PROBLEM

How can we predict whether a molecule is Chiral or not?

answer: Molecules are not chiral if it contains the symmetry (plane of simmetry). Side of the symmetry in question is the flat side of the cut through the middle of the molecule. as an example Erlenmeyer tubes have semetri side. If we cut Erlenmeyer tube vertically, one side will be visible is the mirror image of the other side. One of our hands not have the symmetry due to the half was not are mirror images.

STEREOCHEMISTRY

STEREOCHEMISTRY 

A. Enantiomers and the tetrahedral carbon
Try to pay attention CH3X compounds, CH2XY, and CHXYZ. On the left side is 3 molecule and the right were the mirror image of the three compounds. CH3X compounds, and CH2XY is identical with the shadow of the mirror. If you make a molecular model of each molecule and the molecular mirror image, it will get that you can squeeze a molecule with a mirror image (superimposed). Unlike CH3X, and CH2XY, CHXYZ not identical a mirror image. You can not do superimposed molecular models and molecular models of the mirror image, just as you squeeze your right hand with your left hand. Maybe you can squeeze 2 subtituennya, eg X and Y, but the H and Z will each opposite. Similarly, if the coincident H and Z, X and Y will also of each other.

Mirror-image molecules that can not coincide called enantiomers (Greek enantio means contrary / opposite). Enantiomers related to carbon tetrahedral. Suppose that lactic acid (acid 2-hidroksipropanoat) that a pair of enantiomers due to having four groups different (-OH,-H,-CH3,-CO2H) on the carbon atom as center. Enantiomers are called (+)-lactic acid and (-)-acid lactate.

You do not molecule may squeeze (+) lactic acid in the molecule (-) lactic acid. If the two groups may coincide, for example, H and - COOH, the two other groups will not be able to coincide.

B. Chirality
If a molecule can not coincide with means that the mirror image enantiomers of both compounds are called
Chiral / chiral (ky-ral Greek cheir, meaning "hand").

Which has the symmetry of the molecule in various likely to be identical in conformation with the shadow
mirror and is therefore a compound nonkiral or so-called achiral. Most, though not all, the cause of the chirality due to a compound that binds to the carbon atom 4 different groups. Carbon atom is termed as a center of chirality (chirality centers). Note, the chirality is the nature of the whole molecule, where the center of chirality is a characteristic structure cause chirality. Chirality is not only determined by the difference
atom is bonded directly to carbon, but the difference in the fourth groups bound to carbon as a chiral center. Such as 5 - bromodekana a chiral compound as it binds four different groups.

                                                                            Br

                                                                             |

                                     CH3CH2CH2CH2CH2-C-CH2CH2CH2CH3

                                                                             |
                                                                            H
                                                                5-Bromodekana
                                                                         (Chiral)

Substituent butyl substituents similar to the nipple. However, both Another example is not the same metilsikloheksana. whether the molecule The chiral? Metilsikloheksana an achiral molecule, because does not have four different groups attached to one carbon. Atoms C2, C3, C4, C5, and C6 atoms is clearly not chiral because it has two H atoms are identical (-CH2-). C1 atoms bonded to H, CH3, C2 and C6, in which
C2 atom in the C3-C4 terkat while bound to the C5-C6 C4. by because the C2-C3-C4-C5 is identical to the C6 atom C1-C4 is not the atom chiral. So overall, not a chiral molecule compounds metilsikloheksana. 

C. Optical activity
In addition to the chirality, the structures of the couple enantiomer is the same. Therefore, almost all physical properties also the same chemical. For example, each have a pure enantiomer melting point and boiling point with the same partner. only There are two different properties for the enantiomer-enantiomer in a pair of enantiomers, namely:

1. Inter-action with other chiral compounds
2. Inter-action with polarized light

Studies on the stereochemistry at the beginning of the nineteenth century by French scientist, Jean Batiste Biot. Biot discovered the nature of light polarized field (plane-polarized light). A light beam is composed of electromagnetic waves that oscillate at infinite field at an angle perpendicular to the direction of propagation
wave. When a light beam through the polarizer, only isolation waves in a field that can be passed so-called polarized light field. Apparently some of the optically active molecules can rotate plane of polarization. Optically active molecules that rotate the plane of polarization to the right (clockwise) is called dextrorotatory (dextrorotatory) or given notation (+). Conversely, when the rotating field of optically active molecules
polarization to the left (counterclockwise) is said to be levorotatori or negetif notation (-). Specific rotation, [α] D, of a compound can be defined as the rotation of light (λ = 589 nm) is generated when the sample

D. Specific configuration rules
Cahn Ingold Prelog rules
Rule 1: Consider the four atoms directly attached to the chirality center and make priorities based on the decrease in number atom. Atoms that have the priority to occupy the highest atomic number first, while the atom that has a low atomic number (usually hydrogen) occupies the fourth priority.

 
Rule 2: If the creation of priority can not use the rule 1, compare the number of atoms at the second atom of each substituent, followed on the third atom, and so on until found differences in their atomic numbers so that it can be made a priority.

 
Rule 3: Multibonding atom is equal to the number of atoms with single bonds. Having made ​​a priority in the four substituents attached directly to the chiral carbon centers, we can determine the configuration stereochemistry by changing the orientation of the molecules so that the four priorities of substituents are made away from us. The remaining three substituents will look like steer a car. The next step made ​​toward
Turn the car steer us in the order of priority until finally the third priority. If it turns out that steer the direction
we make a clockwise (clockwise) then said to be the center of chirality has the R configuration (the letter R comes from the Latin rectus which means "right"). If we steer the direction opposite to the direction clockwise (counterclockwise) is said to be the center of chirality has the S configuration (the letter S comes from the Latin sinister which means "left").

 
E. Diastereomers
Diastereomers are stereoisomers that are not shadows mirror. Chiral diastereomers having the opposite configuration at the chiral centers but has some configuration The same with the others. As a comparison, enantiomer which has the opposite configuration at all chiral centers.

F. Meso compounds
Mirror-image structure 2R, 3R and 2S, 3S is not identical but a pair of enantiomers. if the observed actually, the structure of 2R, 3R and 2S, 3S is identical if one structure is rotated 180 °.

The structure of 2R, 3S and 2S, 3R are identical because the molecules it has a plane of symmetry so that the achiral. plane of symmetry cut on the C2-C3 bond to half a the mirror image of the next half.

 

The above compound is achiral, but contains two central Chiral called meso compounds.

G. Molecules that have more than two
Chiral Center
Apparently a chiral center in one molecule give two stereoisomers (a pair of enantiomers) and two chiral centers in one molecule to give a maximum of 4 stereoisomers or 2 pairs of enantiomers. In general, a molecule with n center has a maximum of 2n chiral stereoisomer or 2n-1 pairs enantiomer, although it may be less because of possible several stereoisomers are meso compounds. Examples of cholesterol contain chiral centers 8, 28 = 256 possible stereoisomers, although some of them are too complicated to exist, there is only one found in nature.

                                                                                  or

HYDROLYSING NITRILES
This page looks at the hydrolysis of nitriles under either acidic or alkaline conditions to make carboxylic acids or their salts.
The hydrolysis of nitriles Introduction
When nitriles are hydrolysed you can think of them reacting with water in two stages - first to produce an amide, and then the ammonium salt of a carboxylic acid.
For example, ethanenitrile would end up as ammonium ethanoate going via ethanamide.

In practice, the reaction between nitriles and water would be so slow as to be completely negligible. The nitrile is instead heated with either a dilute acid such as dilute hydrochloric acid, or with an alkali such as sodium hydroxide solution.
The end result is similar in all the cases, but the exact nature of the final product varies depending on the conditions you use for the reaction.

1. Acidic hydrolysis of nitriles
The nitrile is heated under reflux with dilute hydrochloric acid. Instead of getting an ammonium salt as you would do if the reaction only involved water, you produce the free carboxylic acid.
For example, with ethanenitrile and hydrochloric acid you would get ethanoic acid and ammonium chloride.

Why is the free acid formed rather than the ammonium salt? The ethanoate ions in the ammonium ethanoate react with hydrogen ions from the hydrochloric acid to produce ethanoic acid. Ethanoic acid is only a weak acid and so once it has got the hydrogen ion, it tends to hang on to it.

2. Alkaline hydrolysis of nitriles
The nitrile is heated under reflux with sodium hydroxide solution. This time, instead of getting an ammonium salt as you would do if the reaction only involved water, you get the sodium salt. Ammonia gas is given off as well.
For example, with ethanenitrile and sodium hydroxide solution you would get sodium ethanoate and ammonia.

The ammonia is formed from reaction between ammonium ions and hydroxide ions.

USEFULL NITRILE

Nitrile gloves are a type of disposable glove made of synthetic rubber. They contain no latex proteins and offer excellent resistance to wear and tears. Nitrile gloves are more puncture resistant than many other types of rubber gloves and can be used to offer superior resistance to many types of chemicals. They are often considered to be one of the the strongest types of disposable glove and are generally safe for people who are allergic to latex.

Unlike other disposable gloves, nitrile gloves have low resistance to friction and are very easy to slide on. As with some other types of disposable gloves, however, powder such as cornstarch may be added in order to make putting on the gloves as easy as possible. Nitrile gloves come in a variety of sizes to fit all hands, from extra small to extra large. They can be made in a variety of textures, cuff lengths and thickness.

These gloves are popular for their high degree of flexibility and superior solvent resistance. They are resistant to many oils and some acids, making nitrile gloves a good choice for many manufacturing environments. Nitrile gloves should not be stored under excessive light or heat, however, as that can make the rubber disintegrate more rapidly.
 

NITRILE

A nitrile is any organic compound that has a -C≡N functional group. The prefix cyano- is used interchangeably with the term nitrile in industrial literature. Nitriles are found in many useful compounds, including methyl cyanoacrylate, used in super glue, and nitrile butadiene rubber, a nitrile-containing polymer used in latex-free laboratory and medical gloves. Organic compounds containing multiple nitrile groups are known as cyanocarbons.

Inorganic compounds containing the -C≡N group are not called nitriles, but cyanides instead. Though both nitriles and cyanides can be derived from cyanide salts, most nitriles are not nearly as toxic.

HISTORY

The first compound of the homolog row of nitriles, the nitrile of formic acid, hydrogen cyanide was first synthesized by C.W. Scheele in 1782. In 1811 J. L. Gay-Lussac was able to prepare the very toxic and volatile pure acid. The nitrile of benzoic acids was first prepared by Friedrich Wöhler and Justus von Liebig, but due to minimal yield of the synthesis neither physical nor chemical properties were determined nor a structure suggested. Théophile-Jules Pelouze synthesized propionitrile in 1834 suggesting it to be an ether of propionic alcohol and hydrocyanic acid. The synthesis of benzonitrile by Hermann Fehling in 1844, by heating ammonium benzoate, was the first method yielding enough of the substance for chemical research. He determined the structure by comparing it to the already known synthesis of hydrogen cyanide by heating ammonium formate to his results. He coined the name nitrile for the newfound substance, which became the name for the compound group.

SYNTHESIS

Industrially, the main methods for producing nitriles are ammoxidation and hydrocyanation. Both routes are green in the sense that they do not generate stoichiometric amounts of salts.

1. Ammoxidation

In ammonoxidation, a hydrocarbon is partially oxidized in the presence of ammonia. This conversion is practiced on a large scale for acrylonitrile

CH₃CH=CH₂ + 3/2 O₂ + NH₃ → NCCH=CH₂ + 3 H₂O

A side product of this process is acetonitrile. Most derivatives of benzonitrile as well as Isobutyronitrile are prepared by ammoxidation.

2. Hydrocyanation

An example of hydrocyanation is the production of adiponitrile from 1,3-butadiene:

CH₂=CH-CH=CH₂ + 2 HCN → NC(CH₂)₄CN

3. From organic halides and cyanide salts

Often for more specialty applications, nitriles can be prepared by a wide variety of other methods. For example, alkyl halides undergo nucleophilic aliphatic substitution with alkali metal cyanides in the Kolbe nitrile synthesis. Aryl nitriles are prepared in the Rosenmund-von Braun synthesis.

4. Cyanohydrins

The cyanohydrins are a special class of nitriles that result from the addition of metal cyanides to aldehydes in the cyanohydrin reaction. Because of the polarity of the organic carbonyl, this reaction requires no catalyst, unlike the hydrocyanation of alkenes.

5. Dehydration of amides and oximes

Nitriles can be prepared by the Dehydration of primary amides. Many reagents are available, the combination of ethyl dichlorophosphate and DBU just one of them in this conversion of benzamide to benzonitrile: 

Two intermediates in this reaction are amide tautomer A and its phosphate adduct B.

In a related dehydration, secondary amides give nitriles by the von Braun amide degradation. In this case, one C-N bond is cleaved. The dehydration of aldoximes (RCH=NOH) also affords nitriles. Typical reagents for this transformation arewith triethylamine/sulfur dioxide, zeolites, or sulfuryl chloride. Exploiting this approach is the One-pot synthesis of nitriles from aldehyde with hydroxylamine in the presence of sodium sulfate.

 

from aryl carboxylic acids (Letts nitrile synthesis)

Sandmeyer reaction

Aromatic nitriles are often prepared in the laboratory form the aniline via diazonium compounds. This is the Sandmeyer reaction. It requires transition metal cyanides.

ArN₂⁺ + CuCN → ArCN + N₂ + Cu⁺

 

Other methods

• A commercial source for the cyanide group is diethylaluminum cyanide Et₂AlCN which can be prepared from triethylaluminium and HCN. It has been used in nucleophilic addition to ketones. For an example of its use see: Kuwajima Taxol total synthesis
• cyanide ions facilitate the coupling of dibromides. Reaction of α,α'-dibromo adipic acid with sodium cyanide in ethanol yields the cyano cyclobutane.

 

In the so-called Franchimont Reaction (A. P. N. Franchimont, 1872) an α-bromocarboxylic acid is dimerized after hydrolysis of the cyanogroup and decarboxylation^.

• Aromatic nitriles can be prepared from base hydrolysis of trichloromethyl aryl ketimines (RC(CCl₃)=NH) in the Houben-Fischer synthesis

Reactions

Nitrile groups in organic compounds can undergo various reactions when subject to certain reactants or conditions. A nitrile group can be hydrolyzed, reduced, or ejected from a molecule as a cyanide ion.

Hydrolysis

The hydrolysis of nitriles RCN proceeds in the distinct steps under acid or base treatment to achieve carboxamides RC(=O)NH₂ and then carboxylic acids RCOOH. The hydrolysis of nitriles is generally considered to be one of the best methods for the preparation of carboxylic acids. However, these base or acid catalyzed reactions have certain limitations and/or disadvantages for preparation of amides. The general restriction is that the final neutralization of either base or acid leads to an extensive salt formation with inconvenient product contamination and pollution effects. Particular limitations are as follows:

• The base catalyzed reactions. The kinetic studies allowed the estimate of relative rates for the hydration at each step of the reaction and, as a typical example, the second-order rate constants for hydroxide-ion catalyzed hydrolysis of acetonitrile and acetamide are 1.6×10⁻⁶ and 7.4×10⁻⁵M⁻¹s⁻¹, respectively. Comparison of these two values indicates that the second step of the hydrolysis for the base-catalyzed reaction is faster than the first one, and the reaction should proceed to the final hydration product (the carboxylate salt) rather than stopping at the amide stage. This implies that amides prepared in the conventional metal-free base-catalyzed reaction should be contaminated with carboxylic acids and they can be isolated in only moderate yields.
• The acid catalyzed reactions. Application of strong acidic solutions requires a careful control of the temperature and of the ratio of reagents in order to avoid the formation of polymers, which is promoted by the exothermic character of the hydrolysis.

Reduction

In organic reduction the nitrile is reduced by reacting it with hydrogen with a nickel catalyst; an amine is formed in this reaction (see nitrile reduction). Reduction to the amine followed by hydrolysis to the aldehyde takes place in the Stephen aldehyde synthesis

Alkylation

Alkyl nitriles are sufficiently acidic to form the carbanion, which alkylate a wide variety of electrophiles. Key to the exceptional nucleophilicity is the small steric demand of the CN unit combined with its inductive stabilization. These features make nitriles ideal for creating new carbon-carbon bonds in sterically demanding environments for use in syntheses of medicinal chemistry. Recent developments have shown that the nature of the metal counter-ion causes different coordination to either the nitrile nitrogen or the adjacent nucleophilic carbon, often with profound differences in reactivity and stereochemistry.

Nucleophiles

A nitrile is an electrophile at the carbon atom in a nucleophilic addition reactions:

• with an organozinc compound in the Blaise reaction
• and with alcohols in the Pinner reaction.
• likewise, the reaction of the amine sarcosine with cyanamide yields creatine
• Nitriles react in Friedel-Crafts acylation in the Houben-Hoesch reaction to ketones

Miscellaneous methods and compounds

• In reductive decyanation the nitrile group is replaced by a proton.An effective decyanation is by a dissolving metal reduction with HMPA and potassium metal in tert-butanol. α-Amino-nitriles can be decyanated with lithium aluminium hydride.
• Nitriles self-react in presence of base in the Thorpe reaction in a nucleophilic addition
• In organometallic chemistry nitriles are known to add to alkynes in carbocyanation:

 

Nitrile derivatives

Organic cyanamides

Cyanamides are N-cyano compounds with general structure R₁R₂N-CN and related to the inorganic parent cyanamide. For an example see: von Braun reaction.

Nitrile oxides

Nitrile oxides have the general structure R-CNO.

Occurrence and applications

Nitriles occur naturally in a diverse set of plant and animal sources. Over 120 naturally occurring nitriles have been isolated from terrestrial and marine sources. Nitriles are commonly encountered in fruit pits, especially almonds, and during cooking of Brassica crops (such as cabbage, brussel sprouts, and cauliflower), which release nitriles being released through hydrolysis. Mandelonitrile, a cyanohydrin produced by ingesting almonds or some fruit pits, releases hydrogen cyanide and is responsible for the toxicity of cyanogenic glycosides.
Over 30 nitrile-containing pharmaceuticals are currently marketed for a diverse variety of medicinal indications with more than 20 additional nitrile-containing leads in clinical development. The nitrile group is quite robust and, in most cases, is not readily metabolized but passes through the body unchanged. The types of pharmaceuticals containing nitriles is diverse, from Vildagliptin an antidiabetic drug to Anastrazole which is the gold standard in treating breast cancer. In many instances the nitrile mimics functionality present in substrates for enzymes, whereas in other cases the nitrile increases water solubility or decreases susceptibility to oxidative metabolism in the liver.The nitrile functional group is found in several drugs.

• 

  Structure of periciazine, an antipsychotic studied in the treatment of opiate dependence.
  
• 

  Structure of citalopram, an antidepressant drug of the selective serotonin reuptake inhibitor (SSRI) class.
  
• 

  Structureof cyamemazine, an antipsychotic drug.
  
• 

  Structure of fadrozole, an aromatase inhibitor for the treatment of breast cancer.
  
• 

  Structure of letrozole, an oral non-steroidal aromatase inhibitor for the treatment of certain breast cancers.
  

 

 

 

 

 

LAKTAM

This issue of Enamine Product Focus highlights Lactams, cyclic amide building blocks. There are numerous examples of Lactams usage in drug discovery, e.g., β-lactam based antibiotics, oral anticoagulant Rivaroxaban, and anticonvulsant Levetiracetam.

                                       

Rivaroxaban, 2008                                                           Levetiracetam, 2000

The specific features of Lactam building blocks that are of advantage to drug design are summarized in the chart below.

Enamine’s Lactam building block collection is represented by many useful scaffolds, for example, piperidones, piperazinones, (thio)morpholiones, pyrrolidones, and their benzo-fused analogues. From combinatorial chemistry standpoint especially interesting lactams in our collection are those bearing additional functionalities, such as carboxyl, chlorosulfonyl, and amino-groups.

                                                                                     

Piperidones                                                 Piperazinones                                                   Morpholinones

       

Thiomorpholinones               Pyrrolidones                              Dihydroquinoxalinones

The procedures developed for the synthesis of our Lactams allow preparation of highly diverse building blocks on 1–10 g scale. In addition we offer synthesis of novel compounds of the requested structure in 4–8 weeks. Scale-up to 1 kg quantity is performed upon request.

Amines

EN300-14698	EN400-15942	EN300-12374
EN400-15247	EN300-04190	EN300-05878
EN300-27804	EN300-35705	EN300-36103
EN300-14296	EN300-14821	EN300-35764

Sulfochlorides

EN300-13073	EN300-13555	EN300-14981

Carboxylic acids

EN300-42819	EN300-26212	EN300-23517
EN300-13491	EN300-08179	EN300-22965

Other Lactams

EN300-29977	EN300-35893	EN300-12065
EN300-35925	EN300-26962	EN300-23715
EN300-27121	EN300-52210	EN300-62393