The Chemistry of Nitrogen Compounds

The Chemistry of Nitrogen Compounds

Dr David A.Widdowson

Course Content

1. Introduction

1.1 Scope
1.2 Coverage
1.3 Course Objectives

2. Nitro Alkanes and Nitro Arenes

2.1 Structure
2.2 Electronic Effects
2.3 Spectroscopy
2.4 Synthesis of Nitro Compounds

2.4.1 Gas Phase Nitration of Alkanes
2.4.2 Electrophilic Nitration of Anions
2.4.3 Nitrate SN2 Displacement of Alkyl Halides
2.4.4 Oxidation with Peracids
2.4.5 Aromatic Nitro Compounds

2.5 Reactions

2.5.1 a Anions
2.5.2 Alkylation

2.5.2.1 Henry Reaction
2.5.2.2 Michael Additions
2.5.2.3 Ambident Nucleophiles

2.5.3 Reduction

2.5.3.1 General
2.5.3.2 Photochemically
2.5.3.3 Metal/H⁺ Reaction
2.5.3.4 H₂/Pd Surface Reactions
2.5.3.5 Sulphur Reagents
2.5.3.6 Metal Hydrides

2.6 Summary

3. Nitroso Compounds

3.1 Structure
3.2 Electronic Effects
3.3 Spectroscopy
3.4 Synthesis

3.4.1 Aromatics
3.4.2 Aliphatics
3.4.3 Tertiary Aliphatics

3.5 Reactions

3.5.1 Addition and Condensation
3.5.2 Reduction
3.5.3 Oxidation
3.5.4 Radical Addition-Spin Trapping

3.6 Summary

4. Amines

4.1 Nomenclature
4.2 Structure
4.3 Electronic Effects
4.4 Spectroscopy
4.5 Physiological Effects
4.6 Synthesis

4.6.1 Alkylation Reactions

3.6.1.1 General
3.6.1.2 Alkylation of Phthalimide Anion-The Gabriel Synthesis
3.6.1.3 Alkylation of Bis(Phenylthio)Amine Anion
3.6.1.4 Alkylation of Trifluoromethanesulfonylamine

4.6.2 Reductive Methods

3.6.2.1 Reduction of Amides
3.6.2.2 Reduction of Nitro Compounds or Azides
3.6.2.3 Reduction of CN Multiple Bonded Systems
3.6.2.4 Eschweiler-Clarke Synthesis

4.6.3 Hydrolytic Methods

3.6.3.1 Hydrolysis of Amides
3.6.3.2 MeOH/BF₃.Et₂O
3.6.3.3 Meerwein's Salt

4.6.4 Rearrangements

3.6.4.1 General Reaction Scheme
3.6.4.2 Hoffmann Rearrangement
3.6.4.3 Curtis Rearrangement
3.6.4.4 Lössen Rearrangement
3.6.4.5 Schmidt Reaction
3.6.4.6 Beckmann Rearrangement
3.6.4.7 Abnormal Beckmann Rearrangement

4.7 Reactions

4.7.1 Basicity and Nucleophilicity
4.7.2 Alkylation
4.7.3 Acylation
4.7.4 Halogenation

4.7.4.1 Aliphatics
4.7.4.2 Aromatics

4.7.5 Nitrosation

4.7.5.1 General
4.7.5.2 Primary Amines
4.7.5.3 Secondary Amines
4.7.5.4 Tertiary Amines

4.7.6 Reaction with Carbonyls
4.7.7 Oxidation

4.7.7.1 Oxygen Addition Reactions
4.7.7.2 Dehydrogenation of Amines

4.7.8 Deprotonation

4.8 Summary

5. a Amino Acids, Peptides and Proteins

5.1 Amino Acid Nomenclature
5.2 Amino Acid Structure
5.3 Amino Acid Synthesis

5.3.1 The Gabriel Synthesis
5.3.2 The Streaker Synthesis
5.3.3 Enantioselective Synthesis

5.4 Peptide and Protein Structure
5.5 Peptide Synthesis

5.5.1 General
5.5.2 Merrifield Solid Phase Synthesis
5.5.3 Peptide Synthesis in Nature

5.6 Summary

6. Nitrogenous Natural Products and Alkaloid Biosynthesis

6.1 Introduction

6.1.1 Amino-acids, Peptides, Proteins and Derived Substances
6.1.2 Vitamins
6.1.3 Porphyrins, Chlorins and Cobalamins
6.1.4 Purines, Pyrimidines, Nucleosides, Nucleotides

