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Flashcards in Ochem 2 Deck (143):
1

  • Aldehydes & Ketones
    • Formation of Acetals/Hemiacetals and Ketals/Hemiketals 
      • Describe the 4 steps of formation 

  1. An alcohol acts as the nucleophile
    • Attacking the electrophilic carbonyl carbon and
    • pushing the pi electrons from the C=O bond up onto the oxygen
  2. The negatively charged oxygen is protonated to form an alcohol and
  • the original alcohol is deprotonated to form an ether
    • This yields:
      • a hemiacetal if it was originally an aldehyde, or
      • a hemiketal if it was a ketone

3. The alcohol is protonated again to form the good leaving group water

  • a second equivalent of alcohol attacks the central carbon 

4. Deprotonation of the second alcohol results in another ether,

  • yielding:
    •  an acetal if it was originally an aldehyde
    • or a ketal if it was a ketone

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2

  • Acid (Acyl) Chloride
    • Acid Chloride Formation 
      • Formula=?
      • What 3 reagents readily produce acid chlorides when added to carboxylic acids?

RCOOH + PCl⇒ RCOCl + H2O

  • Three reagents readily produce acid chlorides when added to carboxylic acids:
    • PCl3
    • PCl5
    • SOCl2

 

2

  • Acid Chloride
    • Acid Chloride Formation
      • Addition of chloride ion (Cl-) to a carboxylic acid does NOT produce an acid chloride
      • Provide a possible explanation for WHY 

  • A chloride ion IS capable of attacking the carbonyl carbon of a carboxylic acid
    • However, when the electrons in the carbonyl bond are kicked up onto the oxygen, and then collapse back down, the substituent that is the best leaving group will leave
      • ...regardless of the original structure of the molecule
  • Chloride ion is more stable (i.e., it is a weaker base) than hydroxide ion
    • so the chlorine will be kicked off to reform the acid

3

  • Acid Chlorides (a.k.a.___)
    • Definition 
    • Nomenclature
      • Common Names (3)

Definition:

  • An acid chloride (a.k.a. "acyl chloride") is any compound containing:
    • a carbonyl
      • with a chlorine substituent on the carbonyl carbon

Nomenclature:

  • Acid chlorides are named with the “–oyl chloride” suffix
    • Ex: propanoyl chloride

Common Names:

  • Know the same three non-IUPAC names we’ve been highlighting for each functional group
    1. Formyl chloride
    2. Acetyl chloride
    3. BenzOYL chloride

Take note that benZYL chloride is NOT an acid chloride

  • It is a chlorine attached to a benzyl group

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3

  • Acid Chloride
    • What property of Acid Chlorides make them IMPORTANT?
    • What 2 things are the cause of this property?

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  • Acid Chlorides are important because:
    • they are the most reactive of the carboxylic acid derivatives
  • Their reactivity is due to:
    1. The withdrawing power of the chlorine
      • which makes the partial positive charge on the carbonyl larger than normal
    2. The fact that chloride ion is a superb LG

3

  • Acid Chlorides
    • Provide a reactant that will form each of the following when reacted with an acid chloride
      1. An ester
      2. An amide
      3. An anhydride
      4. A carboxylic acid

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  1. ROH
  2. RNH2
  3. RCOOH
  4. H2O

4

  • Aldehydes & Ketones
    • General Characteristics
      • Why don’t aldehydes and ketones undergo substitution reactions?
        • ex: SN1, SN2

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In order for a substitution to occur, there must be a LEAVING GROUP

  • Acid derivatives all have leaving groups:
    • Clin the case of acid chlorides
    • -OH in the case of carboxylic acids
    • a Carboxylate ion in the case of anhydrides, etc.
  • The stability of these groups after they leave varies widely, but in the case of an aldehyde or ketone:
    • there are NO groups that would be reasonably stable,
    • and therefore NO candidates to act as leaving groups
  • The aldehyde hydrogen will not leave as H:- , nor will an R group leave from a ketone as a carbanion R:-
  • In both cases, the leaving group would become a strong base
    • Recall that strong bases NEVER make good leaving groups
      • Good leaving groups must be WEAK bases that are stable AFTER they leave
    • For this reason, aldehydes and ketones only undergo addition reactions—lacking a suitable leaving group to undergo substitution

4

  • Aldehydes & Ketones
    • General Characteristics
      • Aldehydes and ketones can also function as Lewis ___s, accepting electrons when WHAT happens?

  • Aldehydes and ketones can also function as Lewis ACIDS, accepting electrons when
    • a base abstracts an alpha hydrogen

4

  • Aldehydes & Ketones
    • Aldol Condensation 
      • Describe
      • Explain the 3 steps 

Aldol Condensation

  • The condensation of one aldehyde or ketone with another aldehyde or ketone

STEPS:

  1. A base abstracts an alpha hydrogen, creating a carbanion
  2. The carbanion will attack any carbonyl carbon in the solution
  3. The oxygen is protonated to form an alcohol

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4

  • Aldehydes & Ketones
    • Aldol Condensation
      • What's a common mistake students make with aldol condensations?
      • How can you avoid this mistake?

THE MCAT LOVES ALDOL CONDENSATIONS!

The common mistake seems to be for students to lose track of the carbanion carbon—often drawing a product with the two original carbonyl carbons adjacent to one another

To avoid this:

  • Always draw out the product
    • Do NOT try to predict it in your head
  • Draw the carbanion nearby the carbonyl and then immediately draw a bond between them

In the product there should always be one carbon in between: 

  • the carbonyl carbon 
  • the carbon bearing the hydroxyl group

This could also be avoided by counting the total carbons before and after the reaction

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4

  • Aldehydes & Ketones
    • α-β Unsaturated Carbonyls
      • Describe
      •  Is an α-β unsaturated carbonyl a base, a nucleophile, or an electrophile?

An aldehyde or ketone with a double bond between the alpha and beta carbons

  • In terms of the MCAT, you should think of an α-β-unsaturated carbonyl as an ELECTROPHILE

 

  • ​It might be tempting to think of the double bond between the alpha and beta carbons as a nucleophile that will undergo electrophilic addition
    • However, the withdrawing effect of the carbonyl decreases the electron density of the double bond deactivating it toward electrophilic addition 

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4

  • Anhydrides
    • Definition
    • Nomenclature
    • Common Names (3)

Definition:

  • An anhydride is a compound with two acyl groups connected to one another by a single oxygen
  • Viewed another way, an anhydride is an ester where the –R group is a carbonyl

Nomenclature:

  • Named by replacing the “-oic” ending of the corresponding carboxylic acid with “-oic anhydride”
    • i.e., benzoic acid⇒benzoic anhydride
  • Mixed acid anhydrides are named alphabetically
    • i.e., ethanoic methanoic anhydride

Common Names:

  • The MCAT will expect you to recognize:
    1. formic anhydride
    2. acetic anhydride
    3. acetic formic anhydride
  • If it is a mixed anhydride made from:
    • ethanoic acid and methanoic acid

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5

  • Aldehydes & Ketones
    • General Characteristics
      • Which is more acidic, the alpha hydrogen of a ketone, or the alpha hydrogen of an aldehyde?
      • Provide a possible explanation

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The alpha hydrogen of an aldehyde is more acidic than a comparable alpha hydrogen on a ketone

  • because the conjugate base in the case of the aldehyde is more stable

In an aldehyde, a hydrogen is attached to the carbonyl carbon

  • Hydrogen is defined as neither a withdrawing group nor a donating group

However, in the case of a ketone, an –R group is attached to that same carbonyl carbon

  • and –R groups are weakly electron donating
    • This will decrease the magnitude of the partial positive charge on the carbonyl carbon in the ketone
      • making it less able to stabilize the negative charge of the carbanion in the conjugate base

6

  • Aldehydes & Ketones
    • General Characteristics
      • Substitution vs. Addition
        • Aldehydes & Ketones undergo...?
        • What 4 FG's undergo nucleophilic SUBSTITUTION?

Aldehydes and Ketones undergo:

  • nucleophilic ADDITION
  1. Carboxylic Acids
  2. Amides
  3. Esters
  4. Anhydrides

undergo...

  • nucleophilic SUBSTITUTION 

7

  • Aldehydes & Ketones
    • General Characteristics
      • MAJOR FUNCTION=?

