absolute configuration ----------- how to determine

an animation to find absolute configuration at chiral carbon
by 
psk chakravarthy

anomeric effect

Originally the thermodynamic preference for polar groups bonded to C-1 (the anomeric carbon of a glycopyranosyl derivative) to take up an axial position.

This effect is now considered to be a special case of a general preference (the generalized anomeric effect) for synclinal (gauche) conformations about the bond C–Y in the system X–C–Y–C where X and Y are heteroatoms having nonbonding electron pairs, commonly at least one of which is nitrogen, oxygen or fluorine. For example in chloro(methoxy)methane the anomeric effect stabilizes the synclinal conformation.

In alkyl glycopyranosides the anomeric effect operates at two sites (i) along the endocyclic C-1 oxygen bond (endo-anomeric effect) and (ii) along the exocyclic C-1 oxygen bond (exo-anomeric effect). The opposite preference is claimed for some systems e.g. glycopyranosyltrialkylammonium salts, and has been referred to as the reverse anomeric effect.

Substitution and Elimination Reactions of Amines

Amine functions seldom serve as leaving groups in nucleophilic substitution or base-catalyzed elimination reactions. Indeed, they are even less effective in this role than are hydroxyl and alkoxyl groups. In the case of alcohols and ethers, a useful technique for enhancing the reactivity of the oxygen function was to modify the leaving group (OH(–) or OR(–)) to improve its stability as an anion (or equivalent). This stability is conveniently estimated from the strength of the corresponding conjugate acids.

As noted earlier, 1º and 2º-amines are much weaker acids than alcohols, so it is not surprising that it is difficult to force the nitrogen function to assume the role of a nucleophilic leaving group. For example, heating an amine with HBr or HI does not normally convert it to the corresponding alkyl halide, as in the case of alcohols and ethers. In this context we note that the acidity of the putative ammonium leaving group is at least ten powers of ten less than that of an analogous oxonium species. The loss of nitrogen from diazonium intermediates is a notable exception in this comparison, due to the extreme stability of this leaving group (the conjugate acid of N2 would be an extraordinarily strong acid).

One group of amine derivatives that have proven useful in SN2 and E2 reactions is that composed of the tetraalkyl (4º-) ammonium salts. Most applications involving this class of compounds are eliminations, but a few examples of SN2 substitution have been reported.

C6H5–N(CH3)3(+) Br(–)  +  R-S(–) Na(+)

acetone & heat

R-S-CH3  +  C6H5–N(CH3)2   +   NaBr

(CH3)4N(+) OH(–)

heat

CH3–OH  +  (CH3)3N

Hofmann Elimination

Elimination reactions of 4º-ammonium salts are termed Hofmann eliminations. Since the counter anion in most 4º-ammonium salts is halide, this is often replaced by the more basic hydroxide ion through reaction with silver hydroxide (or silver oxide). The resulting hydroxide salt must then be heated (100 - 200 ºC) to effect the E2-like elimination of a 3º-amine. Example #1 below shows a typical Hofmann elimination. Obviously, for an elimination to occur one of the alkyl substituents on nitrogen must have one or more beta-hydrogens, as noted earlier in examining elimination reactions of alkyl halides.

In example #2 above, two of the alkyl substituents on nitrogen have beta-hydrogens, all of which are on methyl groups (colored orange & magenta). The chief product from the elimination is the alkene having the more highly substituted double bond, reflecting not only the 3:1 numerical advantage of those beta-hydrogens, but also the greater stability of the double bond.

Example #3 illustrates two important features of the Hofmann elimination:

1. Simple amines are easily converted to the necessary 4º-ammonium salts by exhaustive alkylation, usually with methyl iodide (methyl has no beta-hydrogens and cannot compete in the elimination reaction). Exhaustive methylation is shown again in example #4.
2. When a given alkyl group has two different sets of beta-hydrogens available to the elimination process (colored orange & magenta here), the major product is often the alkene isomer having the less substituted double bond.