6.2 Alkaloid Biosynthesis

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Introduction

Scope

There are many organic functional group which contain nitrogen, the scope of this course will be;

• Nitro compounds, RNO₂
• Nitroso compounds, RNO
• Amines R₃N and their derivatives
• Amino acids, peptides and proteins
• Other nitrogenous natural products - alkaloids and nucleotides

Coverage

For each of these the following area will be considered;

• Structure and stereochemistry
• Physical data and spectroscopic characteristics
• Synthesis
• Chemical reactivities and relationship to electronic properties

Course Objectives

To compare the overview of the common functional groups of organic chemistry by;

• Extending the first year functional group chemistry to N-compounds.
• Explaining the effect of the heteroatom/group on the structure of organic molecules.
• Discussing the effect of the heteroatom/group on the reactivity of organic molecules.
• Rationalising the effect of the heteroatom/group on the transformations of organic molecules.
• Relating the nitrogen chemistry to polyfunctional molecules through an introduction to nitrogenous natural products

By this means, to further the development of a basic understanding of structure and reactivity in simple organic systems and thus prepare the student for the more specialised topics of second year.

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Nitro Alkanes and Nitro Arenes

Structure

The nitrogen is trigonal planar with a bond angles of 120°, there are two resonance forms so implying that the two oxygens are equivalent;

Electronic Effects

These are strongly electron withdrawing both inductively, -I, and mesomerically, by resonance, -R. This means that both the C-N s bond and the p system are strongly polarised, C^d+-NO₂^d-. Due to the -I inductive effect of the s bond the pKa values of nitro group containing compounds can also be affected;
Ph-NO₂, this substituent is ortho, para directing due to the -R resonance effect of the p bond. The -I will also still operate but is less obvious here.

Spectroscopy

I.R.
The n_max for the N=O stretch is 1500-1600 cm^-1, compared to the C=O stretch at 1650-1800 cm^-1. NMR
For a CH protons, adjacent to the group, the chemical shift, d, = 4.3, due to electron withdrawing effect;
U.V .
The nitro group causes a pronounced shift of l_max to longer wavelengths when conjugated to unsaturated p systems, a bathochromic shift. This is why nitro compounds are often yellow.

Synthesis of Nitro-Compounds

Aliphatic nitro compounds are synthesised by; Gas Phase Nitration of Alkanes
This commercial free radical process involves the NO₂ radical;
Electrophilic Nitration of Enolate Anions
The use of the enolate active methylenes forms a stable product due to the chelation of the counter ion;
Nitrate SN2 displacement of alkyl halides
Two products, a nitro compound and a nitrite ester, are produced due to the sodium nitrate acting as an ambident nucleophile, either a N or O nucleophile;
The use of silver nitrate produces only the nitro compound as it is not an ambident nucleophile.
Oxidation with Peracids
Nitro compounds can be produced by oxidised of amine by peracids;
Aromatic Nitro Compounds
These are synthesised by electrophilic aromatic substitution with NO₂⁺ ions;