ELECTROPHILES!

with their carbonyl carbon being attacked by Nu:'s

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7

Aldehydes & Ketones

  • Halogenation of an Aldehyde or Ketone 
    • Describe
    • List the 2 steps 

  • Substitution of a Br, Cl or I for one of the alpha hydrogens on an aldehyde or ketone
  • Multiple halogenations often occur

STEPS:

  1. A base abstracts an alpha hydrogen
    • leaving a carbanion
  2. The carbanion attacks a diatomic halogen (Br2)

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8

  • Aldehydes & Ketones
    • Keto-Enol Tautomerization
      • Aldehydes and ketones cannot act as H-bond donors
        • An exception to this rule is 1,3-dicarbonyl compounds
          • They can act as hydrogen bond donors
      • Draw out a 1,3 dicarbonyl compound and propose an explanation

A 1,3-dicarbonyl can undergo an intramolecular hydrogen bond when:

  • one of the carbonyls is in the keto form and
  • the other is in the enol form
    • This significantly stabilizes the enol compared to a stand-alone enol
  • In this condition:
    • the enol is acting as the hydrogen-bond donor
    • the carbonyl as the hydrogen bond acceptor

The MCAT loves alpha hydrogens so much, it wouldn’t be right to mention 1,3-dicarbonyls without also pointing out that they have ULTRA ACIDIC alpha protons on the carbon between the two carbonyl carbons

  • b/c there's DOUBLE resonance stabilization! 

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9

  • Aldehydes & Ketones
    • Keto-Enol Tautomerization
      • Draw a step-wise mechanism for the tautomerization 

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10

  • Aldehydes & Ketones
    • Keto-Enol Tautomerization
      • Which is more stable, the keto or the enol tautomer?
      • Why?

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The keto and enol forms are in an equilibrium with one another that strongly favors the keto form at room temperature

  • The keto form is more stable
    • because the sum of its bond energies is greater than the sum of the bond energies in the enol form
  • The keto form has a C=O bond, a C-C bond, and a C-H bond
    • that are replaced by a C-O bond, a C=C bond, and an O-H bond in the enol form
  • C-H and O-H bonds are quite close in bond energy
  • C=C has about 250 kJ/mol more bond energy than a C-C bond (almost double)
  • The real difference comes in the difference between a C-O bond and a C=O bond
    • A C=O bond has about 450 kJ/mole more bond energy!
  • What you should know is that carbonyl bonds are much shorter and stronger than alkene bonds
    • That is the most significant difference between the two forms and is the reason the keto form is favored.

11

  • Aldehydes & Ketones
    • Nomenclature
      • There are a few common aldehydes and ketones for which the MCAT will use non-IUPAC names
        • Name the 4 we need to know
        • Hint: FABA

  • There are a few common aldehydes and ketones for which the MCAT will use non-IUPAC names
    • These include:
      1. formaldehyde
        • HCOH
      2. acetaldehyde
        • CH3COH
      3. benzaldehyde
        • C6H5COH
      4. acetone
        • CH3COCH3

12

  • Aldehydes & Ketones
    • Nomenclature
      • What suffixes are they associated with each?
      • If a ketone must be named as a FG, what suffix does it use?
      • What must the parent chain contain?

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Aldehydes

  • are named with the "–al" ending
  • Aldehyde carbons are always considered carbon #1 for numbering purposes

Ketones

  • are named with the "–one" ending
  • If a ketone MUST be named as a substituent, it is called an “-oxo” group
    • as in 4-oxopentanal

In either case, the parent chain must be the longest chain that includes the carbonyl

12

Aldehydes & Ketones

  • Ketones are given the name “-oxo” as substituents
    • What is an aldehyde named if it must be labeled as a substituent?
  •  Aldehydes and ketones can ONLY be substituents when WHAT is present?
  • If the aldehyde or ketone is the TOP priority functional group:
    • Which Carbon is labeled as C-1?

Surprisingly, substituent aldehydes are given the SAME “-oxo” name as ketone substituents!

There really should not be any confusion, however, because:

  • if the identified carbon is TERMINAL:
    • it MUST be an aldehyde
      • and cannot be a ketone
  • and if it is SECONDARY:
    • it MUST be a ketone
      • and cannot be an aldehyde

Remember that aldehydes and ketones can ONLY be substituents when:

there is a HIGHER priority functional group present

  • such as a carboxylic acid

If the aldehyde or ketone is the TOP priority functional group:

then the carbonyl carbon is always labeled as C-1

 

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13

  • Aldehydes & Ketones
    • Physical Properties
      • Solubility & BP trends
        • Aldeyhdes and ketones can act as _____recipients, but NOT as____donors

  • Aldeyhdes and ketones can act as H-bond recipients, but NOT as H-bond donors

13

  • Aldehydes & Ketones
    • Physical Properties
      • Solubility & BP trends
        • Use your knowledge of structure and function to predict the relative water solubility of aldehydes and ketones compared to comparable alkanes or alcohols
        • How will boiling point differ between these same species?

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SOLUBILITY:  

Alkanes

  • Alkanes are non-polar and therefore insoluble in water
  • Aldehydes and ketones can act as hydrogen-bond acceptors when dissolved in water, with water acting as the hydrogen bond donor
    • Therefore, aldehydes and ketones will be far more soluble than alkanes
  • Finally, alcohols can hydrogen bond as both a donor and acceptor with water, so they will be the most soluble
    • These trends assume comparable molecular weight, chain length, etc
      • This is important because a small alcohol such as methanol is water soluble, but dodecanol (big) is considered insoluble

​BOILING POINTS

Alkanes

  • The boiling point of alkanes will be the lowest
    • because their only intermolecular attraction would be van der Waals forces
  • Aldehydes and ketones do NOT hydrogen bond with one another
    • but they are both polar and will therefore have much higher boiling points than alkanes
  • Finally, alcohols will have the highest boiling points
    • due to intramolecular hydrogen bonding (Strong IMFs)

13

  • Aldehydes & Ketones
    • Keto-Enol Tautomerization

Keto-Enol Tautomerization:

  • This is the 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 carbonoxygen bond to the bond between the carbonyl carbon and the alpha carbon 

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14

  • Aldehydes & Ketones
    • α-β Unsaturated Carbonyls 
      • What are the 2 possible ways to visualize this mechanism? 

STEPS:

  • There are two possible ways to visualize this mechanism, based on which resonance form you start with:
  1. With the double bond between the alpha and beta carbons, the nucleophile attacks the beta carbon
    • pushing the double bond over 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
  • Note that the protonated oxygen is really just the enol form of a keto-enol tautomer

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15

  • Aldehydes & Ketones
    • α-β Unsaturated Carbonyls 
      • Draw two possible resonance structures for an α-β unsaturated carbonyl
      • Which one will be the major contributor to the resonance hybrid?

  •  The one on the left is clearly the more significant contributor to the actual structure
    • because it has no formal charges, compared to a charge separation in the structure on the right

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16

  • Aldehydres & Ketones
    • Define

Aldehyde

  • is any compound containing a carbonyl... 
    • with one or more hydrogen substituents on the carbonyl carbon

Ketone

  • is any compound containing a carbonyl... 
    • with two carbon substituents on the carbonyl carbon

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17

  • Amide
    • Properties
      • Among acid derivatives, amides are...?
      • Describe the reactivity of an amide's carbonyl carbon 

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  • Amides are theMOST STABLE  of all acid derivatives
    • Their carbonyl carbons are UNreactive
      • This is because --NH2 is NOT a good leaving group

17

  • Amide
    • Properties
      • ​1° and 2º amides can do what?
      • What about 3º amides?
      • What is the BIOCHEMISTRY connection here? 

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  • Primary and secondary amides can HYDROGEN BOND 
    • ∴ amides are water soluble as long as:
      • they lack long alkyl chains
  • Tertiary amides cannot H-bond

Biochemistry Connection:

  • Amide hydrogen bonding is perfectly illustrated in the secondary structure of proteins
    • In an alpha helix every amine hydrogen forms an H-bond with the carbonyl four residues previous to it in the chain

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18

Amides

  • Hoffman Degradation
    • What happens to the Carbon Chain in this reaction?
    • What does the mechanism include?
    • What do you reach with what, to produce what?

Why is this reaction important?

  • Primary amides (amides with only hydrogens on the nitrogen) react in strong, basic solutions of Cl2 or Br2 to form primary amines
    • The mechanism includes decarboxylation,
      • and thus SHORTENS (!!) the length of the carbon chain

This reaction is important because it allows you to ADD AN AMIDE TO A TERTIARY CARBON

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20

  • Amides
    • Physical Properties
      • The nitrogen of an amINE is normally sp3 hybridized
      • What is the expected hybridization of the nitrogen in an amIDE?

