all sorts of different carbon chains.0959

    Let's look at an example of that; what would happen if I took this aldehyde and I react it with phenyl magnesium bromide.0964

    Phenyl magnesium bromide acts like it is a phenyl minus, great nucleophile; I know my carbonyl is a great electrophile.0971

    Let's see if we could predict the product here; I think that nucleophile is going to attack the carbon, break the π bond.0980

    We now have a phenyl group, a benzene ring; we could draw that out if you want or you could just keep it a Ph but just to remind what is happening here.0990

    We have just added a phenyl ring to this carbonyl carbon; then after workup, step two we are going to end up with an alcohol.1005

    Hopefully you are seeing a trend here that reaction of the carbonyl with a nucleophile is going to give some kind of alcohol product.1014

    Where this comes in handy is if we are given an alcohol as a target molecule, we can keep that in mind as we plan our synthesis.1027

    If we wanted to take a look at the retrosynthesis of this alcohol, retrosynthesis is asking what starting materials do I need?--what starting materials do I need to make this alcohol?1036

    What we just learned was that you can identify that carbon bearing the OH group and you can take any one of these other carbon groups and do a disconnection there.1048

    When I do that disconnection, I think about the two carbons that are coming together to form this new carbon-carbon bond.1061

    Then I ask myself which of those was a nucleophile, which of those was an electrophile, what did they look like as starting materials so that they could come together and make this product?1068

    The R group can be good as a nucleophile; something like a Grignard reagent would be a great way to make any carbon group nucleophilic.1080

    Which means this carbon was my electrophile; what did my electrophile look like?--what kind of electrophilic carbon can I have?1093

    That after a nucleophile attacks it, I am going to have an alcohol at that position?--of course it is the carbonyl.1102

    This guy was the carbonyl; I can draw this ketone for example and an appropriate Grignard... a Grignard.1110

    Let's check our work; if I had this ketone and I react it with this Grignard, after reaction workup, absolutely I would get this alcohol.1131

    That new carbon group would add in to the carbonyl; I would now have an OH at that position.1139

    This is a very nice strategy to keep in mind; if I want an alcohol, the way I make an alcohol is I work backwards to a ketone and a Grignard.1144

    It is good to keep in mind that a ketone plus a Grignard gives an alcohol; a ketone plus a Grignard gives an alcohol; a ketone plus a Grignard gives an alcohol.1156

    It is a great strategy to use anytime you need to do an alcohol synthesis; let's try and do an example; how about if you were given this transform problem.1166

    What are the reagents necessary to convert the given starting material into the desired product?--as usual more than one step might be necessary.1177

    The way that we need to approach these problems, the systematic approach we should have is we should look at the target molecule.1185

    Look at this product as a target molecule and do a retrosynthesis, ask what starting materials do I need?1191

    When I compare this alcohol to my starting carbon chain, I see that I started with this six carbon chain.1199

    But now I have this six carbon ring plus these extra three carbons; that directs me to where I need to do my disconnection.1205

    In other words, I know that in the course of this synthesis, I have to form this carbon-carbon bond; how do I do that?1211

    In order to do that, I look at these two carbons involved and I ask myself which one was my nucleophile, which one was my electrophile?1220

    I am going to come back to the carbon that now has the OH; which part was that carbon?--that carbon was the electrophile as a carbonyl; so this carbon was my nucleophile.1228

    How do I make an alcohol?--I have an alcohol target molecule; how do I make an alcohol?--from a ketone plus a Grignard.1243

    I am really asking what ketone and what Grignard do I need in order to make this alcohol?1253

    I need this three carbon carbonyl; I need acetone as my ketone, as my electrophile.1259

    What Grignard do I need?--I need this cyclohexyl Grignard, MgCl in this case; or remember I could do a lithium here too.1269

    When I say ketone, what I really mean is ketone or aldehyde, something like a ketone; when I say Grignard, that means Grignard; organolithium would do the same reaction.1280

    But ketone plus a Grignard gives an alcohol is a nice simple phrase to remember.1289

    If I had these two components as my electrophile and my nucleophile, they would be able to create the target molecule; that is awesome.1296

    How do I get to where I need to go from where I am?--right now, I am at chlorocyclohexane; can I go from chlorocyclohexane to cyclohexylmagnesium chloride?1304

    Of course, all I need to do is add in magnesium metal; I can make this Grignard reagent; once I have my Grignard reagent, I need to add in an appropriate electrophile.1318

    It is going to be acetone which is the ketone I need in this case; and I am on my way to the my alcohol.1328

    Is there anything missing in these reaction conditions?--would this second part work to give me my alcohol?--there is something that is missing.1335

    I could imagine this Grignard attacking the carbon and breaking the π bond; but that is going to give me an O-; how do I turn this into an OH?--I need to have an aqueous workup.1343

    Any Grignard reaction is always going to be a two-step process; first we react the Grignard with the electrophile.1353

    Then step two, we add in some H3O+; we do some kind of acidic workup.1359

    It is really important to show these numbers here, step one and step two, to show that these two are done in sequence, one after the other.1364

    And we can make this alcohol do this transform; here is another one; what if I had to start with this alcohol and make this new alcohol?1374

    Again I see that I can identify my carbon chain; I have one, two, three carbons here; one, two, three carbons; I clearly see that this is a new carbon-carbon bond that has to be formed in the reaction.1387

    If you didn't try and do this with retrosynthesis, you could fall into a trap; you could say I need to get rid of that hydrogen and I need to replace this with an ethyl group.1406

    Maybe I can react this with some really strong base like NaNH2; I have deprotonated hydrogens before with NaNH2.1421

    Then I can make this anion; then I could use that as my nucleophile and react it with something like ethyl iodide or bromide and do an Sn2.1432

    A lot of times when we just started our starting material and force our way through to the product, we come up with a problem like this; we make mistakes.1450

    This synthesis would never work as shown; what is the problem here?--what is the problem here?--first of all we are reacting with a strong base.1460

    Where do I have an acidic proton in this molecule?--do I have any acidic protons?--I do; it is up here; this is the only acidic proton.1468

    In fact this one is not acidic; even if I didn't have that OH, there is no way I can make this anion; this is completely an unstable anion.1477

    It would be impossible to make it; we can't just invent new reagents and new reactive species and intermediates that we have never seen before.1490

    When have we seen NaNH2 deprotonate a CH?--when is the only time we can do this?--only for alkynes; only if you have a CH on a triple bond, an sp hybridized carbon.1497

    That is the only time we are going to do this little trick and deprotonate and then maybe do an Sn2.1512

    This is a failed approach; the reason we fell into this trap is because we didn't do our systematic approach where we look at our product and think what do I need to make this product?1517

    The retrosynthesis is going to be a better approach; what starting materials do I need?--now I see the bond that I am breaking; I see the two carbons involved in the reaction.1529

    I ask how can they come together?--one of them must have been a nucleophile; one of them must have been an electrophile; which one was my electrophile?1540

    The carbon that is now a single bond O-H used to be the carbonyl; this was my carbonyl; this was my electrophile.1550

    That tells me that this carbon was my nucleophile; it had to be a nucleophile in order to react with it.1560

    I see that it is an alcohol; how do I make an alcohol?--how do I make an alcohol?--I make it from a ketone plus a Grignard.1567

    Who is my ketone?--I need this one, two, three carbon with a carbonyl; look it is acetone again; I need acetone.1579

    Then I need this two carbon group to be introduced as a Grignard, MgBr; or the organolithium would be fine here too.1587

    This is the planning that we need to do; we say if I had acetone in a reaction with ethyl magnesium bromide, I could make this product.1597

    Now I look back and see where I started; I am at isopropyl alcohol; I have isopropyl alcohol; I need acetone.1605

    Have I ever seen that synthesis before, that transformation before?--it looks like I am increasing my number of C-O bonds; what does that mean?1614

    It is an oxidation reaction; of course alcohols can be oxidized to ketones or aldehydes; we need an oxidizing agent; name an oxidizing agent.1625

    We have seen PCC; we have seen Jones; we have seen Swern; which of these would work?--all of them would be good; let's just pick one and go for it.1635

    PCC is usually my favorite because it is so short and easy to remember; and that works in all cases so PCC is good here.1642

    Then what did I want to do with this ketone once I made it? I wanted to react it with the Grignard; once again a two-step procedure.1649

    First I add in my Grignard reagent, MgBr; step two, I do aqueous workup, H3O+.1657

    As usual any synthesis problem, once you see it solved, it looks so simple; every step in a synthesis problem should be a simple ordinary reaction that you have seen a hundred times.1667

    But it is that combination of reactions and reagents and how you use them and what order you use them that make these multistep transformations possible.1679

    Without a systematic approach, without planning first, we can have some really disastrous consequences; it is really good to get into habit of doing this planning from the beginning.1689

    Let's take a look at one more example; this one is again going from one alcohol to another alcohol; I see we have a one, two, three carbon chain.1700

    It is not as obvious in this case where those three carbons are now; you might think this is one, two, three.1715

    But if I did that, now I would say here is my disconnection; somehow on carbon 1, I have to add this ethyl group; tell me what kind of reactivity carbon 1 has here.1724

    How would you get anything to happen with this carbon?--could it be a nucleophile?--could it be an electrophile?--nothing.1734

    There is a problem with this; let's redraw it and let's think of another way to identify those three carbons.1743

    What I am going to suggest is that carbon 1 started out as a methyl; it is a CH3; it is still going to be a methyl in the product.1750

    Where is carbon 1?--it is right here; one, two, three; there is my original carbon chain; there is my disconnection.1757

    I have an alcohol; I want to disconnect it; I think about my starting materials; I know that one approach is a ketone plus a Grignard; that has worked well for us so far.1766

    I look at these two carbons; I think who is going to be my nucleophile, who is going to be my electrophile?--we end up in a bit of a dilemma; we end up in a bit of a dilemma.1779

    This three-carbon chain, just my alkyl group, can be my Grignard; this guy was my nucleophile; but what was my electrophile?1791

    Could my electrophile be this two carbon electrophile, in other words, the aldehyde?--would these combine to give our target molecule?1804

    This carbon would attack and we would get a three carbon with an OH on the wrong carbon.1817

    Remember a disconnection we have seen before was always the alcohol carbon was our carbonyl; here it is not the alcohol carbon that we are asking to be the electrophile; it is the next carbon over.1827

    This approach isn't going to work in this case with this disconnection; let's come back and think about what starting materials we really had.1838

    Again I like the fact that this guy was my nucleophile; but here is the electrophile we need; let's just look at it as a synthon and say I need something that is electrophilic.1849

    I need to imagine an electrophile that is electrophilic not on the same carbon as the oxygen but the next carbon over.1862