Reactions

As the nitro group is strongly electron withdrawing and shows affinity with the C=O group. Thus addition across the N=O is possible and reduction is easy. a Anions
a anions are easily formed with base and stabilised by resonance as nitronate anions, c.f. C=O enolate formation;
The protons on nitro methane, MeNO₂, have a pKa of 10.2, c.f. MeCOCH₂CO₂Et pKa 11. So in order to remove the a protons on nitro alkane an appropriate base in required.
As the nitronate ion is delocalised it is a soft nucleophile and show usual reactivities of stabilised, soft, carbanions.
Alkylation
Henry Reaction
This reaction is analogous to the Aldol reaction;
If R' is aryl the mechanism of elimination is;
If R' is alkyl the mechanism of elimination is;
Michael Additions
The Michael addition is a conjugate addition as the double bond is the soft centre of the ester, the carbonyl carbon being the hard centre. It proceeds by the following mechanism;
Ambident Nucleophiles
Nitronate anions themselves can act as ambident nucleophiles with either attack from the C, a soft nucleophile, or from the O, hard nucleophile. These will attack soft or hard electrophiles respectively;
This ambident behaviour can be seen in the Nef reaction;
O-alkylation is Possible with a hard alkylating agent like Meerwen's Bact, this is a Me⁺ source;
The ambident nature of the nitro group makes it a very versatile reagent.
Reduction
General
In principle the reduction of nitro compounds should follow the path;
The reduction of nitroso groups is generally more easily achieved but the nitro group can be reduced in a number of different ways;
Photochemically
Metal/H⁺ Reactions
Metals, such as Fe, Zn, Sn can be used with H⁺ to reduce the nitro group by a sequence of single electron transfer (SET)/protonation reactions;
The mechanism for the Zn/H⁺ reaction is;
H₂/Pd Surface
Reactions H₂/Pd or Pt can be used by heterogeneous H^- transfer on the metal surface and then reaction with the nitro compound;
Sulphur Reagents
NaSH or Na₂S_x or (NH₄)₂S₂ can be used and possibly precede by SET reactions;
Metal hydrides
Reagents like LiAIH₄, but not usually NaBH₄, reduce the nitro group by hydride, H^-, transfer. The product will depend on the nature of the reducing agent, but the end point is ultimately an amine.
 
 

Summary

• N SP² hybridised and strongly electron withdrawing
• H acidic
• Anion reacts with E⁺, RBr RCHO, Henry reaction etc.
• Soft anion soft undergoes Michael additions
• Group reduced by:
• Metal/H⁺ (electron source)
• H^-, (NaBH₄ or LiAlH₄)
• H₂/Pd or Ni (R)

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Nitroso Compounds

Structure

The nitrogen is trigonal planar with a bond angle of ª125°. Nitroso compounds tend to dimerise in the following way;

Electronic Effects

Nitroso groups are strongly electron withdrawing, like the nitro group, but the situation is complicated by the dimerisation reaction.

Spectroscopy

I.R.
The n_max for the N=O stretch in the monomer is 1560 cm^-1, in the dimer the n_max for the N-O stretch is 1200 cm^-1. NMR
For a CH protons, adjacent to the group, the chemical shift, d, = 4.0, due to electron withdrawing effect.

Synthesis

Aromatics
The synthesis of aromatic nitroso compounds can achieved by nitrosation with NO⁺, form HNO₂, on strongly activated, electron rich, aromatics like ArNH₂ and ArOH;
They can also be produced from nitro compounds by reduction to the hydroxylamine then followed by oxidation;
The nitroso compound comes out of aqueous solution, due to its non hydrophilic nature, and so avoids further oxidation, this is a very general method and can be used for a verity of compounds. The direct reduction from NO₂-R to NO-R is not a generally feasible process though a photochemical method is known, see nitro group section.
Aliphatics
The synthesis of aliphatic nitroso compounds can achieved by nitrosation of active, acidic, methylene compounds under acidic conditions, H⁺/NOCl, N₂O₃ or N₂O₄;
Under basic conditions, C₅H₁₁ONO/NaOEt;
Under neutral conditions enol silyl ether /NOCl;
Another method of synthesis is by Markovnikov addition of NOX (X=Cl, NO₂, NO₃) to olefins.
Tertiary Aliphatics
To synthesis nitroso compounds with tertiary alkyls another method has to be employed;

