And then we could say there's one pair of electrons on that nitrogen. So the Steric number is equal to the number of sigma bonds, which is 2, plus number of lone pairs of electrons, which is 1. And so the Steric number is equal to 3. So this nitrogen must have three hybrid orbitals, and therefore it's sp2 hybridized. So it has three sp2 hybridized orbitals, and therefore, one p orbital-- so an unhybridized p orbital.
So this nitrogen is also sp2 hybridized, and so we can go ahead and sketch in the p orbital like that. And if we look at the number pi electrons in pyridine, there's two, four, and six pi electrons. So that fulfills Huckel's Rule. So there are six pi electrons. And we can see that the pyridine molecule is a ring of continuously overlapping p orbitals-- these p orbitals can overlap side by side-- and those six pi electrons can be delocalized throughout the ring. And so since this meets both of the criterion, pyridine is an aromatic molecule.
So it has some extra stability associated with it. Now, this lone pair of electrons on this nitrogen, that lone pair of electrons occupies an sp2 hybridized orbital. So we said this nitrogen's sp2 hybridized, which means it has three sp2 hybrid orbitals. So one of those sp2 hybridized orbitals formed a bond with this carbon over here.
One of them formed a bond with this carbon over here. And the last sp2 hybrid orbital actually contains that lone pair of electrons. So the lone pair of electrons on that nitrogen does not participate in resonance. That lone pair of electrons is localized to that nitrogen.
And so any time you see a situation like pyridine where you have a nitrogen with a lone pair of electrons and some electrons already participating in resonance-- so those would be the electrons in magenta here-- the electrons in magenta participate in resonance. So the electrons in blue cannot participate in resonance. They are localized to this nitrogen atom. So we've seen that pyridine is aromatic. Let's go ahead and do an example that's similar to pyridine.
This is pyrimidine So let's see if we can analyze the pyrimidine molecule the same way that we analyzed the pyridine. So once again, if I start with my carbons here, each of these carbons is connected to a double bond.
So I have four carbons, and therefore each carbon is sp2 hybridized. I can go ahead and sketch in a p orbital on each of my sp2 hybridized carbons like that. When I study the nitrogens in pyrimidine, I can see it's the exact same situation that we had in pyridine.
So I can see that there's a sigma bond here, a sigma bond here, and a lone pair of electrons here, like that. And so I can see that this nitrogen is sp2 hybridized. And I can see that these pi electrons here are going to be participating in resonance. So for that nitrogen, it's sp2 hybridized. It has a free p orbital, so I can go ahead and draw in the p orbital there.
And I know that the lone pair of electrons in blue-- since this nitrogen is sp2 hybridized-- that lone pair of electrons is going to occupy an sp2 hybridized orbital. It's the exact same situation for this nitrogen. There's a sigma bond.
We have a lone pair of electrons on that nitrogen. And then we also have some electrons already participating in resonance.
And so this nitrogen is also sp2 hybridized. I can go ahead and draw a p orbital on that nitrogen, which means that lone pair of electrons is not gonna participate in resonance. That lone pair of electrons is going to occupy an sp2 hybridized orbital. It's going to be out to the side like that. And so for pyrimidine, once again, I have a total of six pi electrons. And those six pi electrons are going to be delocalized as the p orbitals overlap side by side in your ring.
And so pyrimidine is also aromatic. It meets the criteria for it. And the lone pair of electrons on those nitrogens, those lone pairs are localized to those nitrogens. All right. The pyrimidine general structure is actually very important in biochemistry. So when you study biochemistry, you'll see how important it is. And here's an example. This is the thymine molecule, which is, of course, found in DNA. And you'll always see in textbooks that thymine has a pyrimidine ring.
But at first, it's not so obvious that a pyrimidine ring is present in thymine. Because if I look at the nitrogens in thymine-- we'll start this nitrogen up top here-- I can see that this nitrogen has three sigma bonds to it and one lone pair of electrons.
So three sigma bonds-- so the Steric number would be equal to 3 sigma bonds plus 1 lone pair of electrons. The Steric number should be equal to 4, which implies four hybrid orbitals, which would mean that that nitrogen is sp3 hybridized.
And if it's sp3 hybridized, you wouldn't have any p orbitals to participate for aromaticity. And so this must not be the case. There must be a way to see a pyrimidine ring here. And the answer is because this nitrogen is actually not sp3 hybridized.
It actually has a lone pair of electrons that are delocalized, and not localized to this nitrogen, meaning we can draw a resonant structure for the thymine molecule. So this lone pair of electrons right here in this nitrogen are not localized to that nitrogen as we saw in the previous dot structures. Those electrons can move in here to form a pi bond between the nitrogen and that carbon. That would, of course, push these electrons in here off onto this oxygen.
So we can go ahead and draw a resonance structure. So let's go ahead and put the nitrogen in our ring. And let's go ahead and draw in the rest of our ring like that. And so that lone pair of electrons moved in to form a double bond between that nitrogen and that carbon. So that's our situation now. The reaction of tryptophan with cyanoacetates is known to produce cyanoamides in the aim of forming photo-active cross-linking bioprobes [13,14]. In view of these observations and in continuation with studies involving the synthesis of unusual hormones and amino acids derivatives , we have used in this study, L-tryptophan is used to form new heterocyclic compounds of potential biological activities.
Compound 2 reacted with an equimolar amount of ethyl cyanoacetate in 1,4-dioxan under reflux to give the methyl a-imino acetonitrilocarbamido indolopropanoate 3 via elimination of ethanol. Moreover, the 13C NMR spectrum showed 8 Therapeutic agents containing pyridine, thiophene, and pyrazole moieties have attracted the attention of researchers in pharmaceutical chemistry; these heterocycles have been found to show various biological activities [18,19]. The reactivity of compound 3 towards the reaction with active methylene reagents was investigated.
Thus, compound 3 reacted with equimolar amount of either malononitrile 4a or ethyl cyanoacetate 4b in ethanolic triethylamine solution gave the a-pyridoindolopropanoate derivatives 6a,b, respectively. Formation of the latter products took place via the intermediate formation of 5a,b which underwent ready intramolecular cyclization to give compounds 6a,b Scheme 2. The IR spectrum of each of 6a and 6b showed two CN groups stretching at v and cm-1, respectively.
The :H NMR of compound 6a showed a singlet at 8 4. Moreover, each of compounds 6a,b showed a singlet at 8 6. The study also extended to the reactivity of compound 3 towards nitrogen nucleophilic reagents. Thus, compound 3 reacted with equimolar amounts of either hydrazine hydrate or phenylhydrazine in refluxing ethanol containing a catalytic amount of triethylamine to give the corresponding pyrazolyltryptophan methyl ester derivatives 8a,b.
The reaction took place via a simple addition of hydrazine hydrate or phenylhydrazine to the CN group in compound 3 to give the intermediates 7a,b which readily afforded compounds 8a,b via water elimination Scheme 2. Moreover, compound 3 reacted with hydrox-ylamine hydrochloride in cold ethanolic sodium acetate solution to give the corresponding oxadiazinomethylenoindole derivative 9 Scheme 2.
Structures of compounds 8a,b and 9 were supported by their compatible analytical and spectral data cf. Compound 3 reacted with equimolar amounts of either malononitrile 4a or ethyl cyanoacetate 4b and elemental sulfur in ethanolic triethylamine solution under reflux to afford the corresponding thiophenotryptophan methyl ester derivatives 10a,b Scheme 3.
The reaction of compound 3 with equimolar amount of benzaldehyde in ethanolic triethylamine solution under reflux afforded the condensated product benzalacetonitrilocarbonyltryptophan methyl ester derivative 12 Scheme 4.
Thus, 12 reacted with either malononitrile 4a or ethyl cyanoacetate 4b in refluxing ethanolic triethylamine solution to give the methyl a-pyridoylindolopropanoate derivatives 14a,b, respectively via the intermediacy of 13a,b Scheme 4.
The reactivity of compound 12 towards the reaction with nucleophilic reagents was investigated. Thus, the reaction of 12 with equimolar amounts of either hydrazine hydrate or phenylhydrazine in ethanolic triethylamine solution under reflux afforded the corresponding carbonylpyrazolotryptophan methyl ester derivatives 15a,b, respectively Scheme 5.