    What electrophile have we seen before that the Grignard can be adding to?--how about if we add this lone pair back in, what electrophile would you end up with?1869

    How about an epoxide?--have we ever seen an epoxide as an electrophile, an epoxide being an electrophile?--of course.1882

    Ketone plus a Grignard is not the only way to make alcohols; it is just going to be the most common way we are going to see repeated throughout.1892

    But of course you can maybe have a disconnection at the next carbon over; you could do an epoxide ring opening to give that pattern.1900

    If I had this Grignard and this epoxide, yes they would combine to give the target molecule we are shooting for.1911

    Now I look back at where I am; I am at an alcohol; I need to turn this into a Grignard; where do Grignards come from?--let's keep doing our retrosynthesis.1917

    How would you make propyl magnesium bromide?--I would need a bromine in that position; I would need a halide of some kind in that position; then I could convert it to the Grignard.1926

    What I am going to need to do first is convert this to a bromide or a chloride or an iodide, your choice; what would be a good reagent to do that?1938

    Maybe PBr3 would be a good choice; there is no chance of rearranging; remember that makes a good leaving group and it displaces it with the bromine.1949

    Now we have our alkyl halide; what did we want to do with that?--we wanted to make that the Grignard reagent.1960

    We just add in some magnesium metal; now we have the Grignard; that is our nucleophile; what do we do with that nucleophile?1964

    What electrophile do we need?--we wanted this epoxide; this is called ethylene oxide; this will bring us to our target molecule by reacting with ethylene oxide.1973

    As usual with our Grignard, it is going to be two steps; first step one is react it with the epoxide; step two is do H3O+ workup.1984

    Synthesis of alcohols requires identifying the disconnection; then looking at the two carbons involved and saying who would be a nucleophile, who would be a good electrophile?1994

    As always, we want to work back to starting materials and reagents that are recognizable, that are simple, that are things we have seen before, we have used before.2005

    So we know the synthesis is going to work once we put it all together; here is one more.2012

    I am starting out with the phenyl and this carbonyl; I still have the phenyl and this carbon; now I have two carbon groups that I need to add in.2022

    This is going to be a little more challenging; we can start with either one of them; let's start with this disconnection here.2033

    These are the two carbons that we want to come together; this is an alcohol; let's try to go back to a ketone plus a Grignard.2042

    The carbon that now has the OH was my carbonyl; I need this ketone; my Grignard in this case was the three carbon chain; there is my electrophile; there is my nucleophile.2056

    I need to have this ketone and this Grignard if I want to make the target molecule; that is good.2073

    But now I compare my aldehyde and my ketone and say how do I get from an aldehyde to a ketone?2080

    Can I deprotonate this CH with a strong base and add in that alkyl group?--could I deprotonate here??no.2092

    When we are trying to take that approach, again we are grasping at things because we don't know how to get there.2102

    We have to think about the reactivity of this carbon; carbon 2 is a carbonyl carbon; it is an electrophile.2109

    How are we going to add in this isopropyl group?--we are going to add it as a nucleophile.2117

    Let me show this is a nice example because after working backwards a little bit, maybe we get stuck.2123

    Let's go ahead and start working forwards a little bit and see if we could bridge the gap in between.2129

    If I wanted to add this isopropryl group, how do I make it nucleophilic?--I just add on a metal, magnesium bromide or lithium.2136

    Step one, magnesium; step two, H3O+; I would be able to add one of my carbon groups; this clearly is moving me towards my target molecule.2144

    The question is how do I add the second carbon group?--can I just add in my second Grignard?--is that going to add in the second one?--do alcohols react with Grignards?2156

    In fact they do; they don't do it to form a carbon-carbon bond; this simply acts as an acid and the Grignard acts as a strong base; in fact you would just deprotonate.2171

    That is not what we want to do; this is where our planning came in; when can we use this propyl Grignard?--when we have a carbonyl to react it with; we don't have a carbonyl; we need a carbonyl.2181

    If I had this carbonyl, now I could see where I can go with it; I could add in my Grignard; how do I go from an alcohol to a carbonyl?--this is an oxidation; all we need is PCC.2197

    We can get to our carbonyl; now we are ready to add in our second equivalent of the Grignard or our second type of Grignard, H3O+, and it works.2210

    In this case because I had to add two carbon nucleophiles to my carbonyl carbon, the strategy was to add the first carbon nucleophile to give me an alcohol product.2223

    Then I had to reoxidize to a new carbonyl so that I could add a second equivalent of the Grignard, a second nucleophile, to add the second carbon group.2235

    I like this example because sometimes when you are doing your retrosynthesis, if you get stuck, just trying working forwards a little bit.2245

    When we go in both directions, hopefully that will get us through the entire synthesis.2253

    Another interesting reaction we can have for carbonyls is a very special kind of nucleophile called a Wittig reagent; this undergoes what is known as a Wittig reaction.2261

    Notice it is spelled with a ?w but it is pronounced with a ?v; it is a German word, German name.2273

    A Wittig reagent is an example... there is a typo... of resonance stabilized carbanion; it looks like this; it has a P+ attached to a C-; this is called an ylide.2281

    An ylide means that you mean have a + and a ? charge in the same structure; it is called a phosphonium ylide because that is what we call a P+; phosphonium ylide.2294

    This has resonance stabilization; there is this second resonance form we could draw for this; that is taking this lone pair and bringing it in as a π bond.2306

    This is another way that we can draw it; the Wittig reagent is something we can draw either way; we should get used to seeing it either way.2318

    Sometimes it is just drawn as a phosphorus carbon double bond; sometimes it is drawn with a P+ and C-.2324

    It doesn't matter which way we draw it; it is the same thing; we are going to see what it does.2330

    But this resonance stabilized which is why it is okay to have this C-; ordinarily we don't want to have a negative charge on a carbon; but this is a possibility; this one is okay.2334

    What are we going to do with it?--when we see a Wittig reagent like this and we react it with either a ketone or an aldehyde.2346

    What we are going to do is we are going to identify the carbon group that is attached to the phosphorus; we are going to replace the oxygen of the carbonyl with that carbon group.2353

    Where we used to have a C-O double bond, we are now going to have a C-C double bond; here it was a CH2; so now it is going to be a CH2.2364

    The Wittig reaction turns a ketone or an aldehyde into an alkene; this is an excellent method for synthesizing alkenes from ketones and aldehydes.2375

    Let's take a brief look at the mechanism; the mechanism is a little strange compared to some we have seen before.2392

    But I do want you to see how it is not just magical where this carbon-carbon double bond comes from.2396

    The reaction starts out simple enough because when we look at this resonance form of the Wittig reagent and we see the C-, we see how it is clearly a nucleophile.2403

    We have a C-; our carbonyl we know is an electrophile; what is going to happen first?2413

    Same thing that always happens; our nucleophile attacks the carbonyl, breaks the π bond; this now gives us an O-; attached we have the carbon group plus this triphenylphosphine group.2418

    Because we have a P+ and an O- that are close to each other, what happens is the oxygen then bonds to the phosphorus to make this four-membered ring.2434

    It is called an oxaphosphetane; we get this oxaphosphetane intermediate; very rare to see a four-membered ring; I know that; but phosphorus on the periodic table is below nitrogen.2444

    Phosphorus is bigger; it has bigger arms; that four-membered ring is not nearly as strained as we would associate with a carbon or an oxygen type ring.2455

    This is not our final product; this falls apart; this falls apart by undergoing a pericyclic reaction.2467

    What happens is this bond breaks and becomes a π bond; and this bond breaks and becomes a π bond; these four electrons and these two arrows all rearrange at once.2478

    What we form then is a... this is where we get our π bond for our carbon-carbon double bond; what else is formed in this reaction?2491

    We get a phosphorus with three phenyl groups on it and a P-O double bond; we get this triphenylphosphine oxide as a byproduct of our Wittig.2499

    This is something that we can separate, we could filter off; we are left with an alkene product.2512

    Where does the Wittig reagent come from?--it is going to be two steps to prepare this; it comes from an alkyl halide.2519

    For example, if we wanted to make... let's redraw the Wittig reagent we just used on the previous slide.2526

    If I wanted to make this Wittig reagent which has just one carbon on it, the way I would start is I would start with the one carbon alkyl halide.2531

    Obviously I need to introduce this triphenylphosphino group; that is what I used; this is called triphenylphosphine; triphenylphosphine, awesome nucleophile.2542

    Again phosphorus is right underneath nitrogen; we know nitrogen is a very good nucleophile, loves to do the Sn2.2554

    Phosphorus, because it is even bigger, more polarizable, it is an excellent excellent nucleophile.2560

    When it sees an alkyl halide, it very readily will do an Sn2 mechanism, backside attach, and form this carbon-phosphorus bond.2566

    Phosphorus now has four bonds; we count one, two, three, four; just like nitrogen, phosphorus wants five; it is missing an electron; that is why we have a P+.2578

    That is our first part; let me draw this in the other resonance form also so we can think about...2592

    It is always nice to consider where we are heading when we are considering a mechanism or a synthesis on how to get there.2602

    We have introduced this P+ part; what we now need is the C- part; we started with a CH3; now we want it to be a CH2.2609

    What has happened here?--it looks like we have done a deprotonation; we need to deprotonate; the reagent we need for that is a very strong base.2619

    The base that we typically use in the Wittig reagent is butyllithium, extremely strong base; where have we seen butyllithium before or any organic lithium?2630

    We have seen it as an organometallic reagent just like a Grignard; this would be an incredibly strong base; it is just like any organolithium we have seen or like a Grignard reagent.2643

    This is one that is just pretty available, commercially available; so it is an excellent strong base to use anytime we need it.2657

    What we are going to do is we are going to grab one of these protons; let's just make this a CH2; we could see one of these protons and our butyl minus that we have.2664

    Of course we are going to put that in quotes because it is not really butyl minus; it still has the metal attached; but it acts like butyl minus as a base.2675

    It is going to grab that proton and either put those electrons right on the carbon so we have a P+C-.2681

    Or you could draw the other resonance form where it brings the two electrons in as a π bond; either way we now have the Wittig reagent.2687

    We got there in two steps--Sn2 with triphenylphosphine and then strong base to deprotonate that carbon.2695

    Let's try a predict-the-product for a Wittig reaction; we are starting with an aldehyde or a ketone; this is the substrate for a Wittig reaction.2703

    Here is our Wittig reagent; I see we have a P+ and a C-; how do we predict the product of a Wittig?2714

    Very very simple; I know the mechanism is a little scary, but predicting the product is very simple.2723

    We find the carbon group of the Wittig reagent; it is whatever group is attached to the phosphorus; we replace the oxygen on the carbonyl with that group.2729

    We replace our C-O double bond with a C-C double bond; what did this have?--this had three carbons; we are going to add three carbons.2741