Reactions

Addition and Condensation
As the nitrosyl group is strongly electron withdrawing and more similar to the C=O than the NO₂ group There is polarisation of the N=O bond and so behaves as a weak C=O. It undergoes addition of nucleophiles and condensation with primary amines and the anions of active methylene compounds, e.g malonates, b ketoesters;
The best method for preparation of secondary hydroxylamines is by addition of a Grignard reagent to a nitroso group and carrying out an acidic work up;
The production of a nitrone can be seen in the following reaction;
The hetero Diels-Alder reaction is also possible;
Reduction
Reduction occurs as for NO₂ groups with metals, metal hydrides, hydrogen/ catalyst.
Oxidation
Oxidation is readily brought about with peracids inter alia, this is not possible for nitro groups.
Radical Addition-Spin Trapping
Monomeric nitroso compounds are used to detect transient free radicals, mainly carbon centred radicals, by 'trapping' them as stable nitroxide radicals. These can be detected and assayed in an EPR spectrometer, this is the electron equivalent of the NMR spectrometer. EPR stands for Electron Paramagnetic Resonance. This allows the intermediacy of such otherwise undetectable transients to be proven and is therefore a valuable mechanistic probe.
If the following thermal decomposition of benzoyl peroxide, a radical initiation reaction, is to be monitored;
The phenyl radical would be undetectable by EPR but by addition of a tertiary nitrosyl the more stable nitroxide is produced which is observable;

Summary

• N SP² hybridised and electron withdrawing
• ON group like carbonyls undergoes addition with RMgX, condenses with RNH₂ and 'active methllene', e.g malonate anion
• When a-H present, readily isomerises to oxime
• Very rapid addition of radicals R across N=O bond to give stable nitroxide radicals

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Amines

Nomenclature

• R-NH₂ Primary Amide
• R₂-NH Secondary Amide
• R₃-N Tertiary Amide
• R₄-N⁺ Quaternary Ammonium Ion

Beware of possible confusion of the nomenclature of the alkyl moiety and the amine moiety. Thus Me₃CNH₂, tert-butylamine, is a primary amine.

Structure

The Nitrogen is SP³ hybridised but rapidly inverting, for NH₃ the inversion rate is = 2 x 10¹¹;
The fact this rate of inversion is so regular is exploited in the ammonia clock. An important implication of this is that chiral amines racemise rapidly. This can be stopped by use of a rigid framework, an example of which is 1-aza-bicyclo-[2,2,2]-heptane;

Electronic Effects

The nitrogen in an amine is both electronegative and able to donate its loan pair into a p system. Therefore it has both -I and +R effects, the +R effect is greater than the -I effect though.

Spectroscopy

I.R.
The n_max for the N-H stretch as 3300-3400 cm^-1. NMR
For protons in the a position to a primary amine, e.g -CHNH₂, the protons have a chemical shift of d 2.5-3. Protons in the a position to a tertiary amine, e.g CH₃NR₂, have a chemical shift of d 2.0-2.5. Protons in the a position to a quaternary ammonium ion, e.g -CHN⁺R₃, have a chemical shift of d 3.5 - 4.0.

Physiological Effects

Amines are an important group of compound intimately concerned in many biological processes, not only at the a amino acid protein level. Because of their hydrogen bonding properties, amines are much involved in the binding polar molecules to macromolecules as in enzyme-substrate and hormone-receptor interactions. Consequently, very many medicines and crop protection agents, which frequently act as antagonists or agonists for natural substances, contain basic nitrogen. Similarly the alkaloids, which are by definition natural nitrogenous compound, are much involved in folk medicine and in natural biocides.

Synthesis

Because of the widespread importance of this functional group, many methods of preparation of the various types of amine have been devised. These can be classified as; Alkylation Reactions
The synthesis of primary, secondary, tertiary and quaternary amines involving direct alkylation of ammonia and lower amines. The reaction proceeds with nucleophilic attack by the loan pair on nitrogen and then abstraction of the extra proton with a base that is more nucleophilic than the amine. It is not generally an efficient process because of ready over reaction;
 
 

Other leaving groups that can be exploited in direct alkylation are;
Due to the problem of over alkylation more specific methods have been developed;
Alkylation of Phthalimide Anion-The Gabriel Synthesis

Hydrazionlysis of the product releases the primary amine. Alkylation of Bis(Phenylthio)Amine Anion, (PhS)₂N^-

Acid cleavage again gives the primary amine. Alkylation of Trifluoromethanesulfonylamine Anion, RN-SO₂CF₃

Cleavage with LiAlH₄, or base, gives the secondary amine. Reductive Methods

• Reduction of Amides

This can be achieved with LiAlH₄ or better still the electrophilic BH₃.THF. This method is best for tertiary Amides but is also OK to use for secondary and primary amines with the use of BH₃.THF as this reagent is a little more delicate than LiAlH₄! This method also gives an unambiguous synthesis of primary, secondary and tertiary amines.