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  • Because the nitrogen in an amide donates its lone pair via resonance, both the C-O and the C-N bond have double-bond character
    • Therefore the hydbridization of the nitrogen will be closer to sp2 than to sp3 

21

  • Amides
    • Physical Properties
      • What does Resonance (aka "Double Bond character") do to amides?

Resonance (Double Bond Character) LIMITS ROTATION:

  • The lone pair on the amide nitrogen resonates with the carbonyl double bond
    • ...giving both the C-O and the C-N bonds double bond character
      • This prevents rotation

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22

  • Amides
    • Properties
      • Would you expect amIDES to be more or less basic than comparable amINES?
      • Why?

  • Nitrogen has less electron density in an amide than it would in a normal amine
    • b/c of donation of the lone pair on the nitrogen into the conjugated system
      • Therefore, it will be LESS BASIC than comparable amines

One could also consider the effect of induction

  • The carbonyl carbon has a strong partial positive charge 
    • ....which will withdraw electron density from the amine through the sigma bond

23

  • Amides
    • Definition
    • Nomenclature

 Definition

  • An amide is any compound containing a carbonyl with an amine substituent on the carbonyl carbon

Nomenclature

  • Named by replacing the “-oic” ending of the corresponding carboxylic acid with “amide”
    • i.e., benzoic acid⇒benzamide

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24

  • Amines
    • Addition of Amines to Carbonyls
      • aka, the Formation of ___s and ___s
        • Amines add to ___ and ___ to form these ^^^
    • Describe the 3 steps

Addition of Amines to Carbonyls....

aka Formation of ENAMINES and IMINES

  • Amines add to aldehydes and ketones to form imines and enamines

STEPS:

  1. The amine acts as a nucleophile
    • ...attacking the electrophilic carbonyl carbon
  2. The oxygen is protonated twice
    • creating the good LG water
  3. A base abstracts a hydrogen from the nitrogen and kicks off water in an E2 mechanism
    • This forms either an imine or an enamine
      • (depending on the substitution pattern of the nitrogen)

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24

  • Amines
    • Addition of Amines to Carbonyls (Formation of Enamines and Imines)
      • What do 1°, 2°, and 3° amines yield, respectively? 

  • Primary (1°) amines:
    • yield IMINES
  • Secondary (2°) amines:
    • yield ENAMINES
  • Tertiary (3°) amines
    • DO NOT REACT

25

  • Amines
    • Definition
    • Properties
      • Amines can act as either...?
        • 1° and 2° amines usually act as?
        • 3° amines always act as?
          • Why?
      • Amines with 4 R groups act as...?
        • as long as...?
      • ​​​Amines are capable of...?

Definition:

  • An amine is any organic compound that contains a basic nitrogen atom

Properties

  • Amines can act as either bases or nucleophiles
    • Primary or secondary amines usually act as nucleophiles
    • Tertiary amines ALWAYS act as bases
      • (because they are too sterically hindered to act as nucleophiles)
  • Amine Basicity:
    • Basicity decreases from tertiary to secondary to primary to ammonia due to the electron donating effects of the R- groups
    • Amines attached to aromatic rings are significantly less basic than standard amines
  • Amines with four substituents act as ELECTROPHILES
    • as long as they have at least one hydrogen
    • ex: Ammonium, NH4+ 
  • Amines are capable of hydrogen bonding

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27

  • Amines
    • Gabriel Synthesis
      • Describe the steps
      • Draw the e- pushing mechanism

STEPS:

  • The phthalimide ion (a reactive species with a full negative charge on the nitrogen) acts as a nucleophile
    • ...attacking the alkyl halide
      • via SN2

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28

  • Amines
    • Gabriel Synthesis
      • = the formation of what from what?
      • What does this rxn AVOID?

Formation of a 1° amine from a 1° alkyl halide

  • Avoids the side products of alkyl amine synthesis

29

  • Amines
    • Properties
      • Which functional group forms stronger hydrogen bonds, alcohols or amines?

  • ALCOHOLS will form stronger hydrogen bonds
    • because there is a greater difference in electronegativity between oxygen and hydrogen than there is between nitrogen and hydrogen
  • This greater dipole will create a stronger electrostatic attraction
    • ...and therefore a stronger hydrogen bond

29

  • Amines
    • Nomenclature
      • It's UNIQUE for amines
      • Describe the 4 steps for naming amines
        • Hint: It does matter whether the amine is primary, secondary, etc.

Naming amines is a bit unique, so be sure you understand the system:

  1. Name the alkane to which the N is attached e.g., propane)
  2. Add “amine” in place of the “e” on the end of “ane” (e.g., propanamine)
    • It is also acceptable to separate the substituent name (e.g., propyl amine)
  3. If the amine is secondary, the longest chain is included in the name as indicated above
    • The other chain is added at the beginning, proceeded by the letter “N-" 
      • e.g., 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
  • e.g., N,N-diethylpropanamine, or N-ethyl-Nmethylpropanamine, or N,N-dimethyl-N-ethylpropanamine (ATTACHED) 

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29

  • Amines
    • Reduction Synthesis of Amines
      • Describe the reduction of Nitro and Nitrile groups
      • What do they both get REDUCED TO?
      • What do most O-Chem books focus on these groups being reduced by?

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Nitro groups

  • can be reduced to the associated primary amine
    • via all of the listed reducing agents
      • e.g., LiAlH4, NaBH4, and H2/catalyst with pressure
  • Most O-Chem books focus on nitro groups being reduced by:
    • metals in HCl M•HCl
      • M=Fe, Zn, Sn

Nitrile groups

  • can be reduced to the associated primary amine
    • via all of the above listed reducing agents
  • Most O-Chem books focus on nitriles being reduced by:
    • LiAlH4

30

  • Amines
    • Reduction Synthesis of Amines
      • Describe the reduction of Imine and AmIDE groups
        • What are both reduced TO?
        • What do most O-chem books focus on these groups being reduced BY?

​Hint: Amides can only be reduced with ONE reducing agent....

Imines

  • can be reduced to the associated 1° amine
    • via all of the above listed reducing agents
    • O-Chem books focus on Imines being reduced by:
      • BH3
      • -:CN or
      • H2 / catalyst 

Amides

  • reduce to the associated 1° amine
    • via LiAlH4 ONLY

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32

  • Amines
    • Tautomerization
      • Define
        • what is it analogous to?
      • Draw

Tautomerization

  • An enamine and imine interchange
    • via a proton shift

Analogous to the keto-enol tautomerization

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33

  • Amines
    • Amine Basicity
      • Offer a plausible explanation for the decreased basicity of aromatic amines

  • Aromatic amines are less basic because they donate their electron pair into the ring
    • forming a conjugated system with the ring

34

  • Amines
    • Addition of Amines to Carbonyls (Formation of Enamines and Imines)
      • Provide a possible explanation for why tertiary amines DO NOT REACT with carbonyls
        • Hint: Attempt to draw out a mechanism

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  • Tertiary amines are not good nucleophiles
    • because they are TOO STERICALLY HINDERED
  • They are more likely to act as a base
  • Even if they were to attack the carbonyl carbon, this would form:
    • an unstable quaternary amine
      • with a full positive (+) formal charge
    • This would be a better LG than the water formed by protonation of the carbonyl
      •  ...and would therefore be kicked back off anyway

36

  • Amines
    • "Reduction Synthesis of Amines"
      • ...Is the reduction of what 4 groups? 
        • using common reducing agents, such as? (3)

  • Reduction of:
    1. AmIDES
    2. Imines
    3. Nitriles
    4. Nitro groups
  • using common reducing agents such as:
    • LiAlH4
    • NaBH4
    • H2/catalyst with pressure.

37

  • Amines
    • Synthesis of Alkyl Amines
      • Describe
      • Formula=?
      • Describe the 2 Steps 
      • Remember that this rxn results in many side products
        • Why?

Formation of an alkylamine from an amine and an alkyl halide

NH3 + CH3Br ⇒ NH2CH3 + HBr 

STEPS:

  1. Ammonia acts as a nucleophile, attacking the alkyl halide via SN2
    • ...and kicking off the halide ion
  2. The halide ion acts as a base, abstracting a hydrogen
    • This quenches the charge on the nitrogen

NOTE:

This reaction results in many side products

  • because the resultant amine is still a good nucleophile and can react again

39

  • Amines
    •  _____synthesis is the most common human-body example of an amine acting as a nucleophile

Protein Synthesis

  • the amine acts as a nucleophile
    • attacking the carbonyl carbon of another amino acid to form a peptide bond

40

  • Anhydrides
    • Properties
      • Anhydrides are excellent _____

Anhydrides are excellent ELECTROPHILES!

  • The two carbonyl carbons are highly reactive to nucleophiles
    • because the leaving group is a resonance-stabilized carboxylate ion

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41

  • Carboxylic Acids
    • Decarboxylation
      • Draw a mechanism for the base-catalyzed decarboxylation of a β-keto acid

  • Without a base catalyst, this mechanism can also be visualized as a 6- member, concerted, “ring-like” intramolecular reaction
    • ....that does not require protonation of the enolate ion

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42

  • Carboxylic Acids
    • Describe "Decarboxylation"
      • What is lost, what is left behind?
      • What does the process usually require?

Decarboxylation

  • The loss of a CO2 molecule from a beta-keto carboxylic acid
    • leaving behind a resonance-stabilized carbanion
  • The process usually requires catalysis by a base
  • The carboxylate ion usually retakes the hydrogen from the base, forming a keto-enol tautomer

43

  • Carboxylic Acids
    • Esterification
      • Define
      • Formula=?
      • What is required 1st in order for this rxn to proceed?
      • How can you get higher yields?
      • Esterification is how ____s are formed

Reaction of an alcohol with a carboxylic acid to form an ester (ROR)

RCOOH + ROH ⇒ RCOOR + H2O

  • The hydroxyl group will never leave without being protonated first
    • ....to form the “good leaving group water”
      • thus this reaction requires an acid catalyst
  • ​Higher yields can be obtained by reacting an anhydride with an alcohol

This is how triacylglycerols are formed:

  • A glycerol undergoes esterification with three fatty acids

45

  • Carboxylic Acids
    • Nucleophilic Attack of Carbonyls 
      • Formula=?

(ex: __+__⇒__)

RCOOH + H2O ⇒ RCOOH2+ + Nu:⇒ RCONu + H2O

46

  • Carboxylic Acids
    • Physical Properties
      •  Surprisingly, short-chain carboxylic acids are also soluble in many relatively non-polar solvents
        • Such as chloroform (even though they are clearly polar)
      • Provide a possible explanation for this observation

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  • Theoretically, the carboxylic acid dimer (pictured below) would have no net dipole moment

This explains its solubility in non-polar solvents

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48

  • Carboxylic Acids
    • Describe the "3 Key Features of Carboxylic Acids"

  1. Resonance Stabilization
    • The carboxylate ion is uniquely stable due to resonance stabilization
  2. Induction
    • Alpha substituents can either donate or withdraw from the carboxylate ion
      • increasing or decreasing acidity
        • REMEMBER: To predict acidity examine the stability of the conjugate base!
          • (A principle applicable to any acid)
  3. Hydrogen Bonding
    • It is worth mentioning twice; don’t forget that carboxylic acids can not only hydrogen bond, but do it twiceto form dimers

50

  • Carboxylic Acids
    • Definition
    • Nomenclature
    • What are some common acids whose non-IUPAC names you should know? (3)

 A carboxylic acid is any compound containing a carbonyl with a hydroxyl substituent on the carbonyl carbon

NOMENCLATURE

  • Carboxylic acids are named with the “-oic acid” ending
  • A carboxylate ion is the result of abstraction of a proton
    • leaving a negative charge on the oxygen
  • Carboxylate ions are named with an “-ate” ending
    • e.g., formic acid ⇒formate
  • If it is a salt formed between the carboxylate ion and a metal:
    • name the metal first
    • then the ion
    • e.g., benzoic acid⇒benzoate⇒sodium benzoate

Common Names:

  • There are few common acids for which the MCAT will use non-IUPAC names
  • These include:
    1. Formic acid (HCOOH)
    2. Acetic acid (CH3COOH)
    3. Benzoic acid (C6H5COOH)

51

  • Carboxylic Acids
    • Physical Properties
      • Describe BP & Solubility properties

  • Carboxylic acids have very high boiling points
    • due to their ability to form strong dimers involving two hydrogen bonds
  • Without 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)

52

  • Define "Electrophiles"

"Electron lovers"

  • is attracted to e-s / e- rich centers
  • Usually POSITIVELY CHARGED

53

  • Describe Nucleophilic Addition
    • What reacts with what?
    • What happens as a result? (2) 

  • Is an addition reaction 
  • Here, a compound with a double or triple bond (aka one that has 1 or 2 π bonds)
    • ...reacts with electron-rich reactant ("nucleophile") 

As a result:

  1. Disappearance of the double bond
  2. Creation of two new single ("σ") bonds

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53

  • Describe Nucleophilic Substitution (both kinds)

  •  Here, an electron nucleophile selectively bonds with (or attacks) the positive or partially positive charge of an electrophile or a group of atoms

...to REPLACE a so-called "leaving group"

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55

  • Esters
    • Describe "Saponification"
      • How does it utilize an ester? 
      • What 2 things does it yield?
      • Describe the 3 steps 

Saponification (HYDROLYSIS OF AN ESTER)

  • Hydrolysis of an ester to yield:
    1. an alcohol 
    2. the salt of a carboxylic acid

STEPS:

  1. The 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 associates with the Na+ or K+ in the solution to form “soap”

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56

  • Esters
    • INorganic Esters
      • Familiar Examples
        • ATP, GTP and UTP are examples of inorganic ______ esters
        • FADH2 and NADH are examples of ______ esters 
        • FMN, DNA and RNA are examples of ______ esters

Familiar Examples:

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

58

  • Esters
    • Properties
      • Esters act as H-bond...?
      • Without LONG ALKYL CHAINS, esters are...?

Esters act as H-bond recipients, but NOT donors

  • Without long alkyl chains:
    • they are SLIGHTLY soluble in water
    • but LESS soluble than acids or alcohols

59

  • Esters
    • Describe "Transesterification"
      • What reacts with what to create what?
      • What else is req'd to carry out transesterification?
      • Formula=?

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

RCOORa + RbOH⇒RCOORb + RaOH

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60

  • Esters
    • Acetoacetic Ester Synthesis
      • = formation of ___ from a ___
      • Describe the 3 steps

Formation of a ketone from a β-keto ester

STEPS:

  1. A base abstracts the acidic alpha hydrogen, leaving a carbanion
  2. The 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

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61

  • Formation of Acetals/Hemiacetals and Ketals/Hemiketals
    • How can you tell them apart? 

Acetals/ketals

  • have two –OR substituents and​

Hemiacetals/hemiketals

  • have one –OR substituent plus one alcohol substituent (-OH group)

The MCAT will sometimes refer to both hemiacetals and acetals as simply “acetals

  • On other occasions they have differentiated the two
  • Be aware of both conventions

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61

  • Esters
    • Definition
    • Nomenclature
    • Common Names (3)

Definition:

  • An ester is any compound containing a carbonyl with an –OR group substituted on the carbonyl carbon

Nomenclature:

  • Esters are named with the "–oate" ending, with the R portion of the –OR group named and placed in front of the name
    • ex: "methyl" pentanoate

Common Names:

  • The common name applies to the second half of the name
  • The first portion of the name will be different for different R groups
    • We will use methyl for all three examples:
      1. methyl formate
      2. methyl acetate
      3. methyl benzoate

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62

  • Imines & Enamines are to Amines as ______ & ____ are to Carbonyls 

  • Ketones & Enols

64

  • INorganic esters
    • Draw a Lewis structure for:
      1. phosphoric acid
      2. sulfuric acid
      3. nitric acid

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65

  • Inorganic Esters
    • Draw: 
      • ​GTP

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65

  • Inorganic Esters
    • Draw: 
      • ​UTP

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66

  • Inorganic Esters
    • Draw:
      • ATP

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67

  • Lab Techniques
    • Chromatography (in general)
      • Generally speaking, the first substance “out” (of the tube, exit port, at the top of the paper, etc.) will be.....?

the LEAST POLAR    

68

Lab Techniques

  • Describe how "AFFINITY Chromatography" is used to separate molecules or products
    • To elute, the bound _____ molecules must disrupt  WHAT?
      • ​What 2 ways could you accomplish this?

Used to isolate a specific molecule or product based on:

  • a VERY SPECIFIC affinity or binding interaction

To elute, the bound target molecules must disrupt the binding interaction

This could be accomplished via:

  1. a SALT SOLUTION, but often requires
  2. a chemical REVERSAL OF THE RXN that BOUND the target TO the column

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70

  • Lab Techniques
    • Describe "Column Chromatography"
      • Which compounds will be eluted at the bottom of the column first?