    That is a nice way to check that you have done the Wittig reaction; this started with three carbons; we are adding a three carbon aldehyde and a three carbon Wittig.2753

    We need to have a six carbon product; that is a good way to make sure you haven't lost any carbons; maybe if you are doing a line drawing, you might come up with that a little bit.2761

    So we are going to get an alkene product; the Wittig reaction is a great way to make alkenes.2773

    Knowing that, if we ever have an alkene as a target molecule, one way we can make this is by doing a Wittig reaction.2782

    The Wittig disconnection is completely breaking through the carbon-carbon double bond because in the Wittig reaction, both of those two bonds are formed during the course of the mechanism.2790

    What it will do is it will completely cleave it; one of these carbons was the nucleophile; one was the electrophile; because it is an alkene, you can pick either one.2803

    Typically the one that is a little less hindered would be the better electrophile; we could put the carbonyl in the less hindered position.2815

    In other words, an aldehyde would be better than a ketone for the Wittig, a little faster; but both would be okay.2826

    Which means this guy was my nucleophile; how do you make it a nucleophile?--it is going to be a Wittig reagent.2831

    One possible disconnection for an alkene is to work backwards to a suitable Wittig reagent; what does this Wittig reagent look like?2840

    It is this six-membered ring with the PPh3 attached with the double bond; or you could draw the C-P+, same thing.2849

    This is our Wittig reagent; that is our nucleophile; what is the electrophile?--we had this two carbon carbonyl; that is just an aldehyde; it is acetaldehyde.2858

    Typically when we draw aldehydes, we usually draw in that CH in the line drawing; it is acceptable to leave it off; but convention usually puts it in there; we will add that in there for clarity.2872

    In this case, it is an aldehyde; that is going to be our electrophile; this is the Wittig reagent we need; let's see if we could do a synthesis of this.2885

    You may be given instructions where you could just use a Wittig reagent and assume it is commercially available.2897

    But if you had instructions... let's say you had instructions where the starting materials had to be alcohol starting materials only; for example; that makes the problem a little more challenging.2902

    In other words, now you have to make this Wittig reagent starting from an alcohol; you have to make this aldehyde starting from an alcohol.2917

    Let's think then about this Wittig reagent; where do Wittig reagents come from?--we saw that it is a two-step synthesis; it comes from an alkyl halide in that position.2925

    We need a halogen in that position--chloride, bromide, iodide, your choice, whichever one you want.2936

    I need cyclohexyl bromide; but I have to start with cyclohexyl alcohol; how could I convert that to the bromide?--there is a variety of reagents; I could use PBr3.2946

    Or in this case because there is no possible rearrangements to give any other product, I could maybe use something like HBr; that would work well to give this bromide.2963

    A few possibilities here; those would both be good; then how do I go from the bromide to the Wittig reagent?--how do I get this double bond PPh3?2972

    Remember there is going to be two steps; we can do them both over one arrow; the first step would be to introduce the phosphorus as triphenylphosphine--great nucleophile; that does the Sn2.2985

    Then the second step is to add a strong base, something like butyl lithium, to do a deprotonation; those are two-step procedure to make the Wittig.2997

    Then we want to add this aldehyde; where does the aldehyde come from?--if we had to have an alcohol starting material, we could start with the two carbonyl alcohol, ethanol.3006

    How could I go from an alcohol to an aldehyde?--that looks like an oxidation reaction; I know how to do that; we have PCC, Swern, and Jones; are all three of those okay here?3017

    Remember because this is a primary alcohol, this is the case where if we use something like Jones conditions, sodium dichromate and acid, chromic acid oxidation.3033

    This would over oxidize and give me the acid; in fact I want to use either PCC or Swern to do this.3044

    Now I have my aldehyde; now I have my Wittig reagent; I mix those together and I have my target molecule.3051

    Now that we know about the Wittig reaction, this is going to be one additional way that we can do a disconnection for a target molecule.3058

    It turns out that this synthesis is often much more reliable then forming an alkene by dehydration or by elimination reaction; so the Wittig reaction is very widely used in synthesis of alkenes.3066

    Everything we have seen up to now of reactions of aldehydes and ketones have been carbon nucleophiles; well, we saw the hydride nucleophile.3083

    But we also saw carbon nucleophiles--the acetylide or cyanide or a Grignard or the Wittig, forming new carbon-carbon bonds.3089

    We are going to shift gears now and take a look at reactions with oxygen nucleophiles; what is interesting about oxygen nucleophiles is right here--we see that this is reversible.3099

    The other reactions we saw, I know the cyanohydrin was one exception for that, but hydride and Grignard and Wittig, these are all reactions...3113

    Once you form a carbon-carbon bond, you don't go back from there; you don't break that carbon-carbon bond.3121

    But the oxygen nucleophiles are going to be something that you can form the C-O bond and it is going to be possible to break that C-O bond.3126

    The first oxygen nucleophile we will consider is addition of water; when we do that, the product we get is called a hydrate; as usual, this carbonyl is going to be my electrophile.3133

    If water was my nucleophile; if we just think about the pattern we have seen up till now, what does the product look like after a nucleophile attacks the carbonyl?3144

    We know that we end up with an OH where the carbonyl used to be; if water was my nucleophile, what do we end up with here?--we end up with another OH.3154

    What we have done is we have added water to the carbonyl; the oxygen is the nucleophile and then we protonate the original oxygen.3168

    This structure is called a hydrate; it is called the hydrate of an aldehyde or a ketone because we have literally added water to it.3178

    It turns out that this is a pretty unstable arrangement of functional groups; a carbon does not want to have two separate CO bonds and two OHs attached to it; this is extremely unstable.3188

    In fact because it is reversible, it turns out that the reverse reaction is favored; anytime you have this arrangement, it would rather rearrange and do a mechanism to get back to the carbonyl.3201

    This is more stable as the carbonyl; can you think of why that is that we would want to have this carbonyl instead of the two separate C-O bonds?3210

    Remember we started talking about how stable the carbonyl functional group is, how energetically favorable it is; this has resonance; we don't want to give that up to form this product.3224

    Although ketones and aldehydes can react with water, as a nucleophile, it is very rarely a favorable reaction; so I am not going to spend much time about it.3239

    There are a few exceptions though where the hydrate is in fact formed to a significant amount; one such example of that is formaldehyde.3251

    The very unique example of an aldehyde is when we have two hydrogens attached to the carbonyl; that is called formaldehyde; it turns out that this is very reactive; it is extremely reactive.3263

    We have just these hydrogens here; compared to a ketone that has carbon groups, alkyl groups, that can donate electron density, this is a great electrophile.3279

    It is very reactive; it is a huge partial plus; it has no steric crowding of any kind because we have just hydrogens here.3291

    That makes it really susceptible to nucleophilic attack; if you put it in a solution like even a water solution where water is around, water will attack it.3299

    It turns out that in an aqueous solution, you have the vast majority, 99 percent of the structure looks like this instead of the carbonyl.3308

    Because this carbonyl is really quite reactive; but any other aldehyde and any other ketone, we have the opposite; it would prefer to be a carbonyl.3318

    Another interesting example is that the hydrogen is going to be favored when you have a significant partial positive right next to the carbonyl.3328

    This is an interesting molecule; it is known as chloral; we know that the carbonyl carbon is partial positive.3339

    It has a significant partial positive because of the resonance contributor that puts a positive charge on the carbon.3347

    If on the α carbon, meaning the next carbon over, I put three chlorines, I know each of those chlorines is electronegative; those chlorines pull electron density away from this carbon.3354

    It turns out that this α carbon is also significantly partial positive; this is going to be something that destabilizes this molecule; the adjacent partial positive destabilizes the molecule.3365

    What is going to happen is again when you put this in water, we are now going to get formation of the hydrate; instead of a carbonyl, we have two OH groups.3385

    This now is going to be favored in the forward direction because you have less of a partial positive when you have the two separate OHs.3396

    This carbon is now less of a partial positive so we don't have those extremely electron deficient carbons right next to each other.3411

    This would be something that in this rare case, rather than have the carbonyl, we would rather have two separate OH groups.3418

    This molecule is called chloral hydrate; it is something that can be isolated because it is reasonably stable.3427

    This has an interesting history; if you have ever heard of Mickey Finn knockout drops or watched an old movie where they suggest that they slipped him a Mickey.3432

    This is the molecule that used for that--chloral hydrate; it can give off chloroform which acts as an anesthetic; this is something that can be used to render a person unconscious.3444

    A chloral hydrate is an example of one of those unique molecules where we would prefer to have the OHs.3457

    The other oxygen nucleophile we are going to consider is if we have an alcohol reacting with a carbonyl; this is a reaction that can be driven in the forward direction and can be quite useful.3467

    When we react an alcohol with a carbonyl, a ketone or an aldehyde, the product we are going to get is known as an acetal.3480

    Let's take a look at this reaction; if we take a ketone, this is our electrophile; we react it with an alcohol as a nucleophile, here is our alcohol, in the presence of TsOH.3487

    This is tosic acid; you could just say HA here; it doesn't have to be tosic acid; but you do need an acid catalyst.3500

    Tosic acid is a nice choice; that stands for toluene sulfonic acid; it looks a little like tosyl chloride, the reagent we have used before.3509

    If we have the tosyl with an OH group here, this is extremely acidic; in fact this structure looks a lot like sulfuric acid.3517

    Sulfuric acid has these two SO double bonds; it has an OH here and another OH here; we know sulfuric acid is a very strong acid; for the same reason, tosic acid is a very strong acid.3525

    But by adding in this aromatic ring, it makes it soluble in organic solvents; it makes it more nonpolar; so this is a nice acid to use when we are using organic solvents.3536

    What happens... let's imagine what can happen; what product would you get if alcohol was your nucleophile?3551

    We would end up adding an OR group to the carbonyl carbon; where we used to have a carbonyl, we would get an OH; this structure is in fact what is formed.3559

    However this is just an intermediate structure; the reaction doesn't stop here because the second equivalent of alcohol is going to come in and react.3571

    What will happen is we will end up replacing the carbonyl oxygen with two separate C-O bonds, both of them being OR groups.3580

    When you have one carbon with two OR groups attached, it is no longer called an ether; an ether would be if we had just one OR group.3590

    But this one carbon with two OR groups is described as an acetal; this functional group is called an acetal.3599

    For that reason, this structure here where you are just half way towards the acetal is called a hemiacetal, just like a hemisphere is half of the globe.3608

    Because you have just one OR group, we call this a hemiacetal; this is not stable; it will continue until we get the full acetal.3622

    We just talked about for the hydrate how we would rather have a carbonyl than two separate C-O bonds; why is it possible in this case to get the two separate C-O bonds?3630

    You are right; it is not something that is going to happen spontaneously and just on its own; the other product in this reaction, what is missing here?3641