• Reduction of Nitro Compounds or Azides

Reduction can be achieved with LiAlH₄ or H₂/Pd. The aliphatic substances can be synthesised by nucleophilic displacement of X from RX with NO₂-R or N₃-R.

• Reduction of CN Multiple Bonded Systems

The reduction of compounds such as, RC=N, R₂C=NOH, can be achieved with LiAlH₄ or H₂/Pd.

• Eschweiler Clarke Synthesis

This involves the reductive alkylation of in situ generated RN=CR₂ with HCO₂- or NaBH₃CN;

This reaction requires acidic conditions to produce the protonated form of the first product. This means that a mild hydride, H^-, source is required an example of this is HCO₂H/HCO₂^-Na⁺;

It is also possible to use NaBH₃CN which is acid stable at pH 4.

Hydrolytic Methods

• Hydrolysis of Amides

Simple hydrolysis of the amide with H₃O⁺ or OH^- is possible; For hindered or sensitive systems it is inefficient or impossible. Special methods for these transformations include;

• MeOH/BF₃.Et₂O

If R is aryl then it may be quite resistant to hydrolysis, a method of mild non-aqueous acid hydrolysis can then be used;
• Meerwein's Salt

Meerwein's salt, Et₃O=BF₄^-/H₂, is used for mild hydrolysis of acid sensitive amides such as as b lactam side chains, this is an important reaction for the synthesis of penicillins;

Rearrangements

• General Reaction Scheme

A group of similar reactions involve the migration of an alkyl group, R, from carbon to electron deficient nitrogen, the nitrene or nitrenium ion. The nitrene is produced from the loss of a good leaving group, Y. The products, isocyanates, are readily hydrolysed to amines; Theses reactions are a convenient source of many amines from carboxylic acids, with the loss of the carboxyl carbon atom, or ketones, with the loss of one of the groups on the carbonyl carbon. Example of such rearrangements are;

• Hoffmann Rearrangement,Y=Br

   
 






• Curtius Rearrangement,Y=N₂

   
 






• Lössen Rearrangement,Y=OAc

   
 






• Schmidt Reaction,Y=N₂

   
 






• Beckmann Rearrangement

This is a rearrangement of ketoximes, RC(=NOH)R';
• Abnormal Beckman Rearrangements

This occurs with the oximes of aldehydes and other carbonyls in which R or R' in R (=NOH)R' can form stable carbocations;

Reactions

Basicity and Nucleophilicity
The lone pair of electrons on the nitrogen atom renders the amine basic and nucleophilic. The pKa's of the conjugate acids of simple amines increase with increasing alkyl substitution, this is due to the electron release from the alkyl groups, up to the di-alkylamine level. Thereafter the pKa diminishes because of increasing steric hindrance to protonation. The larger the pKa the stronger the base. Some pKa's of some conjugate acids in water at 25°C are;

Amine	pKa
NH3	9.25
EtNH2	10.80
Et2NH	16.09
Et3N	10.85
PhNH2	4.58
PhNEt2	6.56

Aromatic amines are generally less basic, and nucleophilic, than their alkyl counterparts because of back donation of the nitrogen lone pair into the aromatic p system and therefore rendering it less available for direct reaction, this is the +R effect; In general nucleophilicity parallels basicity except for increase of stability due to steric hindrance.
Alkylation
This has been largely discussed under synthesis. One important area is the alkylation of aryl amines which N-alkylate;
Quaternary salts undergo the mechanistically important Hoffmann elimination reaction. In this, the pyrolysis of quaternary ammonium hydroxides produces the less substituted, less thermodynamically stable, olefin, in contrast to the more common Saytzeff elimination which produces the more substituted more thermodynamically stable, olefin;
This indicative of a kinetically controlled reaction, and so is reversible, with an early transition state. Consider the reaction profile;
It can be seen that the activation energy, DG^ý, for the Hoffmann product is lower than for the normal thermodynamic product, this implies that the process is controlled by the proton removal step;
As the C-H bond gets weaker, CH₃>CH₂>CH, the proton becomes more acidic so under these circumstances the more acidic methyl group proton will be preferentially removed, this results in the less substituted olefin, and the stability of the product is irrelevant to the process. The stereochemistry of the reaction is trans coplanar;
Syn coplanar reactions are known when a trans array is geometrically prohibited, this is seen in some caged ring systems like bicyclo-[2,2,1]-heptane;
Acylation
Acylation of primary and secondary amines with RCOX where X is a good leaving group like a halogen, OCOR' or OR group. It is a very common process, occurring via the tetrahedral addition product of the active carbonyl group;
Halogenation
Aliphatics
N-Halo,Cl, Br, I, compounds are readily formed with Hal⁺ reagents;