Similarly compound 12 reacted with hydroxylamine hydrochloride in ethanol containing sodium acetate solution to afford the isooxazolotryptophan methyl ester derivative 16 Scheme 5. The chemical structures of compounds 15a,b and 16 were confirmed via the analytical and spectral data cf.
Tryptophan 1 reacted with an equimolar amount of ethyl cyanoacetate in refluxing dimethylformamide solution to give the acetonitrilocarbonyl tryptophan 17 Scheme 5. The structures of the latter products 18 and 19 were confirmed based on their compatible elemental and spectral analyses cf. The appropriate precautions in handling moisture sensitive compounds were undertaken. All melting points of the newly synthesized compounds were measured using an electrothermal capillary melting point apparatus and are uncorrected.
The reactions were followed using TLC analyses which were performed using Merck 60 F aluminum sheets and visualized by UV light run. Although tryptophan methyl ester is commercially available in the hydrochloride form we preferred to syntheses the native methyl ester via the procedure indicated below.
To a solution of tryptophan 1 The reaction mixture was stirred for 24 h, and then evaporated under vacuum. The formed solid product neutralized by sodium carbonate solution 1 N , extracted by chloroform and dried by anhydrous sodium sulfate.
The solid product formed after evaporation of the solvent, filtered off, dried and crystallized from methanol. Caled, for C12H14N Found: C, To a solution of 2 1. The reaction mixture was heated under reflux for 3h. The solid product formed by evaporation under vacuum was filtered off, dried and crystallized. Caled, for C15H15N The formed solid product, in each case filtered off, dried and crystallized from the appropriate solvent.
Caled, for C18H17N Caled, for C18H16N Methyla-imino 5-aminophenylpyrazoloyl indolopropanoate 8b General Procedure. To a solution, of compound 3 1. The formed solid product, in each case, was filtered off, washed with water and crystallized from the appropriate solvent.
To a solution of compound 3 1. C, The formed solid product was filtered off, dried and crystallized from the appropriate solvent.
A solution of compound 3 1. After addition of the diazonium salt was completed, the reaction mixture was stirred at room temperature for 30 min. The formed solid product filtered off, dried and crystallized from EtOH. To a solution of compound 12 1.
The formed solid product, in each case filtered off, dried, and crystallized from the appropriate solvent. Caled, for C22H21N Caled, for C28H2JN Methyl a-iminocarbonyl 3-aminophenyllsooxazoloyl indolo-propanoate Caled, for C22H20N4O4 To a solution of tryptophan 1 1. The reaction mixture was heated under reflux for 4h and then was evaporated in vacuum. The remaining product was triturated with diethyl ether, and the solid product was collected by filtration. Caled, forC14H13N To a solution of compound 17 1.
The formed solid product filtered off, dried and crystallized from dilute ethanol. Caled, for C21H17N A solution of compound 17 1. After addition of diazo-nium salt was completed, the reaction mixture was stirred at room temperature for 30 min. The solid product, separated upon dilution with cold water, was filtered off, washed with water several times, dried and crystallized. Caled, for C20H17N5O3 Webb, C. Eigenbrot, J. Stammer, Tetrahedron 46, , Schiller, G.
Weltrowska, T. Nguyen, C.But if we focus in on both nitrogens, this nitrogen is now in the exact same situation as this top nitrogen. There's a sigma bond. Electrophilic aromatic substitution Video transcript In previous videos, we've already seen that benzene is aromatic because it fits the following criteria. Compound 3 reacted with Snl bad music covers wallpaper amounts of either malononitrile.
The chemical structures of compounds 15a,b and 16 were confirmed via the analytical and spectral data cf. The reaction mixture was stirred for 24 h, and then evaporated under vacuum. Pelcman, Tetrahedron, 51,
So now the Steric number would be equal to 3 plus 0, which is, of course, equal to 3. And for the top oxygen here, it had two lone pairs of electrons but it picked up one more lone pair of electrons, giving it negative 1 formal charge. Bell, T.