  • The mixture to be separated is passed through a column packed with charged glass beads
    • or some other polar matrix
  • The solution is collected in fractions at the bottom of the column
    • i.e., the collecting tubes are changed at regular intervals

In column chromatography, assuming a polar matrix, the MOST NON-POLAR substances will elute first

  • followed by increasingly more polar substances

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71

  • Lab Techniques
    • Distillation
      • What must 2 substances have in order to be "distilled?"
      • What are the names of the 3 distillation techniques we need to know for the MCAT?

Distillation:

  • To separate two substances by simple distillation they must have boiling points that are at least 25˚C apart
  1. Simple Distillation
  2. Fractional Distillation
  3. Vacuum Distillation

73

  • Lab Techniques
    • Describe how "Recrystallization" works

How it Works:

  • The desired product (which still contains impurities) is dissolved in the minimum amount of hot solvent necessary to create a saturated solution
  • The solution is then cooled as slowly as possible
  • Because pure substances usually crystallize at a higher temperature than impure substances,
    • if the temperature is dropped just below the melting point of the product:
      • the crystals that form will be product 
      • the impurities will remain in solution

This is rarely a perfect process, but repeated cycles can produce an increasingly pure product

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74

  • Lab Techniques
    • Describe Ion-Exchange Chromatography

  • The column or stationary phase is coated with cations or anions 
  • The mixture is passed through and oppositely-charged ions adhere to the column
  • The target molecules can then be eluted
    • by washing with a salt solution

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75

  • Lab Techniques
    • Describe the "Simple Distillation" process
      • What 2 things can help improve the separation process?

  • Heat the mixture in a flask
    • the liquid with the lower boiling point evaporates first,
      • enters a collecting arm,
      • cools,
      • and drops into a collecting flask

To improve separation process:

  1. Cool the condensing arm or
  2. Place the collecting flask on ice 

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76

  • Lab Techniques
    • Describe the "Fractional Distillation" process

  • A fractionating column is placed between the heating flask and the condensing arm
  • The mixture is heated to slightly above the boiling point of the more volatile liquid
  • The gas rises through a column of glass beads or metal shards
    • This causes any impurities in the vapor (i.e., molecules from the liquid with the higher boiling point) to condense and fall back into the flask
      • resulting in a better separation
  • The more volatile component will be above its boiling point
    • and therefore will NOT condense
  • This approach allows separation of compounds with boiling points less than 25˚C apart

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77

  • Lab Techniques
    • Extraction
      • Describe how it works (4 steps)

How it Works:

  • The two solvents used will ideally have widely different polarities and densities, and will therefore create a distinct line of separation 
    • If the target product is already dissolved in a solvent that fits these requirements, it can serve as one of the two immiscible liquids
    • If not, the mixture containing the target will be added to the separatory funnel along with two other immiscible solvents
  1. The contents of the funnel are gently mixed or swirled
  2. The mixture is then allowed to sit until the two solvents are fully separated
    • If the target is a polar compound that was synthesized in a non-polar solvent then the target should easily move into the polar layer during mixing (like dissolves like)
    • If the target is a non-polar product it should readily move into the non-polar solvent
  3. After the two layers are fully separated, the bottom layer (usually aqueous) is drained out through the stopcock
  4. The solvent layer containing the product is then evaporated to obtain the target

78

  • Lab Techniques
    • Extraction
      • What are 4 ways to improve separation?

The separation can be aided by one or more of the following: 

  1. Repetition:
    • Rarely is a full separation obtained after only one cycle
  2. Fractional Extraction:
    • Extracting 5mL ten separate times will produce a much better separation than extracting 50mL all at once
  3. Addition of an acid
    • to protonate the product
  4. Addition of a base
    • to deprotonate the product

79

  • Lab Techniques
    • Extraction
      • Provide an explanation for why the addition of an acid or base might improve separation

  • An acid would protonate bases in the mixture,
    • potentially adding a formal charge and dramatically increasing solubility in the aqueous layer
      • i.e., protonated amines
  • Bases could similarly abstract protons to create a negatively charged species—with the identical impact upon solubility
    • i.e. deprotonated carboxylic acids

81

  • Lab Techniques
    • Extraction
      • 3 Things to Avoid

  1. Mixing TOO vigorously
    • This can result in the formation of emulsions that are difficult to separate
  2. Reactive solvents
    • The chosen solvents should not be reactive with:
      1. Each other
      2. The targeted product
  3. High boiling point
    • If a solvent with a high boiling point is used, it will be difficult to evaporate off the solvent to obtain the product

82

  • Lab Techniques
    • Describe "Extraction"
      • What is its purpose (2)?
      • Two ____ liquids, a ___, and a __-___ are used
      • What does the separation depend on?

Purpose:

  • Used to:
    1. Separate two compounds
    2. To remove a desired product from a reaction mixture

Two immiscible ("un-mixable") liquids, a polar (aqueous) and a non-polar (organic) are used

  • ​The separation depends on the target molecule having differential solubility in the two solvents

83

  • Lab Techniques
    • Describe "Gas Chromatography" 
      • On a gas chromatograph, how many peaks will there be for each unique compound in the mixture?
      • What causes one peak to be higher than another on a gas chromatograph?

Gas Chromatography:

  • A liquid is used as the stationary phase
  • The mixture is dissolved into a heated gas and then passed through the liquid
  • Various components reach the exit port at different rates based on
    1. Boiling point, and
    2. Polarity
    • Only consider polarity if the two substances have almost identical boiling points

On a gas chromatograph, there will be one peak for each unique compound in the mixture

  • The height of the peak in a gas chromatograph is relative to the ABUNDANCE of that component

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84

  • Lab Techniques
    • Describe "Gravity Filtration"
      • What is the purpose of using fluted filter paper? 

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  • Physical separation of a solid (either crystallized product or solid impurities) from a liquid by passing it through filtration paper
    • Fluted filter paper is recommended

Fluted filter paper increases the surface area for filtration

84

  • Lab Techniques
    • Gravity Filtration
      • It is sometimes preferable to filter a mixture while it is still hot or to use a hot solvent
      • Other times, it is recommended to use a cold solvent during filtration
      • Why?

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Whether you would want to filter hot or cold would be determined by the conditions

  • If you are filtering out a solid impurity, filtering hot could prevent your product from crystallizing on the filter paper
  • However, if you are close to the freezing point of the solid then filtering hot could bring impurities back into solution
  • In other cases you may be trying to capture product that crystallized upon cooling of your reaction mixture
  • In that case you would certainly want to fitler cold or else you would redissolve your product

85

  • Lab Techniques
    • IR Spec
      • What does an IR Spec look like for Hexanoic Acid?

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  • Notice how the O-H and C=O absorbances OVERLAP

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86

  • Lab Techniques
    • IR Spec
      • Describe the similarities between vibrational frequency in:
        • IR spectroscopy
        • a mass-spring system ("Hooke's Law")
      • How do bond strength and molecular weight impact frequency?
      • Wrt Hooke's Law, what are bond strength and MW analogous to?

  • The bond roughly follows Hooke’s Law
    • and either atom can be compared to the mass
  • A STRONGER bond
    • is analogous to a spring with a larger spring constant (k)
    • (∴ a weaker bond would be analogous to a spring with a smaller spring constant)
  • The MW of the atom
    • is analogous to the size of the mass on the spring

PER HOOKE'S LAW: 

Stronger spring (larger k) increases oscillation frequency according to:

f = ½π √k/m

  • A weaker bond would therefore vibrate at a lower frequency

A smaller atom (lower MW) has a higher vibrational frequency

  • ∴ a larger atom has a lower vibrational frequency

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87

  • Lab Techniques
    • IR Spec
      • What 2 things determine the "Vibrational Frequency" of polar bonds?
      • Do IR absorbances represent the entire molecule?

The Vibrational Frequency is determined by:

  • 1) Strength of the bond
  • 2) MW of the bonded atoms 

 

IR absorbances do NOT represent the entire molecule

  • They only represent a single polar bond in the molecule 

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88

  • Lab Techniques
    • IR Spec
      • What does an IR Spec for Diethylamine look like? 
      • CH3CH2NHCH2CH3

  • Notice how shallow the amine absorption is

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88

  • Lab Techniques
    • IR Spec
      • What does an IR Spec for acetonitrile look like? 

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  • Notice how sharp and deep the absorbance for the C-N triple bond (nitrile) is 

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89

Lab Techniques

  • IR Spec
    • 7 IR Absorbances 
      • How many cm-1?
      • Characteristics (ex: broad, deep, etc.)