    We lost this oxygen; plus we have the hydrogen from this alcohol and the hydrogen from this alcohol; the other product is going to be water that is formed in this reaction.3651

    The way we push this acetal formation reaction forward is we have to remove the water as it is formed, must be removed to push the equilibrium forward.3661

    That is because every step along this mechanism is reversible; every step we do can be undone.3677

    The only way to push it in one direction or the other is by removing one of the products as it is formed, Le Chatelier's Principle; we are just going to keep going forward to replace that.3684

    And if water is not here, we can't do the reverse reaction; so it stops the reverse reaction and promotes the forward reaction.3695

    First let's take a look at an example of this reaction and see if we could predict the product; then we will explore the mechanism.3705

    What if we took this aldehyde and we reacted it with methanol and tosic acid?--methanol and tosic acid.3711

    What is going to happen is we are going to replace our C-O double bond with two separate C-O bonds; the group that is going to be added is whatever OR group we have in our alcohol.3719

    Because it is methanol, we are going to add a methoxy group on one side and a methoxy group on the other side; we are going to go from an aldehyde to an acetal.3736

    We could always assume that we have an excess of our reagents; in fact in this reaction what you would do is you would use the alcohol typically as the solvent.3748

    You have a huge excess of that nucleophile; we assume that we are going to be able to go completely to the acetal because we have enough equivalents.3755

    We need the two equivalents; we will have them both here; of course our other product is water; if you want to balance your reaction and have everything there.3764

    Although typically a lot of times, predict-the-product, we are just looking for the organic product, what is the fate of this organic starting material.3773

    Let's use this example and let's think about the mechanism; how is it that we go from this aldehyde to this acetal?--let's think a little bit about the mechanism before we get started with it.3781

    I notice that they are acidic conditions because I see tosic acid; in fact this is always going to be true; acetal formation always requires an acid; what do you think the first step is going to be?3793

    If you see there is an acid present, what do acids do?--they donate a proton; they are going to protonate something; first step is protonate, always.3804

    When you have an acid around, strong acid around, you are going to find something to protonate; that is what is going to get the reaction going.3816

    Another thing to keep in mind, we have seen acid catalyzed or acidic condition mechanisms in the past.3822

    What was always true was for the charges in that reaction, all of our species are going to be either neutral or they are going to have a + charge.3828

    We are not going to have any strongly basic species like hydroxide or alkoxide; we can't have either of those in acidic conditions.3837

    We will keep that in mind too when we are doing our mechanism; let's take a look at that.3846

    The mechanism for acetal formation is going to start... because we have our acid, is going to start with a protonation step.3852

    Where could we protonate?--we have a couple oxygens here; we can protonate the alcohol; that will happen.3861

    But the protonation that is going to get our mechanism started is instead when we protonate the carbonyl oxygen; we will do that instead.3868

    Remember our mechanism we want to move us in the forward direction; we are going to protonate in the place that we need to; that is up here.3880

    Every step of this mechanism is going to be reversible; we want to make sure that we draw this as an equilibrium as we go from one step to the next.3888

    Protonate the carbonyl, what does that do for us?--why is that a good first step?--we know that a carbonyl... what kind of reactivity does a carbonyl have?3897

    Is it acid, base, electrophile, nucleophile?--it is an electrophile; every carbonyl is an electrophile because it is partially positive on the carbonyl carbon.3908

    What do you think is going to happen once we protonate that carbonyl?--now this carbonyl is positively charged; is that good for being an electrophile?3917

    Sure, an electrophile is supposed to be electron deficient; this is even more electron deficient now; it is actually has a positive charge; this is a great electrophile.3926

    When we see a species like this, we want to think about looking around for a nucleophile and having it attack; what nucleophile do we have?3934

    Our reaction is done in methanol; we have methanol as our solvent; that is most certainly going to be our nucleophile.3943

    What happens when the nucleophile sees a carbonyl?--it attacks the carbonyl, breaks the π bond.3950

    This top oxygen now is back to being a neutral oxygen--two bonds, two lone pairs; tell me about this oxygen; what does that have attached to it?--it still has the CH3 and the hydrogen.3963

    Does it have any lone pairs?--it used to have two; but these two electrons are now in this bond, being shared as a bond; it just has one lone pair left; this now looks like it is not a neutral oxygen.3979

    Let's check; one, two, three, four, five; oxygen has five but it wants six; this is missing an electron; it is positively charged.3993

    I know my mechanism isn't done here; I need to get rid of that positive charge; how can I do that?4005

    I can get rid of this proton because I need to have only two bonds to oxygen; if I get rid of this proton, what I can use is I can use my A- that I formed in my first step to come grab that proton.4011

    Or I can use my methanol to come in and grab that proton; both of those are reasonable; methanol is probably our better choice since that is our solvent; we have more of that.4023

    This has some nice bookkeeping; we can attack the proton and leave the electrons on the oxygen.4033

    Let's take a look at what we have accomplished so far; what mechanism did we have?--we protonate, then we attack, then we deprotonate.4043

    Protonate, attack, deprotonate; have we seen that pattern before?--absolutely; this is a very common pattern that we have for acid catalyzed reactions.4059

    Have we gotten closer to our product?--we have; we know that eventually we got rid of the carbonyl; we know eventually we have to get two methoxy groups here.4069

    We have installed one of them; we have an OCH3 and we have an OH on the same carbon.4079

    What functional group have we just converted the aldehyde into?--when we have an OR and an OH, we call this a hemiacetal.4085

    You know you are going in the right direction in acetal formation, this is an acetal, when the first thing you should be doing is making the hemacetal.4094

    Now we need to again thinking about where we are going, we need to get rid of this OH and replace it with an OCH3; that is where we are headed; how can we do it?4104

    What can we do to move that substitution in the right direction?--how about if we protonate the OH as our next step?--that is not a bad idea too because remember we are in acidic conditions.4114

    If we are stuck somewhere, we have a neutral compound; let's find a place to protonate to get us going again.4128

    What does that do for us?--why would that maybe move us in a forward direction?--by protonating the OH, it gives us a very good leaving group.4138

    We turn this into a great leaving group; if we want to do a substitution and get rid of that group, this would be ideal for that.4151

    Now here is the question: how does this leaving group leave?--we have seen substitution mechanisms before.4159

    We have seen Sn2 mechanisms, backside attack, where our nucleophile comes in in a single step, kicks out a leaving group.4165

    We have seen Sn1 mechanisms where a leaving group just leaves on its own and then a nucleophile comes in.4173

    Neither of those... those mechanisms are for tetrahedral carbons bearing the leaving group like an alkyl halide.4179

    Neither of those examples are going to accurately describe carbonyl chemistry which is what we are dealing with in this unit.4186

    Instead the way we are going to describe this substitution is this intermediate is called the CTI.4193

    That stands for a charged tetrahedral intermediate; we are going to look more closely into that definition on the next slide.4204

    But what we have essentially is on the same we have a leaving group and we have a group that can help push that leaving group out.4213

    What happens with CTIs is they collapse; the collapse of a CTI looks like this; the leaving group leaves; but it doesn't just leave on its own; it leaves with the assistance of that second group.4222

    We use these two arrows to help push the leaving group out; let's see where that brings us; when we follow those electrons around, we end up with this structure.4237

    What did we just kick out?--we just kicked out our molecule of water; we know that we form water in this product.4254

    We know that that water must be removed in order to push the equilibrium forward; this is the point at which the water is removed; the reverse reaction can no longer happen.4263

    Let's take a look at this structure; something is missing on this structure; I had a positive charge and I lost a neutral molecule; there still must be a positive charge somewhere.4274

    Where is it?--yes, this oxygen has one, two, three, four, five; oxygen wants six; this is a O+.4283

    Still we are moving in the right directions; we have gotten rid of that oxygen that we needed to replace, that OH group; where do we go from here?--what does this structure look like?4292

    Do you think it is going to be a good nucleophile, electrophile?--it has a positive charge; it has a carbonyl with a positive charge; have we ever seen a species like that?4301

    Yes, right here; right here; what did we say about this type of carbonyl with a positive charge?--it is a great electrophile; it is a great electrophile.4310

    What do we do next?--we look around for a nucleophile; this is how our second equivalent of the alcohol comes back in, as our nucleophile.4320

    What mechanism can you imagine happening?--it attacks the carbon, breaks the π bond.4331

    Now we have at this bottom carbon, we are back to just a nice neutral methoxy group, OCH3; what do we have on this top carbon?4343

    Because methanol attacked, we have a hydrogen; we have a methyl is still there; one lone pair and positive charge.4353

    How close are we to our acetal product that we have?--how close are we?--we just have one proton left that we need to get rid of; that will give us our acetal and get rid of our positive charge.4364

    Our final step in this mechanism is going to be deprotonation; again I can use my A- to come in and deprotonate.4378

    Look at what we made; we converted the carbonyl, the C-O double bond, into two methoxy groups, two methoxy groups.4396

    Remember what we pointed out, what we just thought about on the previous slide; we said our first step is going to be protonate because we are in acid.4408

    We said all of our species should have positive charges or should be neutral; take a look; there were no negative charges here.4417

    It might be tempting sometimes to use methoxide as our nucleophile; that would be a quick way to put in a methoxy group.4425

    But there is no methoxide in strongly acidic conditions; instead methanol is the nucleophile we have to use.4434

    Note the charges; no HO- or RO-; the other thing to note is that it is catalytic; it is catalytic in acid.4441

    That means for every step where I use an acid and protonate, there is another step somewhere where I deprotonate and get that acid back.4455

    I used HA; then I reformed HA; here is another step; I used HA here, I protonated; but then at the end, I deprotonated and got that HA back.4465

    To form an acetal, you take an aldehyde or a ketone, dissolve it in an alcohol with just a trace amount of acid, just a catalytic amount of acid; we will form acetal.4476

    Next let's take a little closer look at what describes a CTI because we are going to see these mechanisms again and again when we are looking at carbonyl mechanisms.4489

    What does it mean to be a charged tetrahedral intermediate?--the first thing that we are going to start with is something called a tetrahedral intermediate.4499

    Tetrahedral means that we have an sp3 hybridized carbon; that means there is just four single bonds to that carbon; at least two of those groups have lone pairs.4512

    We have a situation like this where attached to a carbon, we have two separate groups that have lone pairs, at least two.4521

    It turns out that this arrangement can be unstable; this is inherently unstable; we saw that when you have an OH and an OH, that structure is not so good.4529

    When you have an OR and an OR that structure is something that can react and can be undone.4539

    The way it becomes unstable is when it becomes a charged tetrahedral intermediate; this is what CTI stands for.4546

    It is when you have this same situation, tetrahedral carbon with two groups with lone pairs; but now one of the group has a charge.4555

