Pharmacist Blog about what I encounter and find useful/interesting

Breaking Bad chemical structure on poster I noticed a new poster from my favorite TV show Breaking Bad, the series focuses on a chemistry teacher going "bad", becoming a big drug dealer in meth. Here it is, taking from their official facebook: It is kind of obvious for watchers that this molecule is actually the product they synthesize is methamfetamine . People that are in doubt, the structure is correct . I have no idea about you, but when I first heard about drugs and other anaesthesia, I thought these molecules had big complicated structures. As for this example, methyl-amfetamine, it isn't hard to right down nor the structure is far from complicated. To go more into detail on this molecule I advise to search the web a bit more, I do not know much about this drug so I will not try to determine its effects and other functions (tip: a good reason to watch the series).

How I felt the first time I got introduced to Chemistry, and I'm sure, a lot of other people have had the same feeling.

Feeling of an organic chemist

I currently have examinations so I'll have a break from blogging.

Alkanes and radicals Addition of radicals on an alkene Look at the two reactions below, the first reaction is in normal circumstances, which will result in a normal Markovnikov reaction  ( with the addition of a   protic acid  HX to an  alkene , the acid hydrogen (H) becomes attached to the carbon with fewer   alkyl   substituents , and the  halide  (X) group becomes attached to the carbon with more alkyl substituents). In the second reaction, peroxide is used as condition, this will result in an anti-Markovnikov  reaction. The peroxide will generate Br radicals in small amounts (this is the initiation for this anti-reaction).  Let's see the peroxide mechanism in detail. As stated above, an alkyl peroxide is a radical initiator. The electrophile will add on the sp2 carbon which carries the most hydrogens (where also the radical with most alkyl groups will be formed). The termination reactions will have several other outcomes....

Alkanes and radicals Selectivity & reactivity principle Radical bromation is more selective than radical chlorination. Have a look on following illustrations to get more insight in this process: Why is it that the Bromation radical is more selective? This can be explained using the Hammand postulate. Bromation is an endothermic process, while chlorination is exothermic . The postulate states the following: Endothermic process: a rather productish (radical) transition state Exothermic: a rather reagentic (alkane) transition state Thus the Bromine atom can see the difference between the 1°, 2° and 3° hydrogens more clearly.  The more reactive a particle is, the less likely it will react selective. ( More reactivity = less selectivity, vice versa ). Alkanes undergo Bromation and Chlorination, but no Fluoration or Iodisation. Iodisation simply does not occur, and Fluoration is a way to heavy reaction to be useful.

Alkanes & radicals Relative stabilities of alkyl radicals Alkyl  groups stabilize carbocations about 5 to 10 times better than when alkyl groups have to stabilize radicals:  Radicals: Resonance >> Hyperconjugation Carbocations: Hyperconjugation >> Resonance Hyperconjugation makes the carbocations more stabilized than when hyperconjugation occurs with radicals (not so stable). This is explained due to the fact that in carbocations, both electrons sit in the same binding orbital, with radicals however, one of the electrons is sited in the anti-binding orbital.  Product spread The product spread (product outcome) is determined by CHANCE and REACTIVITY. The chance (or probability) is based on the relative amount of primary and secundary protons (in the example below 6:4), but secundary hydrogens are more reactive than primary hydrogens, this means both chance and reactivity determine the outcome of the reaction.  Thus to det...

Alkanes and radicals Introduction Let's start with one of the most complex compounds consisting of alkanes and cycloalkanes (naftenes) that can be separated by distillation: Petroleum . Some tips when writing reactions with radicals, have a look on these reactions below, when an heterolytic bond gets cleaved, the arrowhead gets two barbs. When there is a homolytic bond that gets cleaved the arrowhead that shows the direction of the radical, gets one barb, have a look: Alkanes are little reactive, they will not react fast and heavily, because they only contain strong  sigma  σ bindings (single bonds). They also only have non-partial charged atoms. Although, alkanes DO react with Cl2 and Br2. The reactions are listed below, have a look, first the actual reaction, then shown in detail with different steps : 

Alkylhalides: Substitution Nucleophile substitution reaction ( Sn1 reaction ) Sn1 side reactions I will now discuss some side reactions that can occur when a Sn1 reaction takes place. Carbocation shift Illustrated in the scheme below: Benzyl- and allylhalides  Benzyl- and allylhalides can undergo Sn1 AND Sn2 reactions. How to distinct them? Sn1 conditions: protic solvent and by adding a weak attacking nucleophile. Note: Benzyl- and allylhalides easily undergo Sn1 reactions, because their carbocations are very stable. Sn2 conditions: aprotic solvent and by adding a strong attacking nucleophile. Note: tertiary benzylhalides and tertiary allylhalides will NOT undergo a Sn2 reaction because of the steric effects (see chapter Sn2 reaction blogposts). Sn2 reaction examples Sn1 reaction examples Sn1 and Sn2 reactions in biology, nature and medicines S-Adenosyl methionine This is a biological methylating agens, also known as SAM . It is a frequen...

Alkylhalides: Substitution Nucleophile substitution reaction ( Sn1 reaction ) Solvent effects To start off, have a look on the rate determing step of the Sn1 reaction, what happens with the compound becoming split into 2 ions: The dielectric constant is a measure on how the solvent insulates the opposite charges from eachother. F.e. water will either contain the positive charged ion by using its partial negative oxygen, and it will contain the negative charged ion by using its partial positive hydrogen, thus separating both ions from eachother. A visual picture below from the Organic Chemistry book from Bruice found below to clear this up, on the left side the negative ion gets contained, on the right side the positive ion.  Relative rates of water and ethanol solvents are the following: 100% water    1200 80% water / 20% ethanol   400 50% water / 50% water   60 100% ethanol   10 In the next blog post it wi...

Alkylhalides: Substitution Nucleophile substitution reaction ( Sn1 reaction ) To kick off this new chapter from the alkylhalides, some experimental background theory concerning Sn1 reactions: the reaction rate of the reaction depends ONLY on the concentration of the alkyl halide   (unlike Sn2 reactions where the nucleophile concentration was important aswell !!!). the reaction rate of the reaction INCREASES if the alkylhalide is more branched at its reaction center (again unlike Sn2 reactions where more branched reaction centers are LESS active !!!). This means a tertiary alkyl bromide f.e. will have a huge relative reaction rate, methylbromide on the other hand will have no Sn1 reaction. when an alkyl halide reacts with its enantiomere (cfr. stereochemistry), the reaction product will be a racemic mixture (this is a mixture of two enantiomeres of the same compound) or partial racemic product. Conclusion: this indicates at the presence of a CARBOCATION intermediate ...

Alkylhalides: Substitution (Ir)reversibility Basic rule with substitution reactions: a Sn2 reaction always goes in the direction where the stronger base drives the weaker base away. The stronger base will the place of the weaker base, thus it is a irreversible reaction. For example have a look on following reaction:  CH3-Cl  +   OH-     >>       CH3-OH   +   Cl- Chloride is a weaker base than the added hydroxide ion, this means that the reaction is NOT reversible, thus irreversible. Solvent The problem with second row (O, N, ...) nucleophiles is that they are very small. Because they are so small, polar solvents are not fit for these nucleophiles. These nucleophiles get solvated very fast by these polar solvents, this blocks the nucleophile attacking the alkylhalide on the backside, and thus no reaction will take place. Conclusion : water and alcohol are NOT fit as solvent for 2nd row nucleophiles used with...

Alkylhalides: Substitution Inversion When a Sn2 reaction occurs, the stereo configuration of the molecule which is attacked will changed, it will be inverted relative to the original reactant. This happens because of the attack on the back-side, explained in the previous post. The fenomenon is called the Walden inversion . In the example illustrated below the bromobutane is R configurated, after the reaction attacked by the nucleophile OH- the butanol is S configurated:  Leaving groups As seen before, the reaction rate of the Sn2 reaction is dependent on the kind of leaving group. Good leaving groups are leaving groups which conjugated base is derived from strong acids, which means: weak bases (which are also the most stable bases). What does this mean? This means that Iodide is a much better leaving group than Fluoride. Basically what this means is: I-  <<  Br-   <<   Cl-   <<   F-     BASICITY RI ...

Alkylhalides Substitution reaction Sn2 In the previous blog post there was a little bit of theory explained about the substitution reaction with alkylhalides. In this post I dig deeper into the mysteries of the Sn2 reaction mechanism. Let's start with a very basic substitution reaction of Bromomethane forming methanol. The reaction rate law for the Sn2 reaction (and thus for the example above) is then: As you can see, this law contains the alkyl halide AND the nucleophile, making it a 2nd order reaction (hense the 2 in Sn2 ). k is the 'rate constant', which is different for any reaction but remains constant.  Branched off alkyl halides will have a slower reaction rate than none-branched off alkyl halides. Methyl halide such as CH3-Br has a   relative reaction rate of 12000, a primary alkyl such as CH3CH2-Br already has a relative reaction rate of 40, and a tertiary alkyl halide such as (CH3)(CH3)CH3-C-Br is even too slow to measure the reaction rate....