  1. Carbonyl, C=O
    • 1700 cm-1
    • sharp, deep
  2. Alcohol, OH
    • 3300 cm-1
    • broad, separate from CH
  3. Saturated Alkane, CH
    • 2800 cm-1
    • sharp, deep
  4. Carboxylic Acid, OH
    • 3000 cm-1
    • broad, overlaps CH
  5. Amine, NH
    • 3300 cm-1
    • broad, shallow
  6. Amide, NH
    • 3300 cm-1
    • broad, deep
  7. Nitriles, C≡N
    • 2250 cm-1
    • sharp, deep

90

  • Lab Techniques
    • IR Spec
      • What does an IR Spec for Ethanol look like? 

notice the OH stretch 

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92

  • Lab Techniques
    • IR Spec
      • How does it work?
      • What does a bond need to have in order to show up?
      • What do we vary to produce an IR spec?
      • What exactly is the thing the detector is picking up?

IR (Infrared) Spectroscopy

How it Works:

  • If a bond has a DIPOLE, exposing that bond to an external electric field will cause the atoms to move within that field
    • much like a charged particle attached to a spring
  • Infrared radiation is used to create an oscillating electric field
    • which in turn causes dipolar bonds to oscillate at a specific "vibrational frequency"
  • To produce an IR spectrum, we slowly vary the frequency of the IR radiation.
  • When the IR radiation exactly matches the frequency of vibration of a particular bond, that bond is said to be in “resonance”
    • and it will absorb some of the IR energy
      • This absorbance is what is picked up by the detector
  • A bond with no dipole will NOT be detected by IR

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93

  • Lab Techniques
    • Paper or Thin-Layer Chromatography
      • Where are the samples placed?
      • Where should the level of the solvent be relative to the samples?

  • The sample is usually a mixture of components which is spotted onto the paper or TLC plate near its bottom edge
  • The top of the solvent should always be below this line where the sample is spotted
    • so that the mixture does not simply dissolve into the solvent

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95

  • Lab Techniques
    • Paper or Thin-Layer Chromatography
      • Rf = 0.9 
        • is the substance in question polar or non-polar?

Rf is a ratio of the distance traveled by the component over the distance traveled by the solvent

  • So a number close to one means that the polarity of the component is similar to that of the solvent
    • Because non-polar solvents are normally used, the component is therefore relatively non-polar

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96

  • Lab Techniques
    • Paper or Thin-Layer Chromatography
      • During TLC or Paper Chromatography, components will sometimes form an upward “smear” instead of forming a cohesive dot

      • Provide some possible causes of smearing

  • Smears are usually caused when the solvent is unable to dissolve and carry the components as it moves up the paper via capillary action
    • This can be because too much of the sample was spotted onto the paper and the solvent could not dissolve ALL of the sample
  • It can also occur if there is too big of a difference in polarity between the sample and the solvent
    • If the polarities are too distant the solvent cannot dissolve the sample well enough to carry it
    • By a similar token, if they are too similar, the components may never come out of solution to form a spot and be carried all the way to the top of the paper

97

  • Lab Techniques
    • Recrystallization
      • A student tests the melting point of his crystals to determine purity
      • Does a HIGHER melting point indicate more purity or less?

  • Higher and sharper melting points indicate better purity
  • Impurities lower melting point
    • They also broaden the range across which the crystals melt

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98

  • Lab Techniques
    • UV Spectroscopy
      • How does it work?

 How it Works:

  • The energy difference (in Joules) between two adjacent molecular orbitals, on average, just happens to be about the same amount of energy created by electromagnetic radiation in the UV spectrum
    • Thus, when UV radiation is shone on a molecule, electrons within that molecule will often absorb that energy and “excite” to the next highest energy level
    • This absorbance is recorded on a UV spectrum

100

  • Lab Techniques
    • UV Spectroscopy
      • How much UV absorbance do each of the following exhibit?
        • Single bonds
        • Double & Triple bonds
        • Conjugated Systems
          • More conjugated=farther to?
      • A UV Spectrum is a graph of ___ vs. ___

  • Molecules containing only single bonds show low or no UV absorbance
  • Double and triple bonds absorb UV strongly
    • double
  • Conjugated systems absorb UV even more strongly than do isolated double or triple bonds.
    • The greater the degree of conjugation, the farther to the right the species will absorb 

      • i.e., at a higher wavelength

  • A UV spectrum is a graph of absorbance vs. wavelength (nm)

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101

  • Lab Techniques
    • What is "Vacuum Filtration" and how does it differ from gravity filtration?
    • What are the advantages of vacuum filtration?

  • Vacuum filtration is performed with a Hirsch or Buchner funnel 
  • A vacuum is created inside of the flask which creates suction to pull the filtrate through the filter paper
    • The filter usually has holes in it which are covered by the filter paper

The primary advantage is that it is FASTER than gravity filtration

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102

  • Lab Techniques
    • Paper or Thin-Layer Chromatography (TLC)
      • How do Paper & Thin-Layer Chromatography differ?
      • What does Rf represent?

Paper or Thin-Layer Chromatography (TLC):

  • Paper chromatography uses paper as the stationary phase.
  • Thin-Layer Chromatography (TLC) is nearly identical
    • ...but uses manufactured glass or plastic sheets coated with silica, alumina, etc.

Rf =

  • distance traveled by component, OR
  • distance traveled by solvent

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103

  • Lab Techniques
    • Describe "Vacuum Distillation"
      • Explain why a vacuum would be established inside the apparatus
      • In what cases would one want to use vacuum distillation?
      • Explain how the boiling point is altered during vacuum filtration

Vacuum Distillation

The air inside the apparatus is evacuated to create a vacuum 

  • Vacuum filtration is used because it dramatically lowers the boiling point,
    • allowing you to work at more manageable temperatures with substances that have much higher boiling points at atmospheric pressure
  • This observation is supported by the fact that liquids can be said to boil at the point where vapor pressure equals atmospheric pressure
    • By creating the vacuum, we essentially drive down the atmospheric pressure to meet the vapor pressure

 

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104

  • Lab Techniques
    • Describe Chromatography (in GENERAL)

Separation of one or more compounds by dissolving them in a “mobile phase” and then passing that phase through or across a “stationary phase”

  • The substances in the mobile phase interact to varying degrees with the stationary phase based on their polarity
  • The more interaction that occurs between the two phases
    • the SLOWER the substance will move
  • Substances that do not interact with the stationary phase (or do so to the least degree), will move the FASTEST

105

  • Mass Spectrometry
    • and its connection with PHYSICS
      • If the velocity of particles in the flight tube of a mass spectrometer is held constant while the strength of the magnetic field is increased linearly, how will the mass of particles striking the detector vary with time?
      • Draw a graph of particle mass vs. time for this scenario

  • A linear increase in the magnetic field will create a linear increase in the force exerted on the particles according to:

F = qvBsinθ

  • For a curved flight tube with a detector at the far end, in order for any particle to strike the detector:
    • It must experience exactly the right centripetal acceleration to trace the precise curvature that results in striking the detector
      • As the centripetal force increases, this will occur for increasingly massive particles

The graph below shows the linear relationship between magnitude of the B field and mass of particles at the detector 

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106

  • Mass Spectrometry
    • Describe what these represent:
      • The Height of each peak
      • The Parent peak
      • The Base peak

  • The Height of each peak
    • gives the relative abundance of that fragment
  • The Parent peak
    • represents the original molecule minus one electron 
      • a.k.a. "Molecular Ion Peak"
  • The Base peak
    • is the most common fragment
      • is usually the most stable fragment generated 
      • It is defined as existing at 100% relative abundance
        • In other words, it will be the highest peak on the spectra and the height of all other peaks will be a function of how abundant THAT fragment is compared to the base peak

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108

  • NMR Spectroscopy
    • C13-NMR Spectra
      • What are the 4 Absorbances you should know?
      • How is C13-NMR analogous to IR Spec?

C13-NMR Absorbances you should know:  

  • C – C
    • 0-50ppm 
  • C – O
    • 50-100ppm 
  • C = C
    • 100-150ppm 
  • C = O
    • 150-200ppm

Somewhat Analogous to IR:

  • Whereas H-NMR peaks represent unique hydrogen environments, C13-NMR peaks represent carbon functional groups
    • This is more similar to IR, where the number associated with the absorbance helps you predict the functional group
  • In H-NMR we do not memorize numbers because although they DO tell us the relative degree of shielding, they DON'T directly correlate with specific functional groups

109

  • NMR Spectroscopy
    • How it works
      • Nuclear spin causes small changes in the electric field and a changing electric field creates a ____________.