These N-Hal species are not very stable and readily eliminate HX to give imines (RCH=NR') especially on treatment with bases like NaOEt. Hydrolysis of the imines generates carbonyl groups and the overall process represents a reversal of the Eshweiler-Clark reaction;

Aromatics
In benzene rings carbon attack of Hal⁺ is very common and has been dealt with before in the course. The amino group is electron releasing and o, p directing;
At low temperatures, ² -20°C, N-chlorination is often observed. The mono- or di- N-chloroamines rearrange rapidly on warming to the 2-, or 4-, or 2,4-di-chloroamines;
Nitrosation
Nitrosation, with the active agent of NO⁺ from HNO, NOCl, N₂O₃, N₂O₄, is not subject to any significant steric inhibition, due to the small size of the NO⁺ group, and any nitrogen with a nucleophilic lone pair of electrons will react. The products depend on the nature of the amino function.

• Primary Amines

These react rapidly to generate diazonium ions R-N⁺=N. In the aryl series, ArN₂⁺, these are stabilised by resonance with the aromatic ring. They have a relatively long lifetime and are often stable at room temperature;

They undergo nucleophilic attack by secondary amines at the terminal nitrogen to give the carcinogenic triazenes ArN=NNR₂. Many other nucleophiles will react analogously;

Fragmentation of the aryl diazonium ions can occur by ionic or single electron transfer, SET, radical mechanisms dependent upon the conditions. The copper (I) catalysed reactions, Sandmeyer reactions etc, proceed by the SET mechanism which generates the aryl radicals;

Thermal decomposition or reactions with simple nucleophiles are more likely to proceed via the ionic fragmentation to the highly reactive aryl cations;

In either case, the overall product is the replacement of the N₂⁺ group with a nucleophile, Hal^-, CN^-, OH^- etc. Aliphatic diazonium ions are not stabilised and undergo very rapid fragmentation to N₂ and an alkyl cation;

This species is itself very reactive and therefore indiscriminate in is reactions with nucleophiles. A plethora of products, including those resulting from rearrangement of the initially formed carbocation, are usually observed;

• Secondary amines

These readily form stable N-nitroamines, R₂NN=O. N-Nitrosamines are potent carcinogens and their synthesis should only be undertaken under strictly controlled conditions; The N-nitrosoarylamines readily rearrange on treatment with acid to the para substituted products, the FIcher-Hepp rearrangement;

• Tertiary Amines

Aromatic tertiary amines, ArNR₂, give directly the 4-nitroso-product; In the aliphatic series, the initial N-nitrosation, to form R₃N⁺-NO, is readily reversible but upon warning the product fragments to a secondary N-nitrosamine, R₂NNO, and an aldehyde, RCHO;

Reaction with Carbonyls
Primary amines simply condense to form imines; If R is aryl, Schiff's bases, then conjugation makes them stable;
If R is aliphatic there is no possibility of conjugation and so they polymerise and are not generally isolable;
Secondary amines condense to form enamines, R₂NCR=CR₂;
Enamines are important synthetic intermediates which will be covered in the 2^nd year course, they readily undergo electrophilic attack at the b carbon;
Tertiary amines simply act as bases.
Oxidation

