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Carbonyl Key Features

1) Partial positive charge on carbonyl carbon
2) Alpha hydrogens: acidic
3) Electron donating/withdrawing groups: ED decrease reactivity of the carbonyl carbon, EW increase its reactivity
4) Steric hinderance: bulky substituents attached to carbonyl carbon decrease reactivity
5) Planar stereochemistry: sp2 hybridized carbonyl carbon is planar, can be attacked from either side.

1

Alpha Hydrogens

Hydrogens on a carbon adjacent to a carbonyl carbon are ACIDID due to RESONANCE STABILIZATION of the conj. base. When there are two carbonyls separated by a single carbon, hydrogens in the middle carbon are even more acidic.
The more partial positive the carbonyl carbon is, the more acidic the alpha hydrogens will be.

2

Aldehydes

- Name with the -al ending.
- Aldehyde carbons are always considered carbon #1 for numbering purposes
- Aldehyde substituent is "-oxo" like ketones

3

Ketones

- Are named with the -one ending
- If ketone must be named as a substituent it is called an "-oxo" group

4

Common Aldehydes and Ketones

- Formaldehyde (HCOH)
- Acetaldehyde (CH3COH)
- Benzaldehyde (C6H5COH)
- Acetone (CH3COCH3)

5

Aldehydes and Ketones Solubility and Boiling Point trends

Aldehydes and ketones act as H-bond recipients, but NOT as H-bond donors.
-They don't form hydrogen bonds with one another, but since they are polar, their boiling points are much higher.

6

General Characteristics of Aldehydes and Ketones

- Major function: ELECTROPHILES
- Can act as Lewis acids, accepting electrons when a base abstracts an alpha hydrogen

7

Substitution vs Addition:

- Aldehydes and ketones undergo NUCLEOPHILIC ADDITION (no substitution because no good LEAVING GROUPS)
- Carboxylic acids, amides, esters, anhydrides undergo NUCLEOPHILIC SUBSTITUTION

8

Keto-Enol Tautomerization

Process by which an alpha hydrogen adjacent to an aldehyde or ketone becomes bonded to the carbonyl oxygen, while the double bond is switched from the carbonyl oxygen-carbon bond to the bond between the carbonyl carbon and the alpha carbon

9

Formation of Acetals/Hemiacetals and Ketals/Hemiketals

- Acetals/ketals have TWO -OR substituents
-Hemiacetals/hemiketals have ONE -OR substituent plus one alcohol substituent (-OH group)
Steps:
1. Alcohol acts as nucleophile, attacks carbonyl carbon, pushes up pi bond electrons to the oxygen.
2)Oxygen is protonated (could have been protonated already if acid catalyzed) to form an alcohol and original alcohol is de-protonated to form an ether. This yields a hemiacetal (aldehyde) or hemiketal (ketone)
3) Alcohol is protonated again to form the good leaving group water, and a second equivalent of alcohol attacks the central carbon
4) Deprotonation of the second alcohol results in another ether, yielding a acetal or ketal.

10

Protecting Ketones/aldehydes from Reaction

Ketones and aldehydes can be prevented from reaction with nucleophiles or base by conversion to an acetal or ketal (unreactive unless in acidic conditions). Any terminal DIOL with at least two carbons will work.

Steps:
1) One end of the diol acts as a nucleophile
2) Other end of the diol acts as the "second equivalent of alcohol"
3) Acidic conditions will return the aceta/ketal to the original aldehyde or ketone

11

Halogenation of an Aldehyde or Ketone

Substitution of Br, Cl or I for one of the ALPHA H's on an aldehyde or ketone. Multiple halogenations often occur.

1) Base abstracts an alpha H, leaving carbanion.
2) Carbanion attacks a diatomic halogen (Cl-Cl)

12

The Haloform Reaction

When Halogenation is performed on a methyl ketone (CH3CO-R) with sufficient halogen present to effect replacement of all 3 alpha H's.

1) Complete halogenation using methyl ketone and enough halogen to replace all 3 alpha H's
2) Tri-substituted alpha carbon has a large partial positive charge and is transformed into a decent leaving group. When a strong hydroxide base, such as NaOH, is added, the -OH attacks the carbonyl carbon, kicking the electrons in the C=O up to onto the oxygen.
3) The electrons from the oxygen collapse down, reforming the pi bond, and kicking off the haloform as a leaving group. Results in a carboxylic acid
** Since in basic conditions, the reaction will produce carboxylate ions exclusively (COO-). Haloform acts as a base

13

Aldol Condensation

Condensation of one aldehyde or ketone with another aldehyde or ketone
1) Base abstracts an alpha H, creating a carbanion
2) Carbanion will attack any carbonyl carbon in the solution
3) Oxygen is protonated to form an alcohol
**Always COUNT CARBONS BEFORE AND AFTER

14

Alpha-beta unsaturated Carbonyls

An aldehyde or ketone with a double bond between the alpha and beta carbons
Two resonance structures so two possible ways to visualize mechanism:
1) With the double bond between the alpha and beta carbons, the nucleophile attacks the BETA carbon, pushing the double over to one carbon and forcing the C=O electrons up onto the oxygen
2) With a carbocation on the beta carbon, the nucleophile simply attacks the beta carbon directly
- Starting with either resonance form, the oxygen will get PROTONATED to form an alcohol.
- The protonated oxygen is really just the ENOL form of a keto-enol tautomer.

15

The Wittig Reaction

Transforms carbonyls into an alkene
NO MECHANISM, the product will always be an alkene, with the double bond bormed between the CARBONYL CARBON and the CARBON attached to the polyphenyl group
(CH3)2C=O + Ph3P+--CRR' ====> (CH3)2C=CRR' + Ph3P=O

16

Carboxylic Acids

- "oic acid" ending
- Carboxylate formed when proton is abstacted, leaving negative oxygen. "-ate" ending. If salt is formed, name metal then ion (sodium benzoate)
-Common names: formic acid (HCOOH), acetic acid (CH3COOH), benzoic acid (C6H5COOH)

17

Physical Properties of COOH's

Very high boiling points due to H-bonding (forms strong dimers)
-W/O long alkyl chains, they are soluble in water
- Surprisingly short-chain carboxylic acids are also soluble in many relatively non-polar solvents, such as chloroform (even though they are clearly polar), SINCE THE DIMER WOULD HAVE NO DIPOLE MOMENT, IT IS SOLUBLE IN NON-POLAR SOLVENTS

18

General Properties of -COOH

1) Resonance stabilization: carboxylate ion is uniquely stable due to resonance.
2) Induction: pay careful attention to alpha substituents; they can either donate or withdraw from the carboxylate ion, increasing or decreasing acidity. TO PREDICT ACIDITY EXAMINE STABILITY OF CONJUGATE BASE.
3) H-bonding- do it twice to form dimers

19

Nucleophilic attack carbonyls

RCOOH + H2O --> RCOOH2 + Nu:- --> RCONu + H2O

20

Decarboxylation

- Loss of a CO2 molecule from a beta-keto carboxylic acid, leaving behind a resonace-stabilized carbanion. Process usually requires catalysis by a base.
- Carboxylate ion usually takes back the H back from the base, FORMING A KETO-ENLO tautomer

21

Esterification

RCOOH + ROH --> RCOOR + H2O
Reaction of an alcohol with a carboxylic acid to form an ESTER. Hydroxyl group will never leave before being protonated first to form H2O, requires acid catalyst.
-Higher yields can be obtained by reacting an anhydride with an alcohol.

22

Acid Chloride

Carbonyl with a chloride substituent on the carbonyl carbon
- Named with the "-oyl chloride" ending, an in propanoyl chloride

Common names: Formyl chloride, acetyl chloride, benzoyl chloride.
*** BENZYL CHLORIDE IS NOT AN ACID CHLORIDE,it's just C6H5Cl

- Most REACTIVE of carboxylic acid derivates. Reactivity due to withdrawing power of the chlorine, which makes the partial positive larger, and the fact that the chloride ion is a GREAT leaving group

23

Formation of Acid Chlorides

RCOOH + PCl3 --> RCOCl + H2O
-Three reagents readily produce acid chlorides when added to carboxylic acids: PCl3, PCl5, and SOCl2.
- Addition of a chloride ion (Cl-) to a carboxylic acid does NOT produce an acid chloride

24

Anhydrides

Compound with two acyl groups connected to one another by a single oxygen. Or viewed another way, an anhydride is an ester where the -R group is the carbonyl

-Named by replacing the "-oic" ending of the corresponding -COOH with "-oic anhydride" (mixed acid anhydrides are named alphabetically, like ethanoid methanoic anhydride)

Common names: formic anhydride, acetic anhydride, and ACETIC FORMIC ANHYDRIDE if it's a mixed anhydride made from ethanoic acid and methanoic acid.

EXCELLENT ELECTROPHILES: two carbonyls carbons are highly reactive because the LG is a resonance-stabilized carboxylate ion.

25

Amides

Compound containing a carbonyl with an amine substituent on the carbonyl carbon.
- Replace "oic" ending of the corresponding -COOH with amide (benzoic acid - benzamide)
- Amides are the most STABLE of all acid derivatives, so for MCAT consider their carbonyl carbons unreactive. NH2 isn't a good LG.

26

Properties of AMIDES

Primary and Secondary amides can H-bond and are thus WATER SOLUBLE as long as they lack long alkyl chains. Tertiary amides CANNOT H-bond
-Biochemistry connection: amide hydrogen bonding is perfectly illustrated in secondary structure of proteins.

Resonance Limits Rotation: the lone pair of the amide N resonates with the carbonyl double bond, giving the C-O and C-N bonds double bond character. Prevents rotation.

27

Hoffmann Degradation

-Primary amides (amides with only H's on the nitrogen) react in strong basic solutions of Cl2 or Br2 to form PRIMARY AMINES.
-Mechanism includes DECARBOXYLATION, so SHORTENS THE CARBON CHAIN.
-Can add an AMINE to a TERTIARY CARBON

28

Esters

Any compound containing a carbonyl with an -OR group substituted on the carbonyl carbon
- Named with the "oate" ending, with the R portion of the -OR group named and placed in front of the name, as is methyl pentanoate.

Common names: methyl formate, methyl acetate, methyl benzoate

-Act as H-bond recipients, but NOT donors. W/O long alkyl chains, they are slightly soluble in water; less soluble than acids or alcohols.

29

Transesterification

Reaction of an existing ester with an alcohol, creating a different ester. Also requires acid catalysis.

RCOOR(a) + R(b)-OH --> RCOOR(b) + R(a)OH

30

Saponification (hydrolysis of an ester)

- Hydrolysis of an ester to yield an alcohol and the salt of the carboxylic acid
1) Hydroxide ion (NaOH or KOH) attacks the carbonyl carbon and pushes the C=O electrons up onto the oxygen.
2) The electrons collapse back down and kick off the -OR group
3) Either the -OR group, or hydroxide ion, abstracts the carboxylic acid hydrogen, yielding a carboxylate ion. This dissociates with the Na+ or K+ in the solution to form soap.

31

Acetoacetic Ester Synthesis

Formation of a ketone from a beta-keto ester
1) Base abstracts the acidic alpha H, leaving a carbanion
2) Carbanion attacks an alkyl halide (R-X), resulting in addition of the -R group to the alpha carbon
3) Hot acid during workup causes loss of the entire -COOR group

32

Inorganic Esters

MCAT authors referring to oxo acids such as phosphoric acid, sulfuric acid, and nitric acid, plus their associated esters.

ATP, GTP, UTP are examples of inorganic triphosphate esters. FADH2 and NADH are examples of diphosphate esters. FMN, DNA and RNA are monophosphate esters.

33

Substitution of Acid Derivatives

RANKING OF ACID DERIVATE LG (best to worst)
-Cl > -OCOR > -OH > -OR > -NH2

STABILITY OF CARBOXYLIC ACID DERIVATIVES. Exact opposite, the ones with better LGs will be the most unstable
AMIDE > ESTER > CARBOXYLIC ACID > ANHYDRIDE > ACID CHLORIDE

34

Amines

Organic compound that contains a basic nitrogen atom
-Amines can act as either bases or nucleophiles. Primary or secondary amines usually act as nucleophiles and tertiary amines ALWAYS act as bases (too big)
- Amine basicity decreases from tertiary to secondary to primary to ammonia due to the electron donating effect of the R-group. Amine attached to aromatic rings are significantly less basic than standard amines (donate electrons to conjugated system)
- Amines with 4 substituents (ammonium) act as electrophiles (AS LONG AS THEY HAVE AT LEAST ONE H)
- Amines are capable of H-bonding

35

Amine Nomenclature

1) Name the alkane to which the N is attached (propane)
2) Add "amine" in place of the "e" on the end of "ane" (propanamine). It is also acceptable to separate the substituent name (propyl amine)
3) If the amine is secondary, the longest chain is included in the name as indicated above. The other chain is added to the beginning, proceeded by the letter "N-" (N-ethylpropanamine)
4) If the amine is tertiary, or quaternary, add additional substituents to the front of the name in alphabetical order, all with the prefix N- included (N,N-diethylpropanamine or N-ethyl-N-methylpropanamie, or N,N-dimethyl-N-ethylpropanamine)

36

Amine Tautomerization

Enamine and imine interchange via a proton shift analogous to the keto-enol tautomerization
ENAMINE (C=C) IMINE (C=N)

37

Synthesis of Alkyl Amines

NH3 + CH3Br --> NH2CH3 + HBr
Formation of an ALKYLAMINE from an amine and alkyl halide
1) Ammonia acts as a nucleophile, attacking the alkyl halide via SN2 and kicking off the halide ion.
2) Halide ion acts as base, abstracting a H to quench the charge on the nitrogen.
***MANY SIDE PRODUCTS BECAUSE RESULTANT AMINE IS STILL A GOOD NUCLEOPHILE AND CAN REACT AGAIN.

38

Gabriel Synthesis

Formation of primary amine from primary alkyl halide, AVOIDS THE SIDE PRODUCTS OF ALKYL AMINE SYNTHESIS
1) The phtalimide ion, a reactive species with a full negative charge on the nitrogen, acts as a nucleophile, attacking the alkyl halide via SN2
2) Hydrazine (H2N-NH2) attacks one carbonyl carbon, then the other, after a few proton transfers, the amine will be a LG

39

Reduction Synthesis of Amines

- Reduction of amides, imines, nitriles, and nitro groups via common reducing agents such as LiAlH4, NaBH4, and H2/catalyst with pressure

NITRO GROUPS: can be reduced to the associated primary amine via all of the above.
NITRILES: can be reduced to the associated primary amine via all of the above listed reducing agents. Most books like nitriles being reduced with LiAlH4
IMINES: can be reduced associated primary amine via all of the reducing agents. Books focus on Imines being reduced by NaBH3CN or H2 and catalyst
AMIDES reduce to the associated primary amine via LiAlH4 ONLY

40

Addition of Amines to Carbonyls (Formation of Enamines and Imines)

Amines add to aldehydes and ketones to form imines and enamines
1) Amine acts as nucleophile, attacks carbonyl carbon
2) Oxygen is protonated twice, LG water
3) Base abstracts H from the nitrogen and kicks off water by an E2 mechanism. This form either an imine or enamine (depending on substitution pattern of nitrogen)
-Primary amine yield IMINES
-2nd amines yield ENAMINES
-3r amines DONT REACT

41

Wolf-Kishner Reduction

Complete reduction of an aldehyde or ketone to an alkane via an imine intermediate. When you do the amine addition to carbonyl reaction starting with HYDRAZINE as the amine, the product is an amine-substituted imine. Subsequent addition of a hot, strong base (KOH/heat) replaces the IMINE with two H's, yielding an alkane.
1) CH3COCH3 + H2N-NH2--> IMINE
2) IMINE + KOH/heat --> CH3CH2CH3

42

Hofmann Elimination

Formation of an alkEne via elimination of an amine. YIELDS THE LEAST SUBSTITUTED ALKENE

43

To determine if a group is ELECTRON DONATING or WITHDRAWING

1) Look at the FIRST atom from the point of attachment. Compare its electronegativity to the atoms bound to it. If it's more electronegative, it will bear a partial negative charge and if it is less electronegative, it will bear a partial positive charge.
2) Atoms with full or partial positive charges withdraw from whatever they are attached to. Atoms with full or partial negative charges donate to whatever they are attached to.
3) Hydrogen is considered neither ED or EW
4) Alkenes are WEAKLY EW (MEMORIZE)

44

List of ED and EW

ED: alkyl groups, amines, alcohols, quaternary amines
EW: nitro groups (strong), cyano groups (nitrile), sulphones (assuming connection to sulfur), carboxylic acids, esters (assuming connected to carbonyl, if connected to the oxygen of the -OR group, then it's ED)