Alkylhalides: an initiation Background information Alkylhalides are compounds (in this case salts ) that consist of an alkyl group and an halogen (seventh row in the table of Mendeljev).  Alkylhalides have good leaving groups , these groups are the atoms (or the atom) that will be substituted or eliminated during elimination or substitution reactions on the molecule. This fenomenon is caused by the polar bond formed between the halogen and the alkyl group, making the halogen more afferent to be attacked (substituated / eliminated) by a nucleophile. Nucleophile substitution reaction ( SN2 reaction) A nucleophile 'attacks' the alkylhalide, the leaving group - in this case the halogen - will be taken of the compound and will be replaced (SUBSTITUTED) by the nucleophile (hense the reaction its name). This reaction however is characterized and depended by several factors including: the solvent in which the reaction is taking place the reactivity or acti...

Organometals Organometallic compounds An organometallic compounds are organic bonds which consist of a carbon -- metal bond. Because of the electronegativity the  carbon becomes partial negative charged due to the metal being less electronegative than the carbon.  The most common organomettalic compounds are organolithium and organomagnesium. These compounds are frequently used as catalysts or reagents, but beware, they can be highly explosive because they can rapidly react with oxygen (air) or water. Some examples of the preparation of organometals see below: One of the most known organometallic compound that can be found is VITAMIN B12 , this compound holds as metal the Cobalt atom. However Cobalt only reacts with one bond with one carbon, the rest of its bonds are with nitrogen. Structure of B12 Vitamin:

Ozonolysis Ozone structure Ozone is a molecule stabilized by its typical resonance structure. Oxidation of the alkene  With this kind of reaction, the ozonolysis, alkenes can be split into alcohols, ketons, aldehydes or carbonic acids . Used reagentia and different circumstances will determine the outcome of the reaction.  The simple and basic reaction goes as the following: (work needs to be added in order to get a correct reaction going) Example of a reaction with different circumstances and reagens: First reaction results in Formaldehyde and Propanol , the second reaction, this time in combination with Hydrogen peroxide results in Butanoic acid and Oxalic acid Ozonolysis reaction in detail The ozone and alkene molecules undergo a 6-electron cycloaddition reaction, forming the molozonide - which is very unstable due to the single bonded O's - thus ending in an ozonide which is in contrary to molozonide stable. ...

Alkynes: addition of Hydrogen gas (H2) Performing a catalytic reduction on an alkyn will result in giving an alkane. The alkene intermediate will be formed in the process, but will immediately react into an alkane. The end result is just the formed alkane, without stacking of the alkene intermediate. The Lindlar catalyst In theory this is a "poisoned or defected" catalyst. If you use a normal catalyst you will get the above effect with your alkyne. The Lindlar catalyst contains Palladium combined with Calcium-carbonate and treated with Lead. Palladium is the actual catalyst, the calcium carbonate is the carrier of the substance and the lead is the poisonous compound. Using the Lindlar catalyst instead of another catalyst together with Hydrogen gas, will lead into forming the cis-alkene intermediate instead of the forming of the corresponding alkane. 

Often used Alkynes in medicine  There are not many known Alkynes that hold a good outcome for pharmaceuticals. They are rather toxic and dangerous for humans. Stay alert and be careful when working with Alkynes in the lab or on a workspace. Although specific Alkynes known as ene-diynes possess a very strong and aggressive anti-tumor compound. These molecules are cyclic and contain an alkene (double bond) in between two alkyne (triple bonds) functions, therefore the name "ene < alkene" and "diyne < two alkynes". An example of this anti-tumor working agent is the drug calicheamicin . When released into the tumor cells, it undergoes a strong reaction when it gets in contact with DNA, known as the Bergman cyclization. It will cleave the DNA and thus destroying it.  Structure of calicheamicin :  Trivia: it is rumored Alexander the Great was poisoned with calicheamicin. His death has had the same symptoms as of someone that would drink from th...

I will blog in English in the future to reach a bigger crowd and making it more accessible for more people.

Additie van water op een alkyn Dit is een mogelijke reactie om ketonen mee te bereiden. Toevoegen van Kwik (Hg) kan de reactiesnelheid doen toenemen (enkel bij eindstandige alkynen).

Elektrofiele additie: Waterstofhaliden op alkynen Voorbeeld van waterstofhaliden: HCl, HBr, HF, HI Gebruik van één equivalent waterstofhalide met alkyn (dus 1:1 geen overmaat geen tekort) Bij een overmaat aan het waterstofhalide zal een tweede reactie plaatsvinden op het gehalogeneerde alkyn, ter vorming van een geminaal regioisomeer.

Een alkyn  is een koolwaterstof met tenminste één driedubbele binding tussen een koolstof en een andere verbonden koolstof.  Acyclische formule: Cn H(2n - 2)  Cyclische formule: Cn H(2n - 4) Bij naamgeving wordt aan de  -yn uitgang een zo laag mogelijk nummer toegekend.Substituenten uiteraard zo klein mogelijk.