    When you have this then you get an intermediate; you get a structure that can collapse.4564

    We are going to encounter CTIs in acidic conditions and in basic conditions; of course in this unit, acetal formation is always acidic.4571

    We are going to get something like this; we are going to get a CTI where we have one group with lone pairs and another group with a positive charge.4578

    What we just did let's say is protonate with our acid; that makes this a very good leaving group.4588

    What happens is that leaving group will leave; collapse of a CTI means the leaving group leaves; but it does so with assistance from that lone pair.4594

    It can collapse; we have two arrows; we describe this as a push-pull relationship going on; the leaving group is pulling as usual and doing its leaving group thing.4604

    But you have someone pushing them out at the same time; this makes it a very favorable reaction.4616

    In a base catalyzed situation, our CTI is going to have a negative charge; that is going to make the group that is doing the pushing real good; that makes the other group our leaving group.4622

    Same two arrows; in this case, the group with the negative charge does the pushing and the neutral group is what gets kicked out; so two arrows to collapse a CTI; then we go from there.4636

    The key is when you see a CTI, when you see a charged tetrahedral intermediate, by recognizing that as such, it is going to help guide you in your mechanism.4653

    Because you know what a possible thing that it can do--is it could collapse and kick out one of the groups and go from there.4662

    Let's summarize what we have seen for acetals; if we take a carbonyl and we treat it with an alcohol and some acid like tosic acid; we replace that carbonyl with two OR groups.4671

    In other words, it adds two equivalents of ROH, two equivalents of the alcohol.4683

    It turns out that if you take an acetal and you treat it with water, H3O+, if you treat it with water and acid, the reverse reaction can take place.4695

    We could have a ketone or an aldehyde here; we go to an acetal; if we have an acetal and we treat it with water and acid, it can go back to the carbonyl and kick out your molecules of alcohol.4710

    It is also possible to make a cyclic acetal; the way we get that is we use this; when you take a look at this structure, it contains both equivalents of OH; it is a diol.4727

    If I use a diol rather than a regular alcohol, what can happen is that one molecule can deliver both equivalents of the oxygen.4747

    The structure we are going to end up then has those two oxygens still tethered together; we are going to get a cyclic acetal.4755

    Mechanism for that formation?--exact same mechanism we just saw for the acetal formation.4765

    Except when the second equivalent of oxygen comes in, it is not a separate molecule, a separate alcohol coming in and attacking.4771

    It is going to be an intramolecular attack of the oxygen that is already tethered to the molecule; so we can also make cyclic acetals.4779

    Just like any acetal, reaction of this with H3O+ would regenerate the carbonyl and get rid of that alcohol molecule; in this case, a diol molecule.4788

    Let's take a look at that reverse process; we call that hydrolysis of acetals, reaction of an acetal with H3O+; this is something that regenerates the carbonyl.4803

    If I take an acetal; how do I know this is an acetal?--what does it mean to be an acetal?--we have one carbon with two separate OR groups attached.4813

    When I have this and I treat it with H3O+, that means we have water and we have some strong acid.4825

    You can either see it written as H3O+ or you might see it written as H2O, H2SO4, something like that.4832

    When that happens, we take that carbon with the two separate OR groups and we bring it back to being a carbonyl where both oxygen bonds are going to the same oxygen.4839

    What else do we form here?--these two molecules of methanol are going to come back out; we are doing the reverse of that acetal formation; we call this hydrolysis.4855

    Just a quick question: is this an oxidation?--anytime we have seen a reaction that forms a carbonyl like this before, we described it as an oxidation.4869

    Would this mechanism be described as an oxidation?--why or why not?--what do we expect in an oxidation reaction?--we expect to increase our number of C-O bonds.4887

    How many do we start with?--we started with two C-O bonds; now we have still two C-O bonds; no, because we have two C-O bonds at the beginning and at the ending.4897

    We don't use an oxidizing agent; we are just using water; this is hydrolysis; this is reaction of water; we are trading one C-O bond for a different C-O bond.4912

    It is going to be again characteristic of reactions that we described as hydrolysis down the line; so it is good to think of that term.4922

    Let's see if we could do the mechanism; it turns out that the mechanism is the exact opposite of the acetal formation.4929

    However many steps our acetal formation was, we are going to have that exact same number of steps for the hydrolysis.4939

    In fact every structure along the way that we saw in the forward direction, we are going to go through those exact same structures as we move back to the carbonyl.4946

    We have our acetal; we are treating it with H3O+; think about what you would do first.4956

    How do you get started here?--we have acid; anytime we have acid, we are going to protonate first; we always know how to get started.4965

    Where could we protonate?--it must be one of these oxygens on the acetal; we could just say HA if you want for H3O+; that is fine.4977

    Remember this step though is reversible; we could protonate; we could deprotonate; we could protonate, deprotonate; let's see what happens when we protonate one of those methoxy groups.4988

    What does that do for us?--where do we go from here?--this is a pretty interesting intermediate; it is an interesting intermediate because we have a group with a positive charge.5006

    And on that same carbon, we have another group with lone pairs; we have a name for this; it is some kind of charged tetrahedral intermediate; yes, there it is; this is a CTI.5017

    Ding, ding, ding... bells and whistles going off in our head, every time we see that we structure; what do we know it can do?--it can collapse; that is exactly what is going to happen.5029

    How do we collapse that?--it is going to be two arrows; we have the one group with the lone pairs forming the π bond; that is what is kicking the leaving group off.5040

    These two arrows are going to be very useful to us; you might see this mechanism drawn slightly differently in other textbooks.5053

    But look what happens when we use the two arrows to do that collapse; it brings us to a structure that we recognize; it is a carbonyl; we know what to do with carbonyls.5061

    Here if you are keeping track of all your ingredients, our leaving group just left; we just kicked out one equivalent of our methanol.5075

    Tell me about this oxygen that did the kicking out; this is a now positively charged oxygen; we have a carbonyl with a positive charge.5084

    What do we have?--we have a great electrophile; we just made a great electrophile; what is going to happen to that great electrophile?--it is going to look around for a nucleophile.5093

    What nucleophiles do we have?--we just formed methanol; methanol could add back in and go backwards; remember every one of these steps is reversible.5106

    But what nucleophile do we have the most of?--remember our solvent is water; we have a huge amount of water here; so water is going to be our nucleophile.5114

    It adds into the carbonyl; now we have a neutral methoxy up here; we have water attacking; what is left on this oxygen?5126

    We still have two hydrogens; any lone pairs?--we have one lone pair and a positive charge; very good.5142

    Where do we go from here?--now what?--if you are looking very carefully, you see that we just made a new CTI; that is quite true.5156

    If this CTI collapsed, who is your leaving group?--the water here is your good leaving group; so if this CTI collapsed, where would it bring you?5166

    It would go right back to where we started; again yes, water could add in; water could get kicked back out.5175

    In this case, collapsing the CTI is not going to move us in the forward direction; what will move us in the forward direction?5181

    We don't want water to be our leaving group; what do we want to kick out?--what do we want to replace?--we have two methoxy groups; we want to get rid of both of them.5188

    We have already gotten rid of one; what we eventually want to do is get rid of this other one; what we are going to need to do is make this oxygen the good leaving group, not this oxygen.5198

    How are we going to get there?--let's first deprotonate down here to go back to a neutral intermediate; I want you to look closely at this intermediate, see if you could describe it.5208

    How would you describe this intermediate when you have a carbon with a methoxy and an OH on the same carbon, an OR and an OH?--we call this a hemiacetal.5226

    Of course we went through the hemiacetal; we created this in the acetal formation mechanism; we have to go through that exact same intermediate and the acetal hydrolysis mechanism.5236

    We are here; how do we go from here to the carbonyl?--we said we wanted to get rid of that methoxy group.5248

    Let's protonate up on this oxygen because that is going to turn that top oxygen into the good leaving group.5254

    I feel that we are moving in the right direction here; it looks like a good leaving group; now how does this leaving group leave?--where do we go from here?5277

    Now we have a CTI; ding, ding, ding... we have a CTI; that is the one that has a group with lone pairs and a group with a positive charge; this is now our leaving group that we want to replace.5285

    We essentially went from one CTI and converted it to another CTI, the one that is going to move us in the right direction.5302

    We deprotonate at one position, reprotonate in the other position; now we are ready to kick out that methanol; how do we do collapse?5309

    How do we collapse a CTI?--how many arrows?--we are going to use two arrows; the lone pair forms a π bond; that is what kicks the leaving group out.5317

    Here we just kicked off our second equivalent of methanol; by using those two arrows, it brings us to a very recognizable intermediate.5326

    It brings us very close to our product because now we see the carbonyl; we know we have a carbonyl on our product; we see that we are once again just a proton away.5340

    We just have to deprotonate and we would get to our final product; let's do that; A- can grab that proton; I am going to work myself into a corner.5350

    Make sure you give yourself plenty of room, nice big blank piece of paper when you go to do these acetal mechanisms or acetal hydrolysis mechanisms.5363

    We are getting into the territory of giant mechanisms; don't be afraid to snake around up and down and work that way.5370

    Don't stop and redraw a structure so that you can go left to right because every time you redraw a structure, you have a chance for making mistakes and you have a chance for wasting time.5378

    Both of those we can't afford to do like when it is an exam situation; just go ahead and snake your way down the page; finally we get to our final product.5388

    Also resist the temptation where I now have to flip this over so it looks like the carbonyl up here; no, we are done.5396

    We are back at our aldehyde; we kicked out both of our molecules of methanol; we have completed our hydrolysis of the acetal.5401

    What other nucleophiles can we have to the carbonyl?--there is one more to take a look at; that is a nitrogen nucleophile; we are going to look at two types right now.5414

    We are going to look at either ammonia or a nitrogen with just one carbon group attached; we call those primary amines; it has the formula RNH2.5424

    Of course the nitrogen is going to be a nucleophile; we know the carbonyl is an electrophile; this is a reaction that again is typically acid catalyzed.5439

    If we were to look at the oxygen example, what happened when we had an alcohol?--you might think maybe we replaced the C-O double bond with two nitrogen R groups, kind of like an acetal.5451

    But that is not what happens with nitrogens because nitrogen can have three bonds; what happens instead is we simply replace the C-O double bond with a C-N double bond.5468

    That nitrogen had an R group attached; that R group is still there; that is the product that we get; this is called an imine functional group.5483

    When we have a C-N double bond, we call that an imine; what is the second product that is formed in this reaction?--what else is formed?5491

    We lose these two hydrogens and this oxygen; so eventually somewhere in the course of the mechanism, we are going to producing water.5503

    This is another case where every step, just like the oxygen, every step along the way is going to be reversible.5511

    The only way we can push it forward for the imine formation is we have to remove to drive the reaction forward.5517

    To push the equilibrium in the forward direction and remove the possibility of doing the reverse reaction, we have to remove the water as it is formed.5528

    Just a quick example; what is interesting about these reactions, it has the same general format.5540

    But this group, the one group that is attached to the nitrogen, you can have a wide variety of groups here; it doesn't have to be just a carbon.5547

    It could be another nitrogen; it could be an OH; it could be just about anything; but whatever is attached to this NH2 just is along for the ride.5557

    The way we can draw our product is we replace our C-O double bond with a C-N double bond; we know that nitrogen has three bonds.5567

    We take a look back to see what was attached to that nitrogen; in this case, it was a methyl group; that methyl group is still there.5578

    We know at some point these hydrogens must be lost because in order to get a neutral product, the nitrogen needs to have just three bonds and a lone pair.5585

    That is why we end up dropping the hydrogens and just carrying along that one alkyl group or whatever group happens to be attached.5594

    Let's see if we can do a mechanism for this reaction; let's assume we have an acid catalyst; I think our first step is going to be protonate.5606

    Where should we protonate?--the carbonyl is going to be the place to start; we could just say HA for our tosic acid in this case; we can protonate.5622

    This is a reversible mechanism, reversible step; of course you can protonate; you could deprotonate; what does protonation of the carbonyl do for us?5634

    It turns our good electrophile into a great electrophile; the presence of that positive charge tells me that it is even more electron deficient.5645

    It is really going to be looking around for a nucleophile; what nucleophile do we have around?--the amine is going to be an excellent nucleophile.5654

    In fact the amine is such a good nucleophile, it doesn't even have to have a protonated carbonyl; so you might see some variations in mechanisms when you are looking at imine formation.5661

    This is going to actually be done without the acid catalyst; but it is just nice to show that here.5671

    Our nucleophile is going to attack the carbonyl again reversibly so; this nitrogen now has the methyl; it still has two hydrogens.5679

    What we did was we protonated, then we attacked, and now we can deprotonate to get to a neutral product; I can have my A- come back... and go from here and get to this neutral product.5699

    Protonate, attack, deprotonate--such a common sequence we are going to see for acid catalyzed additions.5720

    We are halfway there; we have introduced the nitrogen; we still have this oxygen; where do we need to go?--we need to eventually get rid of this oxygen.5730

    Remember our second product here is water; we are forming water; that oxygen of the carbonyl is going to leave as water; how do we get that to go?5739

    We protonate the oxygen to make it a good leaving group; again anytime you are stuck here, you are at a neutral product, neutral intermediate, and you have to think about what to do next.5748

    Because we are in acid conditions, the way to get out of that hole is to protonate something; we could protonate this nitrogen but that would move us backwards.5757

    We could protonate this oxygen; that would move us forward; how is that a good thing?--what does that do for us, protonating that oxygen?5767

    How do I know that can take me forward in my mechanism?--not only did I make this a good leaving group, but I also made something else that is kind of special here.5777

    It looks to me like a charged tetrahedral intermediate; yes, this is another case, carbonyl chemistry, we are going to see this again and again, a charged tetrahedral intermediate.5790

    Which means the way I am going to get rid of that leaving group is I am going to collapse that CTI; I am going to use two arrows.5801

    This lone pair is going to form a π bond; that is when it is going to kick out water; here is the point in our mechanism where we lose our water molecule.5809

    Our product for this step is going to be the following; nitrogen with a double bond; of course that is an N+.5822

    We have one, two, three, four; nitrogen wants five; we have an N+ here; we have seen this part of this part of the mechanism before with oxygen.5830

    At this point when we have the oxygen, this is now when we added in our second equivalent of oxygen; we ended up with the acetal with two OR groups.5840

    But the nitrogen could do something different to stabilize this molecule; that is because nitrogen can have three bonds, wants to have three bonds to be stable.5849

    There is a very easy way for it to get rid of its fourth bond; what could we do here?--we can just deprotonate and get rid of that hydrogen; that is exactly what happens.5861

    Our A- comes in and deprotonates; and we are done; the imine mechanism is significantly shorter than the acetal because we didn't have to add in two equivalents of the nucleophile.5870

    We just add one equivalent; it ends up replacing both C-O bonds with C-N bonds; it could still accommodate this third group that it came in with.5881

    Another reaction that we can take a look at, moving away from nucleophilic additions to carbonyls, are oxidation reactions.5895

    This is where we increase the number of C-O bonds while decreasing the number of C-H bonds... the number of C-H bonds.5905

    The biggest case where this is going to be relevant is when we are looking at aldehydes because an aldehyde is the only carbonyl that has a C-H bond that can be lost.5918

    We can lose this in an oxidation; if we give a very strong oxidizing agent like Jones conditions, like chromic acid conditions, absolutely we can replace this C-H bond with a C-O bond.5930

    How would I finish up this structure to make it look like a recognizable functional group?--I would just turn this oxygen into an OH.5942

    We could take an aldehyde and convert it to a carboxylic acid by oxidation, by chromic acid oxidation like Jones conditions, sodium dichromate and acid.5950

    That is just like we have seen this before; we have seen Jones before; if we had a primary alcohol and we used Jones conditions, we made the carboxylic acid.5963

    We have seen this reaction before starting with an alcohol; we saw that if you partially oxidize it to an aldehyde, you wouldn't be able to stop; it would go all the way to the carboxylic acid.5975

    Here we are just seeing an example where if you started with the aldehyde, this could also be subject to oxidation and can go to the carboxylic acid.5985

    If we used our other oxidizing agents though like PCC or Swern, remember we used PCC or Swern to make an aldehyde; that means that they must not react with aldehydes.5993

    If we wanted to do that oxidation would be impossible; we need a strong harsh oxidizing agent, something like chromic acid.6004

    How about if we had a ketone; if we did Jones or PCC or Swern oxidation conditions, any of these, and we tried to do it on a ketone.6011

    Here is a case where there is no CH to lose; we are going to have no reaction with these; the only oxidation we could have would be breaking the carbon-carbon bond.6020

    That is going to be much rare and not going to happen with any of the oxidizing agents we have seen before that would oxidize primary or secondary alcohols.6032

    Very limited options here for oxidizing; we are just going to start with the aldehyde and do a strong oxidizing agent to make the carboxylic acid.6043

    When it comes to reductions of carbonyls, either aldehydes or ketones can undergo reductions.6055

    Remember a reduction now is going to be a decrease in the number of C-O bonds and an increase in the number of CH bonds.6063

    For example, we can go from a ketone or an aldehyde to an alcohol; that would be an example of a reduction reaction; how could we do that?6073

    There is two methods we could use, two types of reagents that will do this; one possibility would be using a hydride reagent.6084

    Something like a nucleophilic hydride like lithium aluminum hydride or sodium borohydride would work great here; that is taking advantage of the fact that this carbon is electrophilic.6092

    If we had a nucleophilic hydrogen, that would clearly add to the carbonyl and give an alcohol product.6106

    In fact we have already seen that in this lesson as one of the examples of the nucleophiles that can attack; that would be one way to reduce a carbonyl.6118

    Another option we have for reducing carbonyls, a very special kind of catalytic hydrogenation, using a special catalyst called Raney nickel.6128

    This is a nickel with hydrogen gas adsorbed onto it; this combination of hydrogen and a catalyst, it does a catalytic hydrogenation; but it is one that reduces a carbonyl.6138

    We have never seen that before; the only catalytic hydrogenations we have seen before have reduced carbon-carbon π bonds, either alkenes or alkynes.6154

    If we use this special catalyst, it will also reduce a carbonyl; just like we saw before for catalytic hydrogenation, you break the π bond; you add a hydrogen here, you add a hydrogen here.6164

    That would also give this alcohol product; what is new here is not just the OH, but it is this CH that is critical.6174

    But because it is catalytic hydrogenation, this is also something that would reduce an alkene.6181

    If you have an alkene in this structure and you want to reduce it to the alkane, you could use Raney nickel.6186

    But if you wanted to only reduce the carbonyl and not the carbon-carbon double bond, then we would use a hydride reagent instead which only is going to go after the carbonyl oxygen.6192

    Another type of a reduction would be to take a ketone or an aldehyde and completely reduce it all the way to an alkane.6205

    When you have a CH2 group, that is called a methylene; it is possible to reduce a carbonyl not only a partial reduction to an alcohol.6216

    But it is possible to completely reduce it to a methylene; again there is two good options for this reduction reaction.6227

    One of them is called the Clemmenson reduction; that is where you use a mercury zinc amalgam and HCl and water; it is called Clemmenson.6235

    Another option is a Wolff-Kirschner reduction; this is a two-step procedure; we add in NH2NH2; sometimes we just draw this as N2H4.6243

    That molecule is called hydrazine; first we treat the ketone or aldehyde with hydrazine; could we predict the product of this first step?--that would be an interesting thing.6252

    What happens with this first step if you were to take hydrazine and react it with acetone or some other ketone or aldehyde?6266

    What did we see as a reaction with a nitrogen, with an amine, and a carbonyl?--what is going to happen is we are going to replace the C-O double bond with an C-N double bond.6275

    Remember how I said whatever group is attached to the nitrogen is just along for the ride?--that is what we get; we get a C-N double bond with a nitrogen attached.6287

    These functional groups are called hydrazones; they have some interesting uses for analysis; if you react with hydrazine, you get a hydrazone.6297

    One reaction that hydrazones will undergo is when you treat them with base and heat, it will do an elimination reaction that replaces the C-N double bond with CHs.6314

    I am not going to talk about either of these mechanisms although the Wolff-Kirschner has a pretty cool mechanism.6325

    You would be able to do the mechanism for the first part; the mechanism for the second part is also an interesting one that you should be able to follow.6329

    But for the most part, these two are usually given as yet another set of reagents in order to do a synthetic transformation.6337

    If you wanted to take a carbonyl and reduce it all the way to the alkane, you could use either Clemmenson reduction or Wolff-Kirschner reduction.6347

    Can you think why chemists have developed these two complementary methods?--a lot of times we just give you one exemplary reagent to use for a given transformation.6356

    Why have these two maybe been used so widely?--it looks like clearly the Wolff-Kirschner reduction involves a strong base.6370

    The Clemmenson reduction, this is a redox reduction, doing a metal reduction; it uses acid.6381

    Clearly depending on the rest of your molecule, what other functional groups you have, in certain cases you would prefer an acidic reduction reaction versus a basic reduction reaction.6389

    That is why you almost always see Wolff-Kirschner and Clemmenson being presented in tandem as two complementary methods you can use.6400

    One last thing to talk about is the reason that we are looking at acetals; why are we spending all this time seeing acetals, looking at the mechanism, how do we make them, how do we take them off.6414

    It is because they have a very useful role in organic synthesis; they also have very useful roles in natural products.6428

    We will see acetals and hemiacetals in a variety of organic structures, especially sugars.6438

    But one other use that they have that is critical in organic synthesis is the use as a protective group.6445

    I just want to talk a little bit, now that we know about acetals and how to make them, I want to show an application of those as protective groups.6452

    The strategy behind a protective group is... let's imagine we are doing a synthesis of a target molecule.6462

    But instead of just having a very very simple target molecule where there is one functional group, let's say we have multiple functional groups.6468

    What we want to do is we want to do a transformation that involves just one part of the molecule; we want all the other parts of the molecule, all the other functional groups to not react.6475

    One way to achieve this and the way that is typically done is we use a protective group that we hide...6483

    We put on a protective group and essentially hide that functional group so that we could do the reaction somewhere else on the molecule.6492

    Then when we are done, we can take that protective group back off and get the functional group that we wanted.6500

    Again if you imagine a target molecule that you are trying to synthesize that has fifty functional groups on here; what we do is we kind of protect them all.6505

    Then we deprotect over here and we do a little manipulation; maybe we reprotect it; then we deprotect over here and we do a manipulation; we reprotect it.6513

    With the use of protective groups, you can make fantastically complicated molecules with a variety of functional groups.6521

    That might appear that you wouldn't be able to do some of those transformations without protective groups; let's see just how acetals fit in this picture.6530

    If you start with a carbonyl, if you have a carbonyl in your structure, we know those are excellent electrophiles; we have seen again and again how nucleophiles can add into them.6541

    If you treat it with an alcohol and you make it an acetal, it is no longer an electrophile, this structure has no leaving group; it has no π bond like the carbonyl did; it has no resonance.6550

    It no longer has the acidic hydrogen that we are going to see that ketones and aldehydes have, carbonyl compounds have; in other words, it is protected; we have taken away that electrophilic nature.6563

    If we try to react it with a nucleophile or a base, if we try to deprotonate it, if we try to do some kind of substitution or addition, it doesn't happen; there is no reaction.6578

    Like an ether is a pretty stable functional group and doesn't do a lot of reactions, acetals are very similar that way.6589

    In fact there is only one reaction that we have seen of acetals; that was the reaction of an acetal with H3O+.6597

    What happened there?--it underwent hydrolysis; it gave us back the carbonyl that we had started with.6605

    In fact this one reaction that it undergoes is useful to us because the key of having a protective group is not only that you can put it on and temporarily hide the carbonyl.6617

    But then you have to be able to take it off as well and get that functional group back; so acetals are really ideal for this situation.6628

    Let's see an example where you would need that; consider the following synthesis; let's say I wanted to make this target molecule.6636

    The plan that I had for that is I would start with this halide; I would react it with magnesium to make this Grignard.6645

    Then I would react with formaldehyde; that Grignard could attack the carbonyl and make this alcohol after a workup.6653

    Good idea, reasonable idea for handling the reactivity of this carbon; but what is the problem with it?--this reaction would never work; this synthesis would never work.6662

    Where do I have an error?--right here I have a Grignard which is a very strong nucleophile; in the same molecule, I have a carbonyl which is a great electrophile.6672

    In fact we just said that we utilize the fact that Grignards react with carbonyls; yet we had a carbonyl right here that we chose to ignore.6685

    You might say it can't happen intramolecularly because it is not the right distance away.6697

    But remember you never have a single molecule of this Grignard reagent; you have a solution of these Grignard reagents; you have millions of them.6704

    Even if they can't react intramolecularly, you certainly would have one molecule attacking the other molecule and doing a Grignard reaction that way.6715

    What would we have in this case, in this plan?--the synthetic plan is we come across some incompatible functional groups.6729

    It is impossible to have a Grignard in the presence of a carbonyl without having them react; how can I synthesize this molecule?6738

    I need to protect my carbonyl; I need a protective group; what I am going to do first is I am going to convert this to an acetal.6747

    This is where the diol comes in handy; a lot of times we will see this being used; of course you could use any alcohol you want.6759

    But if we use the diol, we would get this cyclic acetal; now our carbonyl is gone; our carbonyl is hidden; it is masked; there is no carbonyl any longer.6766

    Now if I took this structure and added magnesium, I could make the Grignard reagent.6785

    This Grignard is okay; it is possible to make this Grignard; these are now compatible; the Grignard would have no reaction with the acetal.6796

    I hid my carbonyl; now I can make the Grignard; I can use the Grignard; I can add in my formaldehyde; and my workup and do my Grignard reaction.6808

    Then at the very end, to get my desired target molecule, I need to remove the protective group; I need to get rid of that acetal; how do I do that?6825

    I use water and acid, H3O+; hydrolysis; I know how to put an acetal on with an alcohol and acid; I know how to take it off with water and acid.6835

    You will notice this workup for the Grignard was H3O+; then removing the protective group was H3O+.6852

    Sometimes we don't have to draw that twice; sometimes you can indicate this H3O+ is vigorous enough conditions.6857

    That it will both protonate the O- and it will hydrolyze the acetal; but maybe we could control the pH here to do them stepwise or so on.6864

    But sometimes you might see them all in one step or you might see them separately; this would be a great way to do a synthesis, have a synthesis be allowed, by using a protective group.6874

    While we are talking about protective groups as a general strategy, let me also introduce the fact that carbonyls are not the only thing that can be protected.6890

    A wide variety of functional groups that are protective groups have been developed for each of those functional groups; for example, an alcohol.6897

    An alcohol is another functional group that is ubiquitous; we have a lot of these; we want to be able to hide an alcohol.6907

    Most notably what we need to get rid of on an alcohol is the acidic proton because that can interact with different reactions; it will be available anytime we have a strong base.6917

    There are several strategies that we can have for this; one that is very commonly used is we take an alcohol and we treat it with trimethylsilyl chloride.6930

    This is called TMS chloride for trimethylsilyl chloride; we take this and some base; what happens is the silicon is going to attach the oxygen.6941

    We are going to lose this proton; we are going to lose this chloride; because we are generating HCl, that is why we need the base here, something like pyridine maybe.6953

    What happens is we attach the silicon onto the oxygen; it is like using tosyl chloride to make the tosylate.6963

    But when we use the TMS chloride, we get what is known as a silyl ether; this is another substrate that is very unreactive; like a regular ether, it is very unreactive.6972

    We no longer have the OH group here; we no longer have that acidic proton; so this is protected; it is protected as the silyl ether.6990

    You could draw this; usually we don't draw out our protective groups, we usually use abbreviations to represent them; this is called the TMS group; so this is called OTMS.7000

    There is a wide variety of silyl ethers we can use; instead of using a trimethyl, you can replace one of these with a tert-butyl; that is called tert-butyl-dimethylsilyl chloride, TBS or TBDMS.7012

    Or you could have three ethyl groups; that is called TES for triethylsilyl; a really wide variety that have different stabilities and different applications.7027

    But they all have these interesting abbreviations; when you are looking at a multistep organic synthesis in literature, it looks like alphabet soup.7036

    You see all these acronyms, all these abbreviations all over the place to represent the protective groups that are being put on and taken off at various points in the synthesis.7045

    What is really cool about silyl ethers and the reason they are so widely used is they are very stable to a variety of reaction conditions except for one.7055

    When we want to take them off, we need to be able to do that; the reagent we use for that is tributyl ammonium fluoride... I'm sorry, tetrabutylammonium fluoride.7066

    Which is called TBAF; it is called TBAF for short; when we are done with our silicon group and we want to take it off, we add in some TBAF.7089

    What happens there is... fluoride is something that loves silicon; it is going to attack the silicon and release the oxygen, something like this.7098

    F- will come in, attack the silicon, cleave that ether, and give us back our alcohol; how many reactions have we seen up till now that uses fluoride as a reagent?7114

    It is going to be very rare; we are not going to be using that ordinarily; we are not going to encounter that unless we want to remove a silicon protective group.7126

    This is another great strategy to hide an alcohol; we can protect as a TMS ether; then we can remove it by using TBAF.7133

    Let's see an example where we might need to use a protective group; in this transformation, we have two things we need to accomplish.7144

    We have a carbonyl that we are going to convert to an alcohol; have we ever seen that transformation?7152

    It looks like a reduction; we need to reduce the carbonyl at some point as part of our transformation.7159

    We also have this carbon as a bromine; now it has a carbon chain; that is a new carbon-carbon bond that we also need to accomplish as part of our synthesis.7170

    We need to do two things; we need to reduce the carbonyl and form the new carbon-carbon bond; we can do either one first; it doesn't really matter.7183

    Let's say we wanted to do this disconnection; if we wanted to do this disconnection first, we look at these two carbons and we say we want to make this.7192

    One of these has to be a nucleophile, one of them has to be the electrophile; because this is the carbon that now has an OH, what does that look like?7207

    I think this was my electrophile as a carbonyl; how about the other carbon?--how do we make this a nucleophile?7218

    Remember we have an alcohol product here; how do we make an alcohol?--what two ingredients do we need?--we want a ketone plus a Grignard.7228

    Ketone plus a Grignard gives an alcohol; this is my carbonyl; the other carbon we are going to make a Grignard.7239

    If I had this Grignard and this ketone... it is not really a ketone; it is two carbons; it is just this aldehyde; let's say it is a ketone in quotes.7252

    In this case, this is an aldehyde plus Grignard; if I had this aldehyde and this Grignard, that could make my product.7262

    That is a good plan; the problem is that this alcohol, that Grignard is impossible to make; we have another example of incompatible groups.7269

    It is incompatible because this Grignard is a very strong base, extremely strong base, just like we use butyllithium as a strong base; a Grignard would be a really strong base.7284

    Of course an alcohol is an acid; it is acidic; if you have a Grignard in the presence of an alcohol, it simply protonates the Grignard; you quench your Grignard; the reaction is over.7294

    There is no way you could use that; what we can do is we can protect; we have to protect our alcohol in order to do this Grignard.7305

    We have a plan here; let's think about getting to this alcohol first; how did we get this alcohol?--how do we go from a ketone to an alcohol?7317

    It looks like we have lost a C-O bond; it is a reduction reaction; what reducing agent would we use?--something like lithium aluminum hydride or sodium borohydride.7336

    You could do sodium borohydride and some kind of protic solvent like methanol or water or ethanol.7348

    We can do that reduction reaction no problem; then instead of making the Grignard, we have to first protect the alcohol.7355

    The way that we would protect the alcohol is we are going to protect it as a trimethyl silyl ether or any of the silyl ethers; but TMS is our most simplest one we can use, the most common.7366

    We could make the TMS ether; how do you make the TMS ether?--you use TMS chloride; you put a leaving group on that silicon; that is what gets replaced by the oxygen.7378

