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Topic: Click Chemistry - MOs  (Read 3512 times)

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Offline Nescafe

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Click Chemistry - MOs
« on: May 15, 2014, 10:01:23 PM »
Hello,

I am trying to understand the orbitals involved in the mechanism of a click. I understand the electrons in the HOMO of the Nuc(which are in a pi orbital) interact with the electrophile LUMO. Is this LUMO a sigma* or a pi*? My guess would be is a pi* since the electrophile in this reaction is an alkyne.

Any help would be appreciated,

Nescafe.

Offline phth

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Re: Click Chemistry - MOs
« Reply #1 on: May 16, 2014, 05:48:11 AM »
HOMO of the alkyne->>LUMO copper(1) catalyst; alkyne and azide replace water by sigma hybrid bonding (see picture steps 1-2). The 3 4p-orbitals and the 4s can hybridize to sp3 (tetrahedral) or to sp2d (square planar). 

Where do the electrons from copper come from? Assuming tetrahedral geometry, the dxz, dyz, dxy are triply degenerate and higher in energy than the doubly degenerate dz^2 and dx^2-y^2 orbitals.  Looking at a graph the triply degenerate orbitals will interact in a pi fashion; the pi* LUMO of the aklyne interacting with either one of those d orbitals.  The nitrogen lone pair raises the energy of the tripple degenerate energy levels with the same letter in its axis because of pi bonding overlap; if the alkyne is z axis, then the pibonding with the dxz and dyz and vise versa.

The amount of overlap contributes to the speed of the reaction, but that discussion is off topic.  Hope this helps,
Disjigaboo

Offline Nescafe

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Re: Click Chemistry - MOs
« Reply #2 on: May 16, 2014, 08:33:48 PM »
Thanks, in the first step of that mechanism, how does the H+ get removed? Does water act as a base to generate H3O+? I have noticed most these reactions are done in ButOH:H2O so perhaps water acts as a base. Also, why do they use this solvent mixture? My guess would be water is required to dissolve the salt (CuSO4) and the sodium bicarb whereas the ButOH is there to dissolve your reactants and with its partial solubility mix with the water layer.

Another question :P Sorry I find the mechanism for click to be very ambiguous, Ln, what is the ligand coordinating? H2O? or ascