23.1 introduction to amines - organic chemistry help ... · klein, organic chemistry 1e why does...

• Amines are derivatives of ammonia:

• Amines are designated as primary, secondary, or tertiary.

• The terms 1°, 2°,and 3° are used differently for amines than for alcohols. HOW?

23.1 Introduction to Amines

Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e 23-1

• There are hundreds of examples of amines found in natural products.



• Some naturally occurring amines take part in neurochemistry.



• The trigonal pyramidal nitrogen atom of an amine carries a partial negative charge on its lone pair.

• HOW do you think the amine is likely to react?



• Amines often react as a base or as a nucleophile.

• What feature(s) of the amine do you think might determine whether it is more likely to act as a base or as a nucleophile?



• The N atom in typical amines is sp3 hybridizes.

• The angles are 108 degrees. WHY?

• The C–N bond lengths are 147 pm, which is slightly shorter than C–C bonds. WHY?

• Under what circumstances would the nitrogen be sp2 hybridized?

23.3 Properties of Amines


• N atoms with three different alkyl groups are chiral.

• Chiral compounds are generally optically active. WHAT does that mean?

• Amine are generally not optically active. WHY?



• Amines with fewer than 5 carbons are typically soluble in water. WHY?

• Explain the boiling points below.



• Many small molar mass amines have unpleasant odors.



• Amines are generally stronger bases than alcohols and ethers. WHY?

• Amines can be readily protonated by strong and weak acids.

• Explain the direction of the equilibrium.

• HOW can basicity be quantified using pKa values?



Klein, Organic Chemistry 1e

Why does the conjugate acid of pyrrole have a lower pKa

(making pyrrole a weaker base) than pyridine or

pyrimidine? HN

N

N

N

pyrrole pyridine pyrimidine

a. Because pyrrole is smaller and more compact and this prevents its lone pair

from reacting as much.

b. Because pyrrole has less carbons and therefore the lone pair is more active.

c. Because pyrrole's lone pair participates in the delocalized electron cloud,

while pyridine's and pyrimidine's lone pairs do not.

d. Because pyrimidine has more lone pairs than pyrrole does.

which is more basic?

15

**Electrons in sp2 orbitals are held more strongly than sp3

Basicity of arylamines

17

• In general, amines with more than FIVE carbons are only slightly soluble in water.

• Solubility is enhanced in the presence of aqueous acid. WHY?

• Describe how an amine could be EXTRACTED from organic impurities using an aqueous acid.



• The pKa of most alkyl amine conjugate acids are between 10 and 11.

• Ammonium ions of aryl amines are more acidic. WHY?

• Are amides also basic? WHY?



Amines + R-X

20

explain

21

Gabriel Synthesis: Avoids multiple alkylations

• step 1

• Step 2

• Step 3

22

• Many biomolecules exhibit amine moieties.

• Let’s examine the equilibrium between amine and ammonium ion at physiological pH (7.3).

• The amine and the conjugate acid make a buffer. HOW?

• Recall that the Henderson-Hasselbalch equation can be used to calculate the pH of a buffer.



• Assuming the pKa of the conjugate acid is 8.3 in the example of an antihistamine, calculate the ratio of amine/ammonium ion.

• Practice with CONCEPTUAL CHECKPOINT 23.9.



• Let’s review all of the methods we’ve learned in previous chapters to synthesize amines.

1.

– Carbon skeleton expanded by 1 carbon.

23.4 Preparation of Amines: A Review



2.

– Carbon skeleton is not changed.



3.

– Reduction with a metal is a bit more mild than reduction with H2. WHY might mild conditions be preferred?

– Why is NaOH used in a final step?


• Let’s learn some new amine syntheses.

• Explain WHY the reaction will not stop at the primary amine but will continue to form a QUATERNARY AMMONIUM SALT.

23.5 Preparation of Amines via Substitution Reactions


• Let’s learn some new amine syntheses.


• N2 is a great leaving group. WHY?

• Does the N2 technically act as a leaving group in the mechanism?


• Recall the method for forming imines.

– If a reducing agent is present, the imine can be reduced in situ to form an amine.

– Reductive amination can be accomplished with a variety of reducing agents.

23.6 Preparation of Amines via Reductive Amination


• SODIUM CYANOBOROHYDRIDE, which is similar to NaBH4, is commonly used.

– The inductive effects of the –CN group make the cyanoborohydride reagent more selective.


• Why can’t NaBH4 be used for reductive aminations? (it would just reduce the ketone first)


• Let’s review reactions that form amines:

23.7 Synthetic Strategies


• Recall that amines can attack acyl chlorides.

• Two moles of the amine are used. WHY?

– Removes HCl which otherwise protonates the amine

• Polysubstitution is not observed. WHY?

• An acyl group can act as a protecting group. HOW?

• An acyl group can help to limit the reactivity of amines in EAS reactions.

23.8 Acylation of Amines


• How might you perform monobromination of aniline??

– Adding bromine won’t work because polysubstitution cannot be avoided.

23.8 Acylation of Amines


• How might you perform the following synthesis?

• The disadvantage of this synthesis is that amide hydrolysis requires harsh conditions.


• Aromatic amines also cannot undergo Friedel Crafts directly.

• How does the addition of the AlCl3 group deactivate the ring?


• To achieve ring alkylation, first, the amine must be acylated.


• Like alcohols, amines can be converted into leaving groups for elimination reactions.

23.9 The Hofmann Elimination


• Like alcohols, amines can be converted into leaving groups for elimination reactions.

• Unexpectedly, the less substituted (less stable) product is observed.


• Sterics in the anticoplanar conformation hinder attack at the more substituted site. Draw an energy diagram.

23.9 The Hofmann Elimination


• Nitrous acid is formed and reacted in situ.

23.10 Reaction of Amines with Nitrous Acid


• The nitrosonium ion is extremely electrophilic (very unstable), so its formation is NONSPONTANEOUS.

• If the nitrosonium ion forms in the presence of a 1° or 2° amine, the equilibrium can be pushed forward. HOW?



• A nitrosamine is formed.



• If the nitrosonium reacts with a 1° amine, a different product results.




– Draw the product of the step below.




Read from right to left

– A diazonium salt is produced.



• Alkyl diazonium salts are extremely reactive (potentially explosive) because of the excellent N2 leaving group.

• Aryl diazonium salts are a bit more stable and synthetically versatile.

23.11 Reactions of Aryl Diazonium Ions


• Treatment with a copper salt yields an aryl halide or nitrile.



• Explain each step in the synthesis below.

• A fluorine can also be installed.



• There are many other diazonium salt substitutions.

• Using this synthesis, amines can be used as directing groups and subsequently replaced with –H atoms.



• Diazonium salts can also be attacked by aromatic rings with an activating group (EAS mechanism).

• Draw each resonance contributor of the sigma complex.



• Azo coupling produces azo dyes.

• WHY are azo compounds colored?

• Varying the substitution on the rings affects the specific dye color.



• Heterocycles are ring compounds that incorporate a noncarbon atom in the backbone of the ring.

23.12 Nitrogen Heterocycles


• Pyrrole is a simple heterocycle that is aromatic. HOW?



• Imidazole is another simple heterocycle that is aromatic. HOW?

• Histamine contains an imidazole ring.



• Pyridine is a six-membered heterocycle.

• The lone pair on the nitrogen in pyridine is not necessary to achieve 4n+2 pi electrons.

• Yet, pyridine is significantly less basic than typical alkyl amines. WHY?



• Pyrimidine is similar to pyridine.

• Pyridine and pyrimidine can undergo EAS reactions, however usually with low yields.



• Amines generally give broad IR peaks between 3300–3500 cm-1 that are less intense than O–H stretching.

– Recall that 1° amines give two N–H stretch IR signals (symmetric and asymmetric stretching).

– 2° amines give one N–H stretch IR signal.

– 3° amines do not give N–H stretching signals.

– 3° amines can give a N–H stretching signal if treated with an acid like HCl. HOW?

23.13 Spectroscopy of Amines


• N–H protons generally appear between 0.5 and 5.0 ppm in the 1H NMR.

– Solvent, concentration, and temperature can affect the chemical shift.

• Because N–H protons are generally exchanged at a faster rate than the NMR timescale, N–H protons generally give broad signals with no splitting.

• If a deuterated solvent is used, N–H proton peaks disappear completely. HOW?



• Explain the shifts for each of the 1H and 13C signals in the molecule below.

– Predict the 1H splitting patterns.

1H signals

13C signals



• Compounds with an odd number of N atoms should have an odd mass molecular ion in their mass spectra.

• How does the molecular ion form?

• Can you think of a compound with one nitrogen atom that does not have an odd mass molecular ion?



• Amines also typically undergo alpha cleavage in the mass spectrometer giving predictable mass fragments.

• Practice with CONCEPTUAL CHECKPOINTs 23.34 and 23.35.



23.1 introduction to amines - organic chemistry help ... · klein, organic chemistry 1e why does...

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