The tendency of Hofmann eliminations to give the less-substituted double bond isomer is commonly referred to as the Hofmann Rule, and contrasts strikingly with the Zaitsev Rule formulated for dehydrohalogenations and dehydrations. In cases where other activating groups, such as phenyl or carbonyl, are present, the Hofmann Rule may not apply. Thus, if 2-amino-1-phenylpropane is treated in the manner of example #3, the product consists largely of 1-phenylpropene (E & Z-isomers).

To understand why the base-induced elimination of 4º-ammonium salts behaves differently from that of alkyl halides it is necessary to reexamine the nature of the E2 transition state, first described for dehydrohalogenation. The energy diagram shown earlier for a single-step bimolecular E2 mechanism is repeated below.

The E2 transition state is less well defined than is that of SN2 reactions. More bonds are being broken and formed, with the possibility of a continuum of states in which the extent of C–H and C–X bond-breaking and C=C bond-making varies. For example, if the bond to the leaving group (X) is substantially broken relative to the other bond changes, the transition state approaches that for an E1 reaction (initial ionization followed by a fast second step). At the other extreme, if the acidity of the beta-hydrogens is enhanced, then substantial breaking of C–H may occur before the other bonds begin to be affected. For most simple alkyl halides it was proper to envision a balanced transition state, in which there was a synchronous change in all the bonds. Such a model was consistent with the Zaitsev Rule.

When the leaving group X carries a positive charge, as do the 4º-ammonium compounds discussed here, the inductive influence of this charge will increase the acidity of both the alpha and the beta-hydrogens. Furthermore, the 4º-ammonium substituent is much larger than a halide or hydroxyl group and may perturb the conformations available to substituted beta-carbons. It seems that a combination of these factors acts to favor base attack at the least substituted (least hindered and most acidic) set of beta-hydrogens. The favored anti orientation of the leaving group and beta-hydrogen, noted for dehydrohalogenation, is found for many Hofmann eliminations; but syn-elimination is also common, possibly because the attraction of opposite charges orients the hydroxide base near the 4º-ammonium leaving group.

Three additional examples of the Hofmann elimination are shown in the following diagram. Example #1 is interesting in two respects. First, it generates a 4º-ammonium halide salt in a manner different from exhaustive methylation. Second, this salt is not converted to its hydroxide analog prior to elimination. A concentrated aqueous solution of the halide salt is simply dropped into a refluxing sodium hydroxide solution, and the volatile hydrocarbon product is isolated by distillation.

Example #2 illustrates an important aspect of the Hofmann elimination. If the nitrogen atom is part of a ring, then a single application of this elimination procedure does not remove the nitrogen as a separate 3º-amine product. In order to sever the nitrogen function from the molecule, a second Hofmann elimination must be carried out. Indeed, if the nitrogen atom was a member of two rings (fused or spiro), then three repetitions of the Hofmann elimination would be required to sever the nitrogen from the remaining molecular framework.

Example #3 is noteworthy because the less stable trans-cyclooctene is the chief product, accompanied by the cis-isomer. An anti-E2-transition state would necessarily give the cis-cycloalkene, so the trans-isomer must be generated by a syn-elimination. The cis-cyclooctene produced in this reaction could also be formed by a syn-elimination. Cyclooctane is a conformationally complex structure. Several puckered conformations that avoid angle strain are possible, and one of the most stable of these is shown on the right. Some eclipsed bonds occur in all these conformers, and transannular hydrogen crowding is unavoidable. Since the trimethylammonium substituent is large (about the size of tert-butyl) it will probably assume an equatorial-like orientation to avoid steric crowding. An anti-E2 transition state is likely to require an axial-like orientation of this bulky group, making this an unfavorable path.

Unimolecular syn-Eliminations

E2 elimination reactions are commonly bimolecular and prefer an anti-coplanar transition state. This important class of functional transformations is complimented by a small group of thermal, unimolecular syn-eliminations, described in the following table. The syn or suprafacial character of these eliminations is enforced by the 5- or 6-membered cyclic transition states (A & B) by which they take place.

The temperature variations noted in the table suggest that these eliminations are facilitated by a negative charge on the O or Z atom and a low C–Y bond energy. Amine oxides have a full negative charge on the oxygen, and the Cope elimination proceeds well at temperatures near or slightly above 100 ºC. Together with the Hofmann elimination, Cope eliminations have proven useful for removing a permethylated amino group from a larger molecule. Sulfoxides are eliminated to sulfenic acids at roughly similar temperatures as the amine oxides. Here, oxygen charge neutralization by p-d bonding to the positive sulfur atom is balanced by the weaker C–S bond. Selenoxides eliminate rapidly at low temperature, reflecting a greater charge on oxygen due to poorer p-d bonding (selenium is much larger than oxygen), and a weak C–Se bond.
Although a six-membered transition state is relatively unstrained, esters and thioesters of alcohols require higher temperatures for elimination. This is expected because of the stronger C–O bond and the lower polarity of C=Z. The thioester function of xanthate derivatives of alcohols undergoes elimination at much lower temperatures than carboxylic esters, probably reflecting a favorable bond energy change from O–C=S in the xanthate to S–C=O in the eliminated fragment.

Some examples of these syn-thermal eliminations are given in the following diagram. The ester pyrolysis in equation # 4 demonstrates the importance of a cis-alignment of the eliminating groups, in this case the acetate ester and the vicinal hydrogen atom. Xanthate ester pyrolysis (equation # 5) is known as the Chugaev (or Tschugaev) reaction. Finally, the conversion of 1º-alcohols to aryl selenium ethers prior to selenoxide elimination, as in example # 3, is carried out via a hypervalent phosphorus species similar to that involved in the Mitsunobu reaction. The preferred aryl group in the selenocyanate reagent is o-nitrophenyl.

Reactions of Aryl Diazonium Salts

1. 1. Substitution with Loss of Nitrogen
2. 2. Bonding to Nitrogen
3. 3. Contributors

Substitution with Loss of Nitrogen

Aryl diazonium salts are important intermediates. They are prepared in cold (0 º to 10 ºC) aqueous solution, and generally react with nucleophiles with loss of nitrogen. Some of the more commonly used substitution reactions are shown in the following diagram. Since the leaving group (N2) is thermodynamically very stable, these reactions are energetically favored. Those substitution reactions that are catalyzed by cuprous salts are known as Sandmeyer reactions. Fluoride substitution occurs on treatment with BF4(–), a reaction known as theSchiemann reaction. Stable diazonium tetrafluoroborate salts may be isolated, and on heating these lose nitrogen to give an arylfluoride product. The top reaction with hypophosphorus acid, H3PO2, is noteworthy because it achieves the reductive removal of an amino (or nitro) group. Unlike the nucleophilic substitution reactions, this reduction probably proceeds by a radical mechanism.'

These aryl diazonium substitution reactions significantly expand the tactics available for the synthesis of polysubstituted benzene derivatives. Consider the following options:

(i)   The usual precursor to an aryl amine is the corresponding nitro compound. A nitro substituent deactivates an aromatic ring and directs electrophilic substitution to meta locations.
(ii)   Reduction of a nitro group to an amine may be achieved in several ways. The resulting amine substituent strongly activates an aromatic ring and directs electrophilic substitution to ortho & para locations.
(iii)   The activating character of an amine substituent may be attenuated by formation of an amide derivative (reversible), or even changed to deactivating and meta-directing by formation of a quaternary-ammonium salt (irreversible).
(iv)   Conversion of an aryl amine to a diazonium ion intermediate allows it to be replaced by a variety of different groups (including hydrogen), which may in turn be used in subsequent reactions.

The following examples illustrate some combined applications of these options to specific cases. You should try to conceive a plausible reaction sequence for each. Once you have done so, you may check suggested answers by clicking on the question mark for each.

Polybromination of benzene would lead to ortho/para substitution. In order to achieve the mutual meta-relationship of three bromines, it is necessary to introduce a powerful ortho/para-directing prior to bromination, and then remove it following the tribromination. An amino group is ideal for this purpose. Reductive removal of the diazonium group may be accomplished in several ways (three are shown).

The propyl substituent is best introduced by Friedel-Crafts acylation followed by reduction, and this cannot be carried out in the presence of a nitro substituent. Since an acyl substituent is a meta-director, it is logical to use this property to locate the nitro and chloro groups before reducing the carbonyl moiety. The same reduction method can be used to reduce both the nitro group (to an amine) and the carbonyl group to propyl. We have already seen the use of diazonium intermediates as precursors to phenols.

Aromatic iodination can only be accomplished directly on highly activated benzene compounds, such as aniline, or indirectly by way of a diazonium intermediate. Once again, a deactivated amino group is the precursor of p-nitroaniline (prb.#3). This aniline derivative requires the more electrophilic iodine chloride (ICl) for ortho-iodination because of the presence of a deactivating nitro substituent. Finally, the third iodine is introduced by the diazonium ion procedure.

Bonding to Nitrogen

A resonance description of diazonium ions shows that the positive charge is delocalized over the two nitrogen atoms. It is not possible for nucleophiles to bond to the inner nitrogen, but bonding (or coupling) of negative nucleophiles to the terminal nitrogen gives neutral azo compounds. As shown in the following equation, this coupling to the terminal nitrogen should be relatively fast and reversible. The azo products may exist as E / Z stereoisomers. In practice it is found that the E-isomer predominates at equilibrium.

Unless these azo products are trapped or stabilized in some manner, reversal to the diazonium ion and slow nucleophilic substitution at carbon (with irreversible nitrogen loss) will be the ultimate course of reaction, as described in the previous section. For example, if phenyldiazonium bisufate is added rapidly to a cold solution of sodium hydroxide a relatively stable solution of sodium phenyldiazoate (the conjugate base of the initially formed diazoic acid) is obtained. Lowering the pH of this solution regenerates phenyldiazoic acid (pKa ca. 7), which disassociates back to the diazonium ion and eventually undergoes substitution, generating phenol.

C6H5N2(+) HSO4(–)  +  NaOH (cold solution)		C6H5N2–OH  +  NaOH (cold)		C6H5N2–O(–) Na(+)
phenyldiazonium bisulfate		phenyldiazoic acid		sodium phenyldiazoate

Aryl diazonium salts may be reduced to the corresponding hydrazines by mild reducing agents such as sodium bisulfite, stannous chloride or zinc dust. The bisulfite reduction may proceed by an initial sulfur-nitrogen coupling, as shown in the following equation.

Ar-N2(+) X(–)

NaHSO3

Ar-N=N-SO3H

NaHSO3

Ar-NH-NH-SO3H

H2O

Ar-NH-NH2  +  H2SO4

The most important application of diazo coupling reactions is electrophilic aromatic substitution of activated benzene derivatives by diazonium electrophiles. The products of such reactions are highly colored aromatic azo compounds that find use as synthetic dyestuffs, commonly referred to as azo dyes. Azobenzene (Y=Z=H) is light orange; however, the color of other azo compounds may range from red to deep blue depending on the nature of the aromatic rings and the substituents they carry. Azo compounds may exist as cis/trans isomer pairs, but most of the well-characterized and stable compounds are trans.

Some examples of azo coupling reactions are shown below. A few simple rules are helpful in predicting the course of such reactions:
         (i)   At acid pH (< 6) an amino group is a stronger activating substituent than a hydroxyl group (i.e. a phenol). At alkaline pH (> 7.5) phenolic functions are stronger activators, due to increased phenoxide base concentration.
         (ii)   Coupling to an activated benzene ring occurs preferentially para to the activating group if that location is free. Otherwise ortho-coupling will occur.
         (iii)   Naphthalene normally undergoes electrophilic substitution at an alpha-location more rapidly than at beta-sites; however, ortho-coupling is preferred. See the diagram for examples of α / β notation in naphthalenes.

You should try to conceive a plausible product structure for each of the following couplings.

amines - nomenclature

Amines are derivatives of ammonia in which one or more of the hydrogens has been replaced  by an alkyl or aryl group. The nomenclature of amines is complicated by the fact that several different nomenclature systems exist, and there is no clear preference for one over the others. Furthermore, the terms primary (1º), secondary (2º) & tertiary (3º) are used to classify amines in a completely different manner than they were used for alcohols or alkyl halides. When applied to amines these terms refer to the number of alkyl (or aryl) substituents bonded to the nitrogen atom, whereas in other cases they refer to the nature of an alkyl group. The four  compounds shown in the top row of the following diagram are all C4H11N isomers. The first two are classified as 1º-amines, since only one alkyl group is bonded to the nitrogen; however, the alkyl group is primary in the first example and tertiary in the second. The third and fourth 
compounds in the row are 2º and 3º-amines respectively. A nitrogen bonded to four alkyl groups will necessarily be positively charged, and is called a 4º-ammonium cation. Forexample, (CH3)4N(+) Br(–) is tetramethylammonium bromide.

Reaction of Amines with Nitrous Acid

1. 1. Primary Amines
2. 2. Secondary Amines
3. 3. Aryl Amines
   1. 3.1. 2º-Aryl Amines:
   2. 3.2. 3º-Aryl Amines:
4. 
   

Nitrous acid (HNO2 or HONO) reacts with aliphatic amines in a fashion that provides a useful test for distinguishing primary, secondary and tertiary amines.

1°-Amines + HONO (cold acidic solution) Nitrogen Gas Evolution from a Clear Solution 2°-Amines + HONO (cold acidic solution) An Insoluble Oil (N-Nitrosamine) 3°-Amines + HONO (cold acidic solution) A Clear Solution (Ammonium Salt Formation)

Nitrous acid is a Brønsted acid of moderate strength (pKa = 3.3). Because it is unstable, it is prepared immediately before use in the following manner:

Under the acidic conditions of this reaction, all amines undergo reversible salt formation:

This happens with 3º-amines, and the salts are usually soluble in water. The reactions of nitrous acid with 1°- and 2°- aliphatic amines may be explained by considering their behavior with the nitrosonium cation, NO(+), an electrophilic species present in acidic nitrous acid solutions.

Primary Amines

Secondary Amines

The distinct behavior of 1º, 2º & 3º-aliphatic amines is an instructive challenge to our understanding of their chemistry, but is of little importance as a synthetic tool. The SN1 product mixtures from 1º-amines are difficult to control, and rearrangement is common when branched primary alkyl groups are involved. The N-nitrosamines formed from 2º-amines are carcinogenic, and are not generally useful as intermediates for subsequent reactions.

Aryl Amines

Nitrous acid reactions of 1º-aryl amines generate relatively stable diazonium species that serve as intermediates for a variety of aromatic substitution reactions. Diazonium cations may be described by resonance contributors, as in the bracketed formulas shown below. The left-hand contributor is dominant because it has greater bonding. Loss of nitrogen is slower than in aliphatic 1º-amines because the C-N bond is stronger, and aryl carbocations are comparatively unstable.

Aqueous solutions of these diazonium ions have sufficient stability at 0º to 10 ºC that they may be used as intermediates in a variety of nucleophilic substitution reactions. For example, if water is the only nucleophile available for reaction, phenols are formed in good yield.

2º-Aryl Amines:

2º-Aryl amines give N-nitrosamine derivatives on reaction with nitrous acid, and thus behave identically to their aliphatic counterparts.

3º-Aryl Amines:

Depending on ring substitution, 3º-Aryl amines may undergo aromatic ring nitrosation at sites ortho or para to the amine substituent. The nitrosonium cation is not sufficiently electrophilic to react with benzene itself, or even toluene, but highly activated aromatic rings such as amines and phenols are capable of substitution. Of course, the rate of reaction of NO(+) directly at nitrogen is greater than that of ring substitution, as shown in the previous example. Once nitrosated, the activating character of the amine nitrogen is greatly diminished; and N-nitrosoaniline derivatives, or indeed any amide derivatives, do not undergo ring nitrosation.

reaction of amines

Electrophilic Substitution at Nitrogen

Ammonia and many amines are not only bases in the Brønsted sense, they are also nucleophiles that bond to and form products with a variety of electrophiles. A general equation for such electrophilic substitution of nitrogen is:

2 R2ÑH   +   E(+)      R2NHE(+)      R2ÑE  +   H(+) (bonded to a base)

A list of some electrophiles that are known to react with amines is shown here. In each case the electrophilic atom or site is colored red.

Electrophile	RCH2–X	RCH2–OSO2R	R2C=O	R(C=O)X	RSO2–Cl	HO–N=O
Name	Alkyl Halide	Alkyl Sulfonate	Aldehyde   or Ketone	Acid Halide or Anhydride	Sulfonyl Chloride	Nitrous Acid

Alkylation

It is instructive to examine these nitrogen substitution reactions, using the common alkyl halide class of electrophiles. Thus, reaction of a primary alkyl bromide with a large excess of ammonia yields the corresponding 1º-amine, presumably by an SN2 mechanism. The hydrogen bromide produced in the reaction combines with some of the excess ammonia, giving ammonium bromide as a by-product. Water does not normally react with 1º-alkyl halides to give alcohols, so the enhanced nucleophilicity of nitrogen relative to oxygen is clearly demonstrated.

2 RCH2Br  +  NH3 (large excess)      RCH2NH2  +  NH4(+) Br(–)

It follows that simple amines should also be more nucleophilic than their alcohol or ether equivalents. If, for example, we wish to carry out an SN2 reaction of an alcohol with an alkyl halide to produce an ether (the Williamson synthesis), it is necessary to convert the weakly nucleophilic alcohol to its more nucleophilic conjugate base for the reaction to occur. In contrast, amines react with alkyl halides directly to give N-alkylated products. Since this reaction produces HBr as a co-product, hydrobromide salts of the alkylated amine or unreacted starting amine (in equilibrium) will also be formed.

2 RNH2  +  C2H5Br    RNHC2H5  +  RNH3(+) Br(–)    RNH2C2H5(+) Br(–)  +  RNH2

Unfortunately, the direct alkylation of 1º or 2º-amines to give a more substituted product does not proceed cleanly. If a 1:1 ratio of amine to alkyl halide is used, only 50% of the amine will react because the remaining amine will be tied up as an ammonium halide salt (remember that one equivalent of the strong acid HX is produced). If a 2:1 ratio of amine to alkylating agent is used, as in the above equation, the HX issue is solved, but another problem arises. Both the starting amine and the product amine are nucleophiles. Consequently, once the reaction has started, the product amine competes with the starting material in the later stages of alkylation, and some higher alkylated products are also formed. Even 3º-amines may be alkylated to form quaternary (4º) ammonium salts. When tetraalkyl ammonium salts are desired, as shown in the following example, Hünig's base may be used to scavenge the HI produced in the three SN2 reactions. Steric hindrance prevents this 3º-amine (Hünig's base) from being methylated.

C6H5NH2  +  3 CH3I  +   Hünig's base    C6H5N(CH3)3(+) I(–)  +  HI salt of Hünig's base

The Hinsberg Test: Reaction with benzenesulfonyl chloride

Another electrophilic reagent, benzenesulfonyl chloride, reacts with amines in a fashion that provides a useful test for distinguishing primary, secondary and tertiary amines (the Hinsberg test). As shown in the following equations, 1º and 2º-amines react to give sulfonamide derivatives with loss of HCl, whereas 3º-amines do not give any isolable products other than the starting amine. In the latter case a quaternary "onium" salt may be formed as an intermediate, but this rapidly breaks down in water to liberate the original 3º-amine (lower right equation).

The Hinsberg test is conducted in aqueous base (NaOH or KOH), and the benzenesulfonyl chloride reagent is present as an insoluble oil. Because of the heterogeneous nature of this system, the rate at which the sulfonyl chloride reagent is hydrolyzed to its sulfonate salt in the absence of amines is relatively slow. The amine dissolves in the reagent phase, and immediately reacts (if it is 1º or 2º), with the resulting HCl being neutralized by the base. The sulfonamide derivative from 2º-amines is usually an insoluble solid. However, the sulfonamide derivative from 1º-amines is acidic and dissolves in the aqueous base. Acidification of this solution then precipitates the sulfonamide of the 1º-amine.