Nitration

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Kirill Petko

NITRATION

A little practical guide for students

This little brochure designed for students who do not like refined
scientific language
Nitration, i.e. the introduction of the nitro group instead of the hydrogen
atom is an electrophilic reaction. To pass this reaction, positively charged particle,
nitronium-cation (NO2+), "looks for" high electron density, so a negatively charged
substrate is necessary. It attacks organic molecule which is having high electron
density and as "bouncer", turn away hydrogen atom as a proton (H +). The proton
(H+) is much less reactive than NO 2+, and so, this reaction is not only possible, but
can not be undone. The separation of the hydrogen atom as a hydride ion (H -)
under the influence of particles with a negative charge (for example NO 2-) is
practically not possible, because the stability of the latter is much lower than the
stability of nitride ion. So we have:

NO2+ + RH → RNO2 + H+
For the reaction undergoing we need the reagent (source for nitronium
cation) and the substrate - an organic molecule that has excess electron density.
Consider first:
REAGENT

Nitration usually goes under the action of nitric acid (HNO 3), which is
known in aqueous solution to form H+ ions, i.e. behaves like an acid, and with such

a turn of events, no nitration can be done. Only a proton (H+) molecule can attack

and knock out the other proton. Nothing happens with the molecule (RH):

H+ + RH = RH + H+
• As long as nitric acid behaves just like acid, it is not a nitrating agent.

To pass the nitration reaction nitric acid’s behavior as a base is necessary, namely:
NO2OH = NO2+ + OH-
At first glance it seems even impossible. But the "acidic" and "basic"
properties of molecules dialectically opposite, that is inextricably linked and
both are present in all acids and bases. Their expression is highly dependent on the
solvent, or rather of its acid-base properties. Any acid can be the base, but only
when it is dissolved in a more strong acid or (partly in equilibrium) in a medium
with closely acidity to the acid to be taken in the experiment. Nitric acid in water
(and the water is very weak acid) dissociates by acid type, anhydrous nitric acid
(nitric acid solution in nitric acid), partly forms nitronium cation and "classic"
nitrating mixture - a solution of nitric acid and sulfuric acid has a very high
concentration of nitronium cation. The last two cases are described by the
following:
HNO3 + NO2OH = NO2+ + NO3- + H2O

H2SO4 + NO2OH = NO2+ + HSO4- + H2O

In both cases, the equilibrium water involved. Adding water to the nitrating
mixture shifts the equilibrium to the left, and greatly reduces the concentration of
nitronium cation and binding of water released by adding excess sulfuric acid or
oleum, resulting in a significant increase in the concentration of nitronium cation,
and as a result - increase the power of nitrating mixture. By controlling the
concentration of water one can control the reaction, therefore it is important to
strictly follow the concentrations given in methodology, and in cases of failed
experiments, when nitration does not go, or does too active to form
polynitroproducts, the first thing to be tested - a density of nitric and sulfuric acids,
and subsequent conduct experiments by adding excess sulfuric acid (or oleum) if
you want to enhance nitrating power, and in another case - add some water. Since
water is released as a by-product of the reaction of nitration, the rate of the end of
the reaction decreases. To carry the process to the end, you can either neat heating
or addition of sulfuric acid (water withdrawal) but, please, without fever.

• Like pedal "accelerator" in the car. Carefully selecting the concentration

of water, you can find the optimal speed for the desired substrate.
But not for all substrates. Often complicated by nitration, different side
processes like: Reaction mixture turns black, brown discharge gas goes, or
sometimes, after a significant jump of temperature exposing occurs! And all
because:

• Nitrating mixture - is not only an acid, it is also an oxidising agent

Really, nitric acid is quite strong oxidant. It oxidizes cyclohexanone to adipinic


acid readily. Nitric acid can introduce oxygen into organic molecule. This oxygen
is separated from nitrate anion, which goes into nitrite anion, nitric oxide or NO 2.
But nitronium-cation usually does not share it’s oxygen. At least at
temperatures below r.t. It shares NO2+ part with the molecule completely.
Therefore, the higher the concentration of nitrating mixture, the less of water there
- the weaker oxidant, and more powerful nitrating agent is it. But oxidant
properties present in any case! Oxidative properties are especially evident and
always exceed nitrating at higher temperatures. We can therefore nitrate some
substrates, such as aromatic aldehydes (which as you know to be strong reducing
agents), but only by ≈100% mixture of nitric and sulfuric acids and at
temperatures higher than r.t. A nitration reaction is almost always exothermic.
Therefore, the addition of an aldehyde to the reaction mixture need to be done very
slowly with careful stirring and temperature control. Uncontrolled manipulations
even in a stirred reaction mass can lead to rapid autocatalytic oxidation of all
aldehyde. If "overdo" the nitronium cation concentration by binding water with
oleum, the aldehyde nitration again will fail because sulfuric anhydride (SO 3) in
solution is a strong oxidant.
Nitration of acetyl derivatives of amines may be complicated by their
deacylation. Free aromatic amines, unlike acetyl derivatives, can be easily
oxidized, but if anilinium salts formed earlier (and they are more stable to
oxidation), then nitration undergoes to a different positions because NH 3+ group is
“second kind” orientant. The reaction is exothermic again and deacylation passes
easily at higher temperatures. Therefore, in these cases, the same requirements -
thorough mixing, gradually add, readings and temperature control. In contrast to
the aldehyde group acetylamino group activates the benzene ring. So here is
another possible undesirable process - the formation of dinitro products. So if
acetanilide is nitrated by mixture of ≈100% nitric and sulfuric acids, even at 0 0C,
you can get 2,4-dinitroacetanilide.
Nitration of heterocyclic compounds - derivatives of pyrrole and thiophene
often accompanied by protonation of the ring and polymerization. But if the ring
included with at least one nitro group, it is much more stable. So sometimes these
compounds can be nitrated by nitrating mixture, but at very low temperatures.
More often softer nitrating agents Amyl nitrite type is using.
Quality of nitric and sulfuric acids (if not hydrometer) can be estimated
visually, although this estimation is always very inaccurate, so sometimes you can
avoid unwanted consequences, or to understand the cause of failure.

• If reagent visually in doubt, it is better not to start the experiment, or do a


little (using small amounts of the substance).

Nitric acid, which has a density of 1.0 - 1.35, that is, when the concentration
of the basic substance in water is to 55%, is a colorless substance, at room
temperature has no odor. When concentration is 55-65%, i.e. when density is 1.35-
1.38 noticeably, but small presence of brown gas is over the layer of nitric acid at
room temperature, the acid has a smell, with a slight yellowish or brownish tint. At
concentrations of 65-75%, that is, when the density of 1.39-1.43 the color of nitric
acid - from yellow to brownish-yellow (color similar to the old bulb), and the gas
above is more noticeable. At a concentration of 75-90% when the density of 1.44-
1.49 nitric acid is intensely yellow-brown color, and when you open the vessel,
formed around a cloud of brown gas (nitrogen oxides). But nearly anhydrous nitric
acid should be bright, clean lemon-yellow colour. Pure yellow, "golden" color,
without any mixture of brown, is typical for 100% nitric acid, which has a density
of 1.52. Noticeable presence of nitrogen oxides exist, but less than in the case of
90% nitric acid.
If the concentration of acid in the laboratory are not required to meet the
requirements of the experiment (lower than desired, but if higher, you can simply
diluted with water) under construction out of three main situations.
1. Get 100% nitric acid, by distilling stirring mixture of sodium nitrate
(or potassium, but not ammonium because in this case blast
guaranteed!), with an excess of concentrated sulfuric acid. Mixing
then 100% and more dilute acids, receives need reactant
concentration. This is the most correct way, but it requires
additional synthesis that should be done with great care. Burns
from 100% nitric acid prolonged healing and leave scars for all life.
2. Adding to the reaction mixture excess sulfuric acid or oleum. The
main advantage of this output - simplicity. The main disadvantage -
the inability to recover readings concentration of water and
reagents to the right. But even if we pick the right concetration of
water, bound excess sulfuric acid, concentration of substrate and
nitric acid will be much lower. But this solution is in excess of
sulfuric acid. And yet, very often it is best for the student. If after
mixing the reactants nitration does not go, sulfuric acid must be
added very gradually, dropwise, the appearance of color, or
spontaneous increase in temperature have to be controlled. After
the reaction time over, control the if passage is fullness, and if
necessary sulfuric acid adding have to be repeat.
3. Run nitration at higher temperatures. Looking at the above, this
output is only suitable for those derivatives that do not have gentle
groups capable. Namely - benzene, nitro and halobenzenes, benzoic
acids, some condensed heterocycles quinoline type, and so on.
Even in this case, this output is lowest effective because :
• Dilute nitric acid will not nitrate or at what temperature

The visual assessment of sulfuric acid quality is harder. But compared to


water, concentrated sulfuric acid is much less mobile and more like oil. Therefore,
if the glass with sulfuric acid containing a moving fluid – it is an occasion to
doubt. If a glass of concentrated sulfuric acid (96-100%) for a long time was not
tightly closed, it is guaranteed that it "grabs" the water from air, and acid
concentration would be 65-70%. Dilute sulfuric acid can be concentrated by
evaporation of water to about 90%, but this requires aggressive fluid heating to a
temperature above 250 0C, and so, is dangerous. Therefore, diluted sulfuric acid
can be either "fixed" by adding of oleum, or not be used in nitration reactions.
The preparation of nitrating mixture can also evaluate the quality of the
reagents. When mixing concentrated nitric and sulfuric acids there is a significant
heating occurs. The temperature of the reaction mixture can rise to 50 0C. If heat is
not released - sulfuric acid is diluted! This color of nitric acid disappears, nitrating
mixture became colourless.

• Yellow or brown at room temperature "nitrating mixture" - more oxidizing


than nitrating agent!

Above the surface of nitrating mixture at elevated temperature noticeable


nitrogen oxide is always present. But at r.t. highly concentrated mixture (95-100%
-of acid) completely absorbs nitrogen oxides and has not only color but also smell.
If the mixture used for the preparation of 70% nitric acid at room temperature is
visible presence of brown gas above the liquid, and the mixture may have a slight
brownish tinge.
Getting nitration reaction can be clearly traced in most cases. Once you start
adding substrate to the nitrating mixture (or vice versa - the mix to the substrate)
the reaction appears yellow color and the temperature rises spontaneously. If they
do not, we must activate reaction by one of the ways described above, make sure,
that the reaction goes, then continue adding the substrate. In the case of large
amounts of reagents......

• If all mixed without reaction at first, and then activate nitration, heat may
be such that ambulance is necessary.

If nitration undergoes at a temperature lower than r.t, no brown gas above


the liquid should not be - the nitration allocates water instead of nitrogen oxides.
The gas bubbles from the reaction mixture clearly points or oxidation (if gas is
brown) or other secondary processes (if gas is colorless). At high temperature
nitration, if inactive stable substrates (such as obtaining dinitrobenzene) reaction
bulb is filled with a cloud NO2, because nitric acid partially decomposed, but this
does not affect the outcome of nitration - not oxidized substrate.
The end of the nitration reaction is not determined that no longer stand the
heat, or the intensity of the yellow color is not increased. As mentioned nitration
reaction rate decreases at the end, because:

•The reaction by-product, water is the main nitration "brake"

To check whether the reaction finished, we must take some drops of the
reaction mixture and mix them with water. What not dissolves in water - reaction
product, which was separated from the acid. It also should be compared with the
original substrate. In some cases, it is very easy (for example if the original -
liquid, and the final product - crystals with low melting temperature), in some
cases completeness of the reaction can be confirmed only by thin layer
chromatography. If passed by the end of the reaction, the reaction mixture should
be mixed with water to separate the product from acids. But as you know, when
mixed with concentrated sulfuric acid with water is a significant warming. If the
product contains a group capable oxidation or hydrolysis in acidic medium, even if
these groups "survived" the nitration, they can "die" when pouring the water.
Therefore, the reaction mixture after nitration of aldehydes, nitriles, esters, need
only pour into ice! This must be floured into small pieces ice, and in winter it is
better to use snow. And we have to mix while pouring vigorously, because:

• Local overheating can catalyze spontaneous oxidation.

A very important thing in the nitration process - is stirring. In the case of


small reagents quantities magnetic stirrer commonly used. But in cases where the
nitration occurs at low temperatures, you may experience some difficulties that can
not be overlooked when synthesis preparing. And the main reason - is that:

• The viscosity of nitrating mixture at room temperature and at the frost may
vary hundred times!

If the magnetic “anchor” freely stirred mixture before the nitration, there is
no guarantee that when you cool it to -10 0C, it stops. When the flask with cooling
ice covered with salt, the student often do not sees what is done in the flask.
Added substrate forms a separate top layer, and nothing nitration occurs at this
temperature......

• Cutlets - separately, flies - alone!

Then the ice melts, the temperature increases, the viscosity decreases and the
magnetic stirrer starts stirring the reaction mixture .... All the effects were
described above. Therefore, when cooling the reaction flask, it should be good to
see how behaves a stirrer. Even if it turns, it does not guarantee thorough mixing,
especially the upper layers of the liquid, and such "mixing" is dangerous, because
sometimes even “several drops” accumulation can lead to local overheating, and as
a result - significantly product’s yield reducing.
• All liquid must move rapidly. Only then it is allowed to add substrate.

If you can not adjust, the magnetic stirrer must either be replaced with a
mechanical stirrer, or mix by hands.
After selecting, the product should be thoroughly washed to the separation
of its nitric acid espessially if the product has a "soft" group. Crystallized (i.e.
heat!) of the product, in such cases, you can do only just being sure that all the
nitric acid neutralized and nitrates laundered. It is best to extract the product with
ether and then ethereal solution wash with baking soda and rinsed several times
with water. Otherwise it can “die” during crystallization.

SUBSTRATE

Nitration as other electrophilic reactions easily pass for aromatic


compounds. Because benzene ring is conjugated system with three double bonds
reminds me personally:

• The barrel with electron density, which attracts electrophile like sugar
syrup attracts bee, but filled this barrel - half.

It is easy to pull electron density from benzene ring, as well as electron


density can easily be added. Especially effective adding of electron density is
observed when the possibility of coupling, is increased, i.e. double bonds of the
ring, (π electrons of benzene system) and undivided heteroatom pair, are on the
same quantum-mechanical level.

• If all live on one floor, then visit one another will be ease.
Looking at the periodic table, we can see that the same group as carbon, are
nitrogen, oxygen and fluorine. If the atoms of these elements are near the benzene
ring their’s undivided pair is on the same 2p level, electrons and nuclei of carbon
atoms. The "barrel" is added to the electron density is not divided couples
heteroatom, and it becomes more full, and therefore more accessible to attack
positively charged particles for examle, nitronium cation. As you know, most of
the ortho and para-activated position of the benzene nucleus. For example, in the
case of anisole activation can be illustrated as follows:

In the case of sulfur, phosphorus and chlorine, undivided pair is already at a


higher (3p) level that is "on the floor above" than the π-system of the benzene ring
and so much weaker interface, but also available. On the other hand all of the
above heteroatoms more electronegative than carbon. So they "charge on the"
electron density of adjacent carbon atoms, i.e. deactivate adjacent (ortho) position.
Substituents of this type are more activated just a couple of provisions, unlike alkyl
groups are almost equally activate the ortho position and couple. Thus, the ratio
mononitroproducts of toluene – para and ortho isomers is 57:43, then the mono
nitration of anisole or acetanilid produce almost pure para-nitroproduct. .
Strong electron-donating groups are thousand times activated to
electrophilic reactions. This groups are N (CH3)2, OCH3, NH2, OH, etc. But in the
case of aniline in highly acidic media it forms a salt which have a positive charge,
and thus deactivate attack of positively charged nitronium cation. Nitration of
unprotected aniline takes place in concentrated sulfuric acid and 100% nitric acid
and directed by 75% in the meta position. Anisole can be nitrated with even 40%
nitric acid without heating, and without the addition of sulfuric acid to form almost
pure para isomer. But on action of concentrated nitration mixture phenol or anisole
can be nitrated three times and one can get trinitroderivatives.

• On nitrating the substrates with activating substituent with little error one
can get "extra" nitro groups in the ring.

Acetylamino group having acceptor “balance” on heteroatom is activated


benzene ring, but less than, for example. methoxy group. Acetanilide is nitrated
only in para-position by the action is not too concentrated nitrating mixture (65-
70% nitric acid and 90-95% sulfuric acid). On the action of a mixture of 100% -s
nitric and sulfuric acids 2.4-dinitroacetanilide is formed. In the case of acetoxy
group and fluorine atom, donor and acceptor coupling effect, and inductive
withdrawing effects, are almost identical, so these substituents are not activated,
but does not deactivate the ring, and direct nitration almost exclusively in para
positions. The rate of nitration of benzene and fluorobenzene is about at the same
concentration of nitrating mixture. Other halogens (bromine, chlorine, and iodine
atoms) and the groups in which the after the heteroatom, strong acceptor group
exist, such as OSO2R, OCCl3, OCF3, OCHF2, N (SO2R)2 and N(CF3)2, also direct
nitration in para position ( and a slightly in ortho), but deactivate benzene ring.
Nitration rate significantly dereased (sometimes by hundreds of times) than the rate
of nitration of benzene.

• For example, the N(CF3)2 group deactivates the nitration reaction more
than COOH group, but only direction is para position, unlike COOH group (meta-
orientant).

If at the benzene ring there is a carbon atom or heteroatom which has not
unshared electron pair, followed by - electron withdrawing atom or group bound
with multiple bond (continued π-system) is a deputy pulls electron density on the
ring coupling analogous effect for example, benzaldehyde:
Again, ortho and para locations are active, but they will densities, they
acquire a positive charge, and nitration does not go first to those positions as
nitronium cation - a positively charged particle, and "plus to plus" will not do.
Nitration, though much more difficult, the nitration of benzene, goes mainly in the
meta position. For nitration of aldehydes, ketones, aromatic acids and their esters,
usually highly concentrated nitrating mixture is necessary. But in these cases
bezene ring is not too deactivated and in the case of benzaldehyde, the reaction
goes at low temperature (0-10 0C). Dinitroproducts not formed. The nitration of
benzaldehyde and other derivatives with C=O containing substituents (ketones,
benzoic acid esters, etc.) always produce a certain amount (from 1-2 to 10-15%) of
ortho-nitration products. This is because the nitronium cation attacks oxygen atom
and formed a fragile complex, in which the attacking share appears at the ortho
position of the ring. As a result of the stabilization of this complex, ortho
nitroproduct obtained. The strongest electron withdrawing substituents such as
NO2, SO2OH, SO2R, CCl3, CF3, N(CH3)3+ are very much interfere nitration
reaction. Nitration reaction goes exclusively to the meta position.
In addition to receiving polynitro products, as mentioned earlier, often by-
products of the nitration appear as a result of oxidation or acid hydrolysis of
substrat. About the possible effects of oxidation of aldehydes or acetylamino
derivatives mentioned above. We must pay attention to the nitration of carboxylic
acid derivatives as esters and nitriles. As in the case acetylamino derivatives, the
acid hydrolysis possibility increases by heating. These substrates are more resistant
to acid hydrolysis than acetylamino, but unlike the latter deactivate benzene
nucleus, and therefore the nitration have to lead with some heating! If possible
hydrolysis occurs substrate itself tranforms to carboxylic acid, but the other
product of hydrolysis - is ammonia or alcohol! These substances can be easily
oxidized. More in the case of formation of nitroesters between alcohol and nitric
acid generally lead to explosion. Therefore, in these cases maximum attention
should be paid to the temperature control of the reaction.
If the reaction mixture para and ortho isomers exist, the possibility of
separation would be found on the following principles
1) On steam-distillation, hydrogen bond formation is possible, ortho isomer distills
much better.
2) Due to the symmetric structure of the molecule para isomer usually has a higher
melting point and on crystallization drops first.
3) On the joint fractional distillation ortho isomer usually has a lower boiling point.
4) Ortho isomer usually has higher Rf on chromatography.

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