• Oxygen addition reactions

These have been mentioned previously. Primary amines are oxidised by peracids, like trifluoroperacetic acid and perboric acid, to the nitro compounds; Secondary amines are similarly oxidised to the hydroxylamines, R₂NOH.
Tertiary amines are readily oxidised by many peracids to the amine oxide, R₃N⁺-O^-;
These are useful for their fragmentation on pyrolysis, the Cope elimination reaction;

• Dehydrogenation of amines

Tertiary amines in particular can be clearly dehydrogenated in the a position by oxidation with mercury salts like Hg(OAc₂) or Hg(OCOCF₃)₂;

Deprotonation
Primary and secondary amines can be deprotonated by very strong bases; The pKa's of amines are typically NH₃=34, Et₂NH=36 and ⁱPr₂NH=38; i.e. R₂N^- are strong bases and they are very much used for this purpose in base catalysed reactions. The deprotonation of hindered amines, with bulky R groups, makes for a very strong base which is a very weak nucleophile. Commonly used examples are;
The use of these bases can be useful in synthesis for deprotonation of activated C-H bonds, those adjacent to electron withdrawing groups;

Summary

• N SP³, tetrahedral, normally rapidly inverting therefore achiral
• Electronically has -I (mainly s bond), +R ( p bond ) effects
• All reactivity, in this course, stems from the donation of electrons from the lone pair
• Synthesis by;
• alkylation of lower homologues
• Reduction of RCONR'₂, RN₃, RCN, RNO₂, RCH+NOH etc
• Acyl nitrene rearrangements, Hoffmann, Lössen, Schmidt, Curtius
• Beckmann rearrangements
• Lone pair nucleophilic, reacts with many electrophiles, R-X, RCHO, R₂CO. RCOX, Hal₂, NO⁺,
• Lone pair basic, R₂NH > R₃N > RNH₂ > NH₃

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a Amino Acids, Peptides and Proteins

Amino Acid Nomenclature

Although several hundred a amino acids have been detected in nature, only 21 are found in proteins. The others serve other purposes. Also, despite being less widespread, the D-series amino acids occur quite commonly, e.g in bacterial cell walls. They all have trivial names for a complete list see Vollhardt, 2nd edition. p.1025.

R	Name		R	Name
-Me	alanine		-CHMe3	valine
-CH2CHMe2	leucine		-CHMeCH2Me	isoleucine
-CH2Ph	phenylalanine		-CH2C6H4OH	tyrosine
-CH2OH	serine		-CHMeOH	theonine
-CH2CO2H	aspartic acid		-CH2CONH2	asparagine
-CH2CH2CO2H	alutamic acid		- CH2CH2CONH2	glutamine

Amino Acid Structure

a amino acids are the basic building blocks of peptides, including peptide hormones, and proteins. They can be represented in many ways but the common ways are shown below; Their general structure is chiral when R is not another CO₂^-, NH₃⁺ or H, therefore glycene, R=H, is achiral;

Amino Acid Synthesis

Many methods have been developed to synthesise amino acids, classically; The Gabriel Synthesis
The can be readily adapted for amino acids;
The Streaker Synthesis
This is a direct approach, but not enantioselective;
Enantioselective Synthesis
This modern method of making only one stereo isomer include the asymmetric hydrogenation of dehydroamino acid derivatives. For example the Monsanto synthesis of L-DOPA;
Peptide and Protein Structure
These are oligomers, peptides, and polymers, proteins, of the a amino acids, linked via amide or 'peptide' bonds;
Thus a tetra peptide would be;
Many hormones like oxytocin or antibiotics like penicillin and cephalosporin are peptides, sometimes with modification of the backbone chain, this can be seen in penicillin N;
Penicillin is biosynthesised from the individual amino-acids by an unusual pathway unravelled very largely by the Oxford group lead by Professor Jack Baldwin. The sequence is;
This will be looked at in more depth later.