    Again some kind of base like pyridine we can use here; TMS chloride, pyridine would be a way of making the TMS ether.7388

    The reason I wanted to do that is because I wanted to make the Grignard here; I couldn't make the Grignard in the presence of an alcohol.7397

    Now I no longer have an alcohol; it is protected; now I can add in my magnesium; that has no effect on the TMS ether.7404

    This is protected; it is not acidic; so this is an okay Grignard; there is no problem; those are now compatible functional groups.7416

    What did I want to do with that Grignard?--I wanted to react it with acetaldehyde; I can bring in acetaldehyde, step one.7431

    Step two, H3O+ to workup my Grignard; I am running out of little room here; that forms the new carbon-carbon bond.7442

    We have done the reduction; we have formed the new carbon-carbon bond; we are very close to our final target molecule.7455

    All we have to do is remove the protective group that we put on; we are temporarily hiding a functional group while we do a reaction somewhere else on the molecule.7462

    Then we want to be able to take that protective group back off; how do we get rid of a TMS group?--we use TBAF; TBAF, tetrabutylammonium fluoride to do TBAF.7470

    This is one approach to the synthesis where we do our reduction first and then we do our Grignard; let's see if we could do the other order and see what that synthesis might look like.7483

    Let's say we wanted to do as our last thing, we wanted to do the reduction last which means we undo the reduction first.7496

    Then we could say now I want to do the disconnection of the alcohol which means I go back to my ketone and my Grignard.7511

    Once again this guy was my carbonyl; that was my electrophile who is now an OH; this was my nucleophile as a Grignard; ketone plus a Grignard gives an alcohol.7520

    I would need this Grignard plus the same acetaldehyde electrophile; what do I find in this case?--I have another example where I want to make a Grignard.7536

    Now I have a carbonyl; that is still no good; I can't have a carbonyl here either; this must be protected; I must protect this carbonyl because I can't have a Grignard in the presence of a carbonyl.7549

    Another way to do this problem would be to first protect the carbonyl; how do we protect the carbonyl?--we do so as an acetal.7561

    Again this diol is very commonly used; but you could just use a methanol or ethanol or any other alcohol you want; it is just convenient to draw that cyclic acetal.7570

    Now that I have my protective group on there, now I can make my Grignard with no problems, no incompatibilities; this is okay; this is perfectly fine to make.7585

    This is the protected version of the Grignard that I needed; the reason that I wanted this Grignard was I wanted to react it with acetaldehyde.7601

    Now I could say step one, put in my aldehyde; step two, H3O+; now I have formed my new carbon-carbon bond.7608

    Then as usual I want to get rid of my protective group; after I have done the reaction and I have gotten rid of that incompatible part, now I can remove my protective group.7624

    How do I get rid of an acetal?--how do I get rid of an acetal?--I want to go from the acetal back to the C-O double bond, back to the carbonyl; that is simply hydrolysis.7636

    Remember hydrolysis is the only reaction that we have for an acetal that is going to do strongly acidic conditions in the presence of a nucleophile like water--is going to give me back my carbonyl.7650

    What did I want to do with that carbonyl?--now I could react it with lithium aluminum hydride or sodium borohydride and H3O+.7662

    You might say I have hydride here; can't that react with the alcohol?--actually it can; but this is a case where LAH is pretty cheap; you could just use in excess.7677

    It is okay if you deprotonate over here; that won't stop the reaction with the carbonyl; then the aqueous workup can protonate both of them.7687

    Or maybe you could use sodium borohydride, NaBH4 and methanol, a weaker hydride reagent; then that would be compatible with the alcohol; either one of these would work well,7694

    But the point is in this reaction, because we want to do a Grignard and we have another functional group somewhere else in the molecule, if that functional group is a carbonyl or it is an alcohol.7709

    We have to protect either one of those; we have to protect them so that we could do the Grignard reaction; then deprotect them when that Grignard is done.7719

    Let's look at just a few more transforms, a few more examples, now that we are finished looking at reactions of carbonyl compounds.7731

    How about if we wanted to do the following transformation; we see that we have a three carbon chain here; let's find those three carbons.7740

    It looks like they are right here; one, two, three; what is nice about that is it tells us what disconnection we need to do.7749

    These are the two carbons that we want to bring together; as usual we have to ask what was our nucleophile, what was our electrophile?7758

    We are asking what starting materials do I need?--what starting materials do I need?--we have an alcohol that we are disconnecting; we have seen this again and again.7766

    When we do that the carbon that is now a single bond O-H used to be a C double bond oxygen; it used to be a carbonyl; this was my electrophile as a carbonyl.7779

    How do I make this carbon, an ordinary carbon, a nucleophile?--we add a metal; we make it a Grignard; the alcohol disconnection brings us back to a ketone plus a Grignard.7792

    Our Grignard is this guy; isopropylmagnesium bromide, for example; our carbonyl is not a ketone actually; it is an aldehyde; this is another example where we are using acetaldehyde.7805

    You could leave this structure like this, but we usually draw in that hydrogen there for the aldehyde; what is great about a retrosynthesis is you can check your work.7817

    You can say if I had this nucleophile, if I had this Grignard, and I had this electrophile, this aldehyde, would they come together to make my target molecule?7826

    They would; you can check that mechanism; you can double check; now you know you have a good plan.7836

    Now all we have to do is figure out how to make isopropylmagnesium bromide when we are starting with isopropyl bromide; that isn't too hard to imagine.7840

    All we need to do is thrown in magnesium; once we have the Grignard, we can add in our electrophile followed by H3O+ workup; and we have done our transformation.7848

    Let's see another one; now we have an interesting example; we start with a carbonyl; we want to go to an alkene; we could think about how do we make an alkene?7868

    The other thing we want to keep in mind is that we started with three carbons; we still have just three carbons; we did see a Wittig reaction as a way to make an alkene in this chapter.7883

    Remember a Wittig reaction adds carbons to the carbonyl carbons that are already there; because we haven't added any new carbons, we wouldn't want to be using a carbon nucleophile in this case.7894

    This is simply a functional group interconversion, a functional group interconversion because we are not changing our carbon structure at all.7905

    Then we think about we have an alkene; what are some ways that we can make an alkene?--what starting materials do I need?7913

    What functional groups have I seen where upon reaction they give an alkene product?--we also want to keep in mind that it came from something that we can make from a carbonyl.7920

    We are working forwards a little; we are working backwards a little; we are trying to find that key intermediate structure that we can both get to and go from.7935

    One reaction that is reasonable here is how about dehydration of an alcohol?--if I had an alcohol... I need to do some kind of elimination to form a double bond.7944

    I can either have an alkyl halide and do an E2 or I can have an alcohol and do an E17955

    What is great about an alcohol is I know that that is something I can create from a carbonyl; then I know that I can go to the alkene; that would be great.7962

    How do I go from a carbonyl to an alcohol?--that looks like a reduction reaction; this is lithium aluminum hydride, for example; two steps; H3O+; that give us an alcohol.7974

    Remember we also learned about Raney nickel; Raney nickel, NiH2 also does this reduction of a carbonyl to an alcohol; that would be fine too.7987

    Then once we have this alcohol, we want to dehydrate; we want to lose water; what conditions will remove water from an alcohol?7999

    We need a strong concentrated acid; something like H2SO4 and heat is a dehydration; this would be a good way to do this transformation.8007

    Again two simple reactions we have seen before; but using them in combination, now we see how to go from a ketone to an alkene.8016

    How about the next one?--we want to go from a... what functional group do we have here?--we have an acetal; we want to go to an alkane.8028

    The acetal is closely related to what functional group?--where do you get an acetal from?--you get it from a carbonyl; what is the only place we can go from an acetal?8040

    We can go to a carbonyl; that is the only place we can go; we start with a carbonyl to make an acetal; from an acetal, we can go back to the carbonyl.8051

    This must involve going back to the carbonyl; now do we know how to go from a carbonyl to an alkane?--that looks like some kind of reduction.8063

    So this second part is a reduction; this first part, what does it look like here?--is this an oxidation to get to a carbonyl here?8074

    No, remember we started with two C-O bonds; we still have two C-O bonds; it is not an oxidation; this is simply hydrolysis; acetals can be hydrolyzed to give the carbonyl.8086

    This first step is just H3O+; it gives that big long mechanism we saw for hydrolysis of an acetal.8097

    This second step, how do we go from a carbonyl all the way down to an alkane?--in other words, we want to have two hydrogens here.8104

    We saw two methods for this; we saw the Clemmenson reduction; we saw the Wolff-Kirschner reduction; either one is fine.8112

    Wolff-Kirschner is N2H4 and NaOH and heat; again get some flashcards together to become familiarized with these reagents.8119

    That is the Wolff-Kirschner, the Clemmenson, the zinc mercury amalgam, and HCl; those kinds of reaction conditions will be the acidic redox reaction.8132

    One last example; let's turn the table around and ask what starting material did I need to get to this product?8145

    If we are used to doing transform type problems and we are good at doing those planning, this is a piece of cake.8153

    Because that is every time we do a retrosynthesis, we are asking what materials did I start with?8160

    The key is this is our final product and what was the reagent that we reacted it with?--we had a phenyl group plus a CH2; we had a one carbon plus the phenyl group.8167

    Here is our phenyl group; here is our CH2; this is the new carbon group that has been added.8178

    Furthermore we have a benzylmagnesium bromide; we have a Grignard reagent; what is the reactivity of a Grignard reagent?8186

    This is a nucleophile; we already know that carbon 1 here was our nucleophile; even if we couldn't see it for ourselves, we know what is required; we need a two carbon electrophile.8193

    This was an electrophile; what is it going to look like?--what electrophile can we have that after a Grignard adds to it, we are going to have an OH here?8207

    It is going to be a carbonyl; it going to be a carbonyl; what we need is a two carbon; we could draw it upside down if you want so that you can track along.8216

    A two carbon carbonyl; this aldehyde, once again here is another example of acetaldehyde; then we could treat it as a predict-the-product; see if we got it right.8226

    If we had this Grignard, it would attack the carbonyl, break the π bond, and after a workup, we would get this phenyl plus these three carbons; that would be our final product.8236

    So a lot of interesting things we can do with carbonyls, ketones and aldehydes; we can do some oxidations and reduction reactions.8247

    But the vast majority of our reactions are going to be reacting the carbonyl as an electrophile.8255

    We add a variety of nucleophiles; wee could add the hydride; we could add Grignard; we could the Wittig nucleophiles.8261

    Then we get to the alcohol and amines, we get some of these reversible reactions where we form acetals and we form imines.8267

    Of course the importance of acetals not only extends to natural products such as sugars; we will see that down the road; but also they become very useful in organic synthesis as protective groups.8275

    Thanks for joining me; I look forward to seeing you again soon.8289