Download Chapter 18 – Carbonyl Compounds II (Last Chapter we mostly talk

Chapter 18 – Carbonyl Compounds II
(Last Chapter we mostly talk about rxns of acyl carbonyl groups where we
exchange a Nu for a leaving group. Carbonyls of this type are considered Class 1
carbonyls)
(In this chapter, we’ll talk about acyl carbonyl groups that do not have a leaving
group and this changes the rxn considerably. These types of acyl groups are
called Class II carbonyls).
i.
Class II Carbonyls (Brief)
a. Do not contain a leaving group = Ketones and Aldehydes
b. Two major catagories:
1. Ketones
2. Aldehydes
ii.
Natural Sources
- Common in Nature
- Very Fragrant
- See ppt
*** ppt *** Some Natural Ketones and Aldehydes
18.1 IUPAC Naming
i. Aldehydes
A. Abbreviation
RCHO
B. Rules for Naming:
1. Aldehyde = functional group
2. “e” suffix of parent name replaced w/”al”
Ex.
3. If >1 aldehyde present, use di, tri, tetra in front of “al”
- Don’t remove “e” suffix
Ex.
4. If aldehyde is substituted off ring: use suffix “carbaldehyde”
Ex.
iii.
Naming Ketones
- Same rules as aldehydes
- Replace “e” suffix w/”one”
- >1 ketone use dione, trione … etc.
Ex.
(Butanedione is commonly produced by bacteria of the skin and is one of the
major smells of arm pits and sweaty feet).
(Some ketones are used so frequently that IUPAC simply adopted that
common name)
- Common Ketones:
iv.
Multifunctional groups
(We touched upon this subject a bit last semester in chapter 6, but there was
a lot of functional group combinations that we simply didn’t encounter. In
fact, all that we did cover was a functional group in combination with an
alkene or alkyne)
(At this point we are going to take a look at how to name molecule that
contains a combination of functional groups which may or may not contain
an alkene or alkyne).
A. Priority
- Functional groups have priorities
- Refer to ppt
*** ppt *** Functional group Priorities
(Notice that all of the functional groups have both a prefix and a suffix name.
We choose to use the prefix or suffix name based off of the priority of the
functional group).
B. Naming >1 functional group: No C=C or C=C
1.
2.
3.
-
Use priority of functional group
Highest priority group: Use suffix name
All other lesser priority groups: Use prefix
Prefix will be in front of parent name
Treat as a substituent
Ex 1.
Ex 2.
C. Naming 2 functional groups: Containing C=C or C=C
-Only use suffixes
Ex.
*** ppt *** Name that compound
18.2 Reactivities of Carbonyls
i. General Reactivity as Electrophile
(Because a carbonyl oxygen always pulls electrons away from the carbon to
which it is attached is always positively charged. We saw this w/Class 1
carbonyls and it explains class II carbonyls reactivity as well).
(Basically, the same type of attack occurs at what we saw in the last chapter
… the only difference … there isn’t a leaving group).
- Nu attack at Carbon of C=O
ii. Reactivities of Aldehyde vs. Ketone
- Aldehydes react ~2000 x more rapidly than ketones
(2000 x is a very large difference … why is there such a difference?)
(Well let’s take a look at the overall trend, and see if we can deduce a
reason)
- Overall trend:
- Sterics = #1 reason for reactivity difference
- Bulky groups block Nu attack
iii. Ketone reactivities:
(which of the following do you think would react the most rapidly, 2nd most
rapidly, and the slowest?)
iv. Overall reactivity pattern (Skip)
(Why are ketones and aldehydes in the middle? Ultimately it comes down to
how well resonance structures can stabilize the carbonyl)
- Stability depends on functional group ability to adopt resonance structures:
- Carboxylate and Amides adopt these resonance structures best
- For Acyl halides, acid anhydrides, ketones and aldehydes resonance
structure is little to non-existent
18.3 How CII C=O react
i. Review: CI C=O reactivity
(Class II carbonyls react pretty much the same although do not contain a leaving
group).
ii. CII C=O reactivity
2 cases:
1. Reversible Add’n
- Nu which adds to C=O is or can be converted into a leaving group.
2. Irreversible Add’n
- Nu add’n is permanent: Can’t be converted into Leaving group
18.4 Rxns of C=O w/ Grignard Reagents
i. Review: Grignard
a. To synthesize:
- Stir alkyl/alkenyl halide in Mgo
b. Reactivity – Strong Nu
ii. Add’n to ketone/aldehyde
a. General Rxn w/arrows:
Notes:
1.
2.
3.
Add’n not reversible
Alkoxide (not alcohol) formed in rxn
Must add H3O+
H3O+ = water + acid: Ex. H2O + HCl
(But it doesn’t have to be HCl as the acid … it could be many different thing
such as acetic acid, sulfuric acid … depending on what your molecule can
tolerate).
b. Examples
1. 1o ROH synthesis
2. 2o ROH synthesis
3. 3o ROH synthesis
iv. Grigard add’n to CI C=O compounds
(Grignards reagents can also be added to CI carbonyl compounds. Let’s see
what happens when this reaction is performed)
a. Rxn – Using 2 or more equivalents of RMgBr
- Equivalent of 2 add’n of RMgBr
- X = halogen (acyl halides),-O2CR (anhydride), or –OR (ester)
b. Mechanism:
Notes:
1st add’n of MgBrR form tetrahedral intermediate
Since -OCH3 is a leaving group, it is eliminated
Resulting ketone reacts again w/MgBrR
No leaving group “traps” tetrahedral form of molecule
Add’n of H3O+ protonates alkoxide to give alcohol pdt
Ester showed, but acyl halides, and anhydrides work through same
mechanism
6. 4 steps total in mechanism
1.
2.
3.
4.
5.
c.
Examples
(Of course, Grignards are not the only Nu that can add to a carbonyl. Similar
to Grignard, is an acytilide Nucleophile which also contains a negatively
charge carbon)
(Remembering from chapter 6 last semester, are acetylides good
Nucleophiles? … Yes indeed!)
i.
Review: Synthesis of Acetylide
- NaNH2 = strong base
ii.
Rxn of Acetylide w/C=O
A. For Ketone or Aldehyde
B. For Acyl Chloride, Anhydride, and Esters
- LG = halide (acyl halide), OR (ester), -O2CR (anhydride)
Ex.
(There is one last Carbon Nucleophile we will consider, which is similar to
acetylene is structure called cyanide. )
(You all have probably heard of cyanide before, right? It’s wickedly toxic and in
this reaction cyanide actually adds as a Nu to ketones and aldehydes)
18.7 HCN Rxn w/Ketones and Aldehydes
- Hydrogen cyanide (HCN) is HC=N
(HCN itself is not nucleophilic, but must be deprotonated first).
- HCN = toxic
- Made inside reaction flask (in situ):
HCl + NaCN
- Extra NaCN used to ensure plenty of CNi.
Mechanism :
ii.
Reversibility
- CN add’n is reversible … ie CN- = OK leaving group
- Requires deprotonation:
(This is why there needs to be plenty of HCN in the reaction as it “traps” the
product before the reaction can reverse)
iii.
Example in Synthesis:
*** ppt *** Addition of Carbon Nucleophiles
(Carbon Nucleophiles are not the only Nu that can add to carbonyls in this
fashion. There are actually a ton of other nucleophile that also add, which will
be the subject of the rest of the chapter).
(Another type of common Nu that is used on carbonyls is a hydride ion. Does
anyone know what exactly a hydride ion is?)
(It’s H:-, which is also a strong Nu and a way of adding hydrogen atoms by
Nucleophilic addition).
18.6 Hydride ion add’n to C=O
- Hydride ion = H:- (often called hydride for short)
- Is a reduction rxn: Often called “hydride reduction”
i. Common Hydride sources:
a. NaH - too reactive
b. Hydride Donors: NaBH4 and LiAlH4 – more commonly used
- Na+ and Li+ = spectator ions
- 4 bonds to B or Al = -1 formal charge:
- Donate :H- to remove neg. charge
- Work is same fashion
- BH4- not as reactive as AlH4-
ii. Rxns of H:- w/ketones and aldehydes
a. Mechanism:
1.
2.
3.
Notes:
H:- attacks in similar fashion to acetylide or Grignard reagent
BH4- (or AlH4-) donates H:_
Alkoxide formed, requires H3O+ to make alcohol
b. Example reactions:
iii.
Rxn of H:- w/acyl chlorides, esters, and anhydrides
- Need 2 equivalents
- Produce alcohols as well
a. Mechanism – acid chlorides
1.
2.
3.
Notes:
1st H:- attach produces ketone or aldehyde
2nd attack produces alkoxide
H3O+ generates alcohol (HCl + H2O).
b. Examples
*** ppt *** Natural Hydride Donor NAD/NADH
(The interesting thing about hydride addition is that unlike Grignards and
aceytilide additions, hydride additions will also react with carboxylic acids
and amides)
(The amide reaction is kind of peculiar, and we’ll take a look at that is a few
minutes, but first let’s take a look at the reaction w/a carboxylic acid).
iv.