MAGNETIC FIELD, B

110

  • NMR Spectroscopy 
    • How it works (This is also how MRI's work!)
      • What does the external magnetic field do?
      • What are the nuclei exposed to then?
      • Where do the actual NMR absorbance levels come from? 
      • How does the concept of "shielding" by neighboring Hydrogens factor into all this?

  • All nuclei with an odd atomic or mass number have what is called "nuclear spin"
    • —a concept analogous to electron spin 
  • When an external magnetic field is applied to a group of nuclei they will align their own magnetic fields with the direction of the external field
  • Then, if photons are shone onto the nuclei, some of the nuclei will be able to absorb this photon energy and flip their orientation
    • so that they are lined up AGAINST the external field
      • It is THIS absorbance of energy that is picked up by NMR
    • Different nuclei will require a different frequency photon (i.e., different amount of energy) to cause this flip in orientation 
      • These differences are caused by the degree to which each nucleus is shielded by neighboring hydrogens

111

  • NMR Spectroscopy
    • Propose an H-NMR spectrum for:
      • tert-butyl alcohol
      • Label each peak with the hydrogen environment it represents

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112

  • NMR Spectroscopy
    • Propose an H-NMR spectrum for:
      • 1-bromopropane 
      •  Label each peak with the hydrogen environment it represents

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113

  • NMR Spectroscopy
    • H-NMR Spectra
      • Absorbance Range: __– __ ppm
        • What do the min & max values mean wrt shielding/ deshielding?
        • What reference compound is used? What ppm is it at?

  • Absorbance Range: 0 – 12 ppm
    • 12 ppm is Downfield = Deshielded
    • 0 ppm is upfield = shielded

 

  • ​The reference compound tetramethyl silane
    • Si(CH3)4, or "TMS"
    • is defined as 0 ppm

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115

  • NMR Spectroscopy
    • Reading C13-NMR Spectra
      • What are 2 differences b/t C13-NMR and H-NMR Spectra?
      • Absorbance Range: __-__ ppm
        • What do the min & max values mean wrt shielding/ deshielding?

Important Differences:

  1. NO spin-spin splitting
    • i.e., all peaks are singlets
  2. NO integration
    • i.e., area under the curve does NOT indicate the relative number of carbons
  • Absorbance Range: 0 – 220 ppm
    • 220 ppm is Downfield = Deshielded
    • 0 ppm is upfield = shielded

Reference compound= Tetramethyl silane

  • "TMS," or Si(CH3)4 
  • is defined as 0 ppm

116

  • NMR Spectroscopy
    • T/F?
      • When performed on a large, complex steroid molecule, C13-NMR will detect the presence of every carbon with a distinct chemical environment

FALSE.

  • ​C13-NMR on a large steroid would NOT detect every single carbon
    • because it only detects the carbon-13 isotope
      • which has a relative abundance of only about 1%

117

  • NMR Spectroscopy
    • What does eack peak represent?
    • Describe "Spin-Spin Splitting" 
      • What causes a peak to split?
      • What formula determines how many sub-peaks it will be split into?
      • What do the number of sub-peaks tell us?

Peaks:

  • Each peak represents all of the hydrogens in a molecule that share an indistinguishable chemical environment
    • These are called "equivalent hydrogens"

Spin-spin splitting:

  • The presence of “neighbors” (non-equivalent hydrogens attached to a neighboring carbon) causes splitting of the peak
  • The peak for a set of equivalent hydrogens will be split into exactly n + 1 sub-peaks
    • where n is the number of non-equivalent hydrogen neighbors
  • The number of these sub-peaks tells you how many hydrogens are represented by that peak
    • (# of sub-peaks – 1)
    • This will assist you in deducing which parts of a molecule are represented by each peak

118

  • NMR Spectroscopy
    • Propose an H-NMR spectrum for:
      • Isopropanol

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120

  • NMR Spectroscopy
    • What is this technique used for?
    • Which of the 2 types will be most heavily tested?
    • What must an atom have in order to show up on an NMR? (2 options)
    • For the MCAT, think of MRI's as...?

  • This technique is used to differentiate molecules based on the differing chemical environments of:
    • their hydrogen nuclei (H-NMR), or 
    • their carbon nuclei (C 13 -NMR)
  • On the MCAT, however, H-NMR will be tested about ninety percent of the time
  • An atom must have either:
    • an odd atomic number or
    • an odd mass number

​... to register on an NMR

  • For the MCAT, think of MRIs as an NMR of the human body

121

  • Aldehydes & Ketones
    • Protecting Ketones/Aldehydes from Reaction 
      • Ketones or aldehydes can be prevented from reaction with a _____ or ____ by conversion to an ____ or _____
      • Describe the 3 steps 

  • Ketones or aldehydes can be prevented from reaction with a nucleophile or base by conversion to an acetal or ketal (which are UNreactive in all but acidic conditions)
    • Any terminal diol with at least two carbons will work

STEPS:

  1. One end of the diol acts as the nucleophile 
    1. An alcohol acts as the nucleophile, attacking the electrophilic carbonyl carbon and pushing the pi electrons from the C=O bond up onto the oxygen
    2. The negatively charged oxygen is protonated to form an alcohol and the original alcohol is deprotonated to form an ether. This yields a hemiacetal if it was originally an aldehyde, or a hemiketal if it was a ketone.
  2. The other end of the diol acts as the “second equivalent of alcohol” 
    1. The alcohol is protonated again to form the good leaving group water, and a second equivalent of alcohol attacks the central carbon as shown below
    2. Deprotonation of the second alcohol results in another ether, yielding an acetal if it was originally an aldehyde or a ketal if it was a ketone.
  3. Acidic conditions will return the acetal/ketal to the original aldehyde/ketone

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122

  • Substitution of Acid Derivatives
    • Mechanism Notes
      • ​Recall that the intermediate is ____, that does what?
      • Which substituent will LEAVE as a result of this collapse depends solely on....?
      • Often, the ____ _____ is the better LG, so the original acid derivative is ________ed

  • Recall that the intermediate is:
    • an oxygen anion that collapses down to re-form the carbonyl
  • Which substituent will leave as a result of this collapse depends solely on:
    • its quality as a leaving group
  • Often, the attacking nucleophile is the better LG, so the original acid derivative is simply reformed

123

  • Substitution of Acid Derivatives
    • Mechanism Notes
      • A nucleophile can be added to any carboxylic acid or acid derivative and it will...?
      • Only sometimes, however, will the result be substitution of ___ for ___

  • ​A nucleophile can be added to any carboxylic acid or acid derivative and it will attack the carbonyl carbon
  • Only sometimes, however, will the result be substitution of that nucleophile for the existing substituent

124

  • Substitution of Acid Derivatives
    • Mechanism
      • Ranking of acid derivative LG (best to worst):
        • Cl-
        • -OCOCH3
        • -OH
        • -OCH3
        • -NH2
      • Use structure and function to explain the ordering of each of the above leaving groups

(Best LG) Cl- > -OCOR > -OH > -OR > -NH2 (Worst LG)


Chlorine is the best leaving group because it is a weak base

  • ...that is remarkably stable while holding a formal negative charge
  • This ability to hold a charge is due to the size of chlorine’s electron butt
  • The negative charge is spread out across a much larger distance than it would be for a smaller atom
  • For this reason, bromine would be an even better leaving group, and iodine better yet
  • The –OCOR group is the leaving group portion of an anhydride—the portion kicked off when a nucleophile attacks one of the carbonyl carbons
    • It is a carboxylate ion stabilized by resonance
      • That stabilization makes it much more stable than other leaving groups that place a negative charge on an oxygen

Hydroxide and alkoxide are best compared together

  • It should be noted that under acidic conditions, hydroxide gets the nod as the better leaving group
    • because –R groups are weak donating groups
  • Hydrogen, by comparison is considered neither donating, nor withdrawing
  • Therefore, the –R group on an alkoxide donates more electron density
    • ​...to an oxygen that already bears a full negative charge
  • Under basic conditions the acidic hydroxide gets deprotonated and does not act as a leaving group, therefore only the alkoxide RO can act as a leaving group

Finally, an amine makes a relatively awful leaving group because when it leaves it forms the strong base NH2 -

  • This is a stronger base than hydroxide or alkoxide and therefore is the most unstable bearing a full negative charge
  • This is the reason that amides are the LEAST REACTIVE of the acid derivatives

125

  • The Carbonyl FG
    • A carbonyl is SHORTER and STRONGER than an alkene
    •  Why?
    • Propose an explanation for the greater strength and shorter bond length of a carbonyl compared to an alkene

ALKENE

  • An alkene involves a sigma and a pi bond between two carbons

​CARBONYL

  • A carbonyl involves a sigma and a pi bond between a carbon and an oxygen

Whenever you think about pi bonds, one of the first things you should consider is the amount of overlap of the p orbitals

  • Compared to two carbons, a carbon and an oxygen can get closer to one another
    • because oxygen has a smaller atomic radius
    • This allows for more pi overlap and therefore a stronger bond

126

  • NMR Spectroscopy
    • What does the AREA UNDER THE PEAK tell us?
      • What is an "integral trace" and how does it relate to the area under the peak?

Area Under the Peak:

  • This is a relative representation of the number of hydrogens accounted for by that peak
  • An "Integral trace" (a step-wise line superimposed across the spectrum) makes this easier to determine
    • The relative area under each curve is given by the height of each step.
      • By “relative” we mean that if one peak is 2 units high and the other is 6 units high, this tells you only that the latter is accounted for by 3 times the number of hydrogensNOT that the first peak accounts for 2 hydrogens and the second for 6 hydrogens

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127

  • The Carbonyl FG
    • Draw resonance structures for the stabilization of the conjugate base of an alpha hydrogen 

  • There are two resonance structures for the conjugate base formed by removal of an alpha hydrogen
  • Remember that neither form actually exists
    • —the actual structure is a permanent hybrid of the two
  • In this case, the hybrid will look slightly more like the second structure
    • because the negative charge is on the more electronegative oxygen

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128

  • The Carbonyl FG
    • Rank the following structures in terms of increasing acidity of the alpha hydrogens
      1. CH3COCBr3
      2. CH3COOH
      3. CH3CONH2
      4. CH3COCH3

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3

  • These structures differ in the substituents attached to the carbonyl carbon
    • An electron donating group on the carbonyl carbon will decrease its partial positive charge and thereby make it less able to stabilize the conjugate base
    • An electron withdrawing group will make the carbonyl better at stabilizing the conjugate base and therefore the strongest electron withdrawing group would indicate the strongest acid
      • because it produces the most stable conjugate base
  • #1
    • is the only electron withdrawing group, so it will have the most acidic alpha hydrogens
    • Bromines are BIG!
      • "Suck away" electrons 

The weakest donating group of the other three is the methyl group on #4 

  • Amines (#3) and hydroxyl groups (#2) are both electron donating
    • but amines are better donating groups
      • because nitrogen is less electronegative than oxygen

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130

  • The Carbonyl FG
    • Suggest a scenario in which an addition reaction involving a carbonyl carbon with two non-identical substituents would NOT result in a racemic mixture

  • This scenario would occur if the carbonyl was of the form R1COR2
  • ...and the nucleophile was something such as a Grignard Reagent (R-MgBr)
    • ​...that added either R1 OR R2 to the carbonyl carbon
      • Because two of the substituents would be identical, it could not be chiral
  • This could also happen if water or hydroxide were added to the bond, creating two –OH substituents

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131

  • The Carbonyl FG
    • What are the "5 Key Features of Carbonyls?"

  1. Partial positive charge on the carbonyl carbon
    • This makes the carbon a good electrophile
  2. α hydrogens
    • Hydrogens on the α carbon are surprisingly acidic
      • --especially given that alkane hydrogens normally CANNOT be removed
  3. Electron donating/withdrawing groups
    • The reactivity of a carbonyl with a nucleophile is dramatically affected by the presence of electron donating or electron withdrawing groups on the carbonyl carbon
      • Donating groups: 
        • decrease the reactivity of the carbonyl carbon
      • Withdrawing groups: 
        • increase its reactivity
  4. Steric hindrance
    • Bulky substituents attached to the carbonyl carbon decrease its reactivity
  5. Planar stereochemistry
    • The sp2 hybridized carbonyl carbon is planar
      • and can therefore be attacked from either side
    • When the two substituents on the carbonyl carbon are NOT identical, an addition reaction could therefore create both R and S enantiomers in a racemic mixture

132

  • The Carbonyl FG
    • α Hydrogens 
      • Describe (Hint: Acidity...)

  • Hydrogens on a carbon adjacent to a carbonyl carbon are ACIDIC 
    • due to resonance stabilization of the conjugate base
  • When there are two carbonyls separated by a single carbon (i.e., 1,3-dicarbonyls), hydrogens on the middle carbon are even more acidic
  • The greater the partial positive charge on the carbonyl carbon... 
    • the more acidic its alpha hydrogens will be
    • For this reason, be on the lookout for electron donating and withdrawing groups on the carbonyl carbon

133

  • The Carbonyl Functional Group 
    • Definition=?
    • What analogs of a carbonyl can you treat in the same way as you would a carbonyl?

A carbonyl is a carbon double bonded to an oxygen

  •  For the MCAT, you can treat most carbonyl analogues, such as S=O or N=O, as you would carbonyls

However, it is quite possible that the MCAT would require you to use your basic knowledge of electronegativity, bond polarity, atomic radius, etc., to predict difference in reactivity between an analogue and a carbonyl

134

  • Mass Spectrometry
    • How does it work?

How it works:

  • The molecules of the sample are bombarded with electrons
    • causing them to both break apart into smaller pieces, and ionize
  • This will happen in a random way
    • producing fragments with different masses and charges
  • These fragments are accelerated through a narrow curved magnet called a “flight tube”.
  • Only particles with a certain mass-to-charge ratio (m/z) will follow the exact curved path necessary to NOT hit the walls and exit onto the detector at the end of the flight tube.
  • The strength of the magnetic field is varied from low to high
    • ...changing the curvature of each fragment until all of the fragments have struck the detector

135

  • What will a COLD, DILUTE acid do to an alkene?

  • It will turn it into an ALCOHOL

136

  • The "MAJOR Product" is usually the most ________ed product

Most SUBSTITUTED

 

(Think of alkenes)

137

What is the PRIMARY RESULT of:

GRIGNARD RXNS

What does a GRIGNARD REAGENT (generally) look like?

  • The formation of an additional C-C bond

Grignard Reagent:

RMgX

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138

2° ROH's are OXIDIZED into what?

Does it get oxidized any further?

 

Ketones

is NOT oxidized further

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139

1° ROH's are OXIDIZED into what?

Does it get oxidized any further?

First gets oxidized to ALDEHYDES

With 2+ equiv of oxidizing agent, gets oxidized again into CARBOXYLIC ACIDS

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140

When 2 equiv of a strong REDUCING agent LiAlH4 are reacted with a Carboxylic Acid, a ___° ROH is produced. 

The intermediate in this rxn is best described as...?

  • Strong reducing agents such as Lithium Aluminum Hydride essentially produce basic hydride ions that can attack electrophiles
  • The carboxylic acid will be attacked by the hydride--
    • pushing the double bond up onto the oxygen as a lone pair
  • In any protic solvent this will be protonated to form a hydroxyl group

A gem diol is an exact description of the intermediate, two hydroxyl groups attached to the same carbon

Recall that two hydroxyl groups on neighboring carbons is called a vic diol

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141

What happens in a PINACOL REARRANGEMENT?

  • What type  of "diol" does it require?
  • Describe the 4 steps

Pinacol (below)

 

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Pinacol rearrangement

  • Requires a VIC-diol
    • OH's on neighboring C's

Involves:

  1. the spontaneous disassociation of one of the protonated alcohols
  2. followed by a methyl shift
  3. Following the methyl shift, the other alcohol’s hydrogen is abstracted
  4. and the electrons condense to form a carbonyl
    • ...and quench the carbocation

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142

How do ALDEHYDES compare in acidity to Water and Alcohols?

How does water compare with alcohol? Which is less acidic, and why?

Aldehydes are LESS acidic than either water OR alcohols!

  • Water and alcohols are similar in acidity, but you can compare them by looking at the conjugate bases
  • The alcohol’s conjugate base has an electron donating group ("R") destabilizing the negatively charged oxygen
    • making it less stable
      • therefore less acidic
  • Water doesn't have an e' donating group, therefore the negatively charged Oxygen is more stable (remember: Oxygen LOVES having a (-) charge!)
    • thus more acidic

143

Tosyl chloride (Ts-Cl) is traditionally used to protect _______s or other types of __________s.

HOW does it protect it?

Tosyl chloride is traditionally used to protect alcohols or other nucleophiles

The alcohol attacks the tosyl chloride and becomes "tosylated"