Peptide Synthesis

General
Generally the process involves many steps for each peptide bond formed; Peptide synthesis can be carried out in homogeneous solution but due to the non 100% yield nature of all the protection steps a low yield of the final peptide is found. To get around this problem frequently the Nobel prize winning Merrifield solid phase synthesis is now used. This process uses excess reagents to drive each reaction to 100% yield and so can be used to synthesise peptides of 10-20 units, of any sequence, in good yield. The process can be automated and peptides can be made very quickly.
Merrifield Solid Phase Synthesis
The general principles of this method can be expressed as;

1. Protection of NH₂ group on amino acid;

   
 






2. Resin, chloromethalated polystyrene, cross linked with 1% 1,4-divinyl benzene;

   
 






3. Activation of the amino acid;

   
 






4. Coupling of resin and amino acid;

   
 






5. Deprotection of the amine;

   
 






6. Coupling of resin/amino acid with another amino acid. Peptide growth;

   
 






7. Cleavage of peptide from resin;

   
 

Peptide Synthesis in Nature
The biosynthesis of penicillin N, discussed earlier, is synthesised from its three constituent compounds via enzymic processes;

Summary

• Monomer for peptides and proteins
• N-protection / CO₂H activation for peptide synthesis
• Streaker synthesis, RCHO / HCN / NH₃ + hydrolysis
• Gabriel synthesis, actamidomalonate synthesis
• Monsanto syntheses, chiral hydrogenation
• Resin based solid phase peptide synthesis, Merrifield

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Nitrogenous Natural Products and Alkaloid Biosynthesis

Introduction

Structural types of nitrogenous natural products are extremely varied and one of the most fascinating aspects of organic chemistry. Those commonly met with are;

• Amino Acids, Peptides, Proteins and Derived Substances

These include structural proteins, enzymes, glycoproteins, and the peptide derived materials such as the b lactam antibiotics, the penicillins and cephalosporin C. For further information see Vollhardt chapter 26.
• Vitamins

A miscellaneous collection of structures which are essential dietary constituents in mammals because of their inability to synthesise them. They have in common the fact they are usually cofactors for essential metabolic enzymes, e.g vitamin B₆, the cofactor in the transamination process which introduces the amino-function into amino acids. For further information see Vollhardt chapter 25.
• Porphyrins, Chlorins and Cobalamins

These are the tetrapyrrolic macrocyclic ligands for certain essential metals. They include; Haem, Fe²⁺ or ³⁺, for oxygen transport;

The coenzyme B₁₂, Co²⁺ or ³⁺, for certain liver functions in animals;
 
  Chlorophyll, Mg²⁺, for photosynthesis in plants;

For further information see Vollhardt chapter 25.

• Purines, Pyrimidines, Nucleosides, Nucleotides

The bases of the nucleic acids, DNA and RNA. These are covered in some detail in the biochemistry course in the second year. For further information see Vollhardt chapter 25.
• Alkaloids

Nitrogen containing natural compounds, other than those listed above, usually plant derived and frequently physiologically active. These are the classical folk medicines, some of which, e.g reserpine, a natural anti hypertensive agent and vinblastine, used in cancer treatment, are still important in medicine today. They are usually made in nature from amino acids precursors and are of many structural types. For further information see Vollhardt chapter 25.

Morphine an example of an opium alkaloid.

Alkaloid Biosynthesis

Most alkaloids are plant products derived from amino acids. A widespread pathway is that based on the conversion of phenylalanine, tyrosine and DOPA to a variety of aromatic alkaloids including the opium alkaloids codeine and morphine. The sequence is based on the coupling of 2 phenylalanine, tyrosine or DOPA units to form 1-benzyl-1,2,3,4-tetrahydro-isoquinolines by a series of simple nitrogen based transformations of types familiar from the course. The basic reaction set, the ready interconversion in vivo of carbonyl groups, imines, enamines, and their derivatives, is;
1-Benzyl-1,2,3,4-tetrahydro-isoquinolines are subject to enzymic 'phenol oxidative coupling' in which the one electron oxidant is usually a copper containing enzyme. The process well illustrated by the chemical oxidation of p-cresol with potassium hexacyanoferrate;
Radical coupling between the para and ortho cononical dominates producing Pummer's ketone;
This is the basis for the formulation of the opium alkaloids. The overall sequence is;





 
 










The sections on biosynthesis are intended to link with 'real' organic chemistry and to link with the polyfunctional and mechanistic chemistry presented in second year. They are for interest only and not for examination. purposes.