Rxn w/Carboxylic acids
a. Reaction:
b. Mechanism:
- Not required to know
- See ppt
*** ppt *** LiAlH4 reduction of acid mechanism
c. Example
v.
Amide rxn w/H:-
- Remember Amine = terrible leaving group
- C = O removed instead
(This is kind of like the odd ball reaction because in all other cases the there
is a leaving group that takes off. In this reaction, the carbonyl is taken out
and replaced by hydrogens).
a. Rxn
b. Mechanism:
- Not required to know
- See ppt
*** ppt *** LiAlH4 reduction of amide mechanism
c. Examples
(As I have mentioned before, there are a whole host of Nu that can attack
C=O. So far we mention several Carbon base Nu, and hydride Nu, but there
are many others.)
(Probably one of the most common is the addition of Nitrogen as a
nucleophile. This reaction was first discovered in the 1800’s by Hugo Schiff a
German Chemist, and the product of this reaction is often referred to as a
Schiff base).
*** ppt *** Fill in the Reagent of Product in the Box
18.8 Amine Rxn’s w/Ketones and Aldehydes
i.
Rxn:
- Imine = C=N containing product formed
- Pdt also referred to as “Schiff Base”
-1o amine replaces carbonyl Oxygen
ii.
Mechanism of imine formation:
Notes:
1. 1o amine must be used (otherwise you form a different product)
2. Amine attacks to make tetrahedral intermediate.
3.
a.
b.
4.
5.
6.
iii.
Protonation/Deprotonation occurs to:
Remove + charge from N
Convert -O- into -H2O+ leaving group
Amine uses lone pairs to eliminate H2O
Deprotonation of N produces imine
6 steps total in mechanism
Examples:
- Skip Imine Derivatives, Wolff-Kishner Reduction, Enamine Sections
iv.
Reductive Animation of Imines
(It turns out that Schiff bases or Imines C=N very much resembles a C=O bond
in reactivity.)
- C=N bond similar in nature to C=O bond:
(Consequently, some of the reactions that we perform of ketones/aldehydes
also work well on enamines. One such reaction is hydride addition).
- Hydride ion add’n to amine = reductive amination
a. Rxn:
- NaBH3CN is less reactive form of NaBH4
- Stable in acidic conditions
b. Examples
(Another Common Nu that can add into carbonyl is water and alcohols … or
in general Oxygen Nu)
(We’ll first take a look at water then we’ll move onto alcohols)
*** ppt *** Fill in the Missing Reagent/Product in the Provided Box
18.9 Water Rxns w/Ketone + Aldehydes
(When water adds to a ketone or aldehyde it forms a product called a
hydrate … meaning the molecule is hydrated. I guess the molecule might
have been dehydrated before?)
- Add’n of H2O = hydrate or gem-diol: (gem meaning twin in Latin and in
organic chemistry it means of the same carbon, diol meaning 2 alcohols.
So you can imagine two alcohol twins are formed from this rxn.)
i.
Rxn:
ii.
Mechanism:
Notes:
1.
2.
3.
4.
5.
iii.
H2O = poor Nu
Acid catalyst is required to “activate” C=O for attack
Once protonated, C=O is attacked by H2O
1 deprotonation step gives hydrate
3 steps total in mechanism
Rate of Add’n
(Some ketones and aldehyde spontaneously form hydrates in water free acid.
However, as you can imagine the equilibrium for this process is not the same for
ketone and aldehydes. Addition is much more favorable for one over the other
.. can you guess which one?)
- Add’n of water (Measured by Keq):
- Add’n to aldehyde = more favorable
(But why? …. Well there are 2 reasons)
1.
2.
-
Rationale:
Aldehydes less sterically hindered = easier add’n
Bond angle changes from 120o (sp2) to 109.5o (sp3)
Consequence: two bulky alkyl group brought closer together
(So not only is the add’n harder to perform on a ketone because it’s sterically
hindered, but the hydrate product formed from the addition is actually less
stable too. Kind of like a double whammy)
18.10 ROH rxn w/Ketone and Aldehydes
(Alcohols can add once or twice to an aldehyde or ketone. If only one
equivalent adds the product obtained is called a hemiacetal –from an
aldehyde- or a hemiketal –from a ketone-, literally meaning ½ acetal or ½
ketal)
(If two equivalents added, then one obtains a ketal form a ketone or an
acetal from an aldehyde).
i.
Rxns:
1. For aldehydes:
2. For ketones:
- Details:
1. ROH (like H2O = bad Nu), requires H+ to activate C=O.
2. Hemiacetal/Hemiketals are ridiculously hard to isolate
ii.
Mechanism
(This is probably the longest mechanism you’ll encounter in this class. It’s
not really all that hard, but it is long. For this reason, I’ll break it into two
portions: formation of the hemiacetal and then we’ll conquer the acetal
from the hemiacetal/hemiketal).
- Part 1: Formation of the Hemiacetal/Hemiketal:
- Notes:
1.
2.
3.
4.
1st part = very similar to hydrate mechanism
H+ activates C=O
HOR attacks
Deprotonation give hemiacetal
- Part 2: Formation of Acetal/Ketal
- Notes 2:
5. OH converted to H2O+ leaving group
6. Lone pairs of OCH3 eliminate H2O group
7. OCH3 group gains + charge (like an activated C=O)
8. 2nd HOCH3 attacks
9. Deprotonation step then gives acetal/ketal
10. 7 total steps!
iii.
Reversibility
- Mechanism is reversible
- Add’n of H3O+ to ketal/acetal gives ketone or aldehyde (or possibly the
hydrate depending)
- Rxn:
iv.
Examples
1.
(But keeping in mind that acetal and ketals group that can added then
removed is actually quite useful in organic chemistry. For example if we
wanted to do the following transformation…)
2. Example in Synthesis…
a. Use of LiAlH4:
b. Use of a ketal:
(This idea of using a temporary group in Organic Chemistry that can be added
to protect a functional group from reacting is quite common in organic
chemistry.)
(Because they protect functional groups from reacting the groups that are
added are called protecting groups. So in the case above, the ketal would be
considered a protection group).
*** ppt *** Fill in the Missing Reagent/Product in the Provided Box
18.11 Protecting Groups
(There are many many different protecting groups in Organic Chemistry.
Whole volumes of books are written just on protection groups)
*** ppt *** Protecting Groups
i.
a.
b.
c.
d.
ii.
Very Common Protection Groups
Acetal/Ketal – Protects ketones and aldehydes
Esters – Protects alcohols or carboxylic acids
Amides – Protects amines
Silyl Ethers – Protects alcohols
Other acetal example:
- Dialchol reacts w/aldehyde faster than ketone
- Remember: aldehydes = more reactive
iii.
Esters
-Ester prevents:
iv.
Amides
- Remember:
v.
Silyl ethers
- Probably most common Protecting Group
a. Installing Silyl group:
- Common base: triethylamine or TEA:
b. Removal of Silyl Ether
c. Example in Synthesis
1. w/o protection group:
2. W/protection
*** ppt *** Propose a synthesis to carry out the following transformations
Skip 18.12 - 18.15 (We may come back to this is there is time)
18.16 and 18.17 Conjugate Add’n
(So far in this chapter and the last chapter we’ve considered an addition of a
Nu directly to the carbonyl carbon. This type of addition, however, isn’t the
only way that Nu can add, when a molecule contains a carbonyl group).
(It can also undergo something called conjugate addition or also called 1,4
addition)
- Review: Direct (1,2) Add’n:
- Conjugate (1,4) Add’n:
(For conjugate add’n to occur though there must be certain requirements
that must be met.)
i. Requirements for 1,4 Add’n
1. Must contain conjugated enone
- en = C=C, one = C=O
2. Nu must be weak base
- Typically conj. acid of base >20 (through there are some exceptions to
this, one of which will see in a minute)
(To illustrate the point let’s look at the two types of cases)
Cases:
a. 1,2 add’n Nu (Strong Bases):
Examples:
MgBrR (Grignard Nu), RC=C:-, H:- (NaBH4, LiAl4)
Conj. Acid pka: ~ 50 -70
~25
~ 23
Ex.
b. 1,4 add’n Nu (Weak Bases)
Examples:
:C=N-, NH3 /1o /2o amines, RSH or -:SR, halides (Br:-)
Conj. Acid pka:
9
9-11
-7
8
-9 – -10
Ex.
3. Can’t be acyl chloride or anhydride = too reactive
- Under 1,2 add’n instead:
ii. Exception to rules: Cuprates
- Review: Cuprates = Organometallic Compounds w/Cu
- Add 1,4 (even though pKa of the conjugate acid of a cuprate is quite high)
Ex.
*** ppt *** Indicate whether the Rxn will undergo 1,2 or 1,4 Add’n and show
pdt
18. 18 Nature 1,4 Add’n (Not tested on)
- Enzymes actively use 1,4 add’n
- Refer to ppt
*** ppt *** Enzyme Catalyzed 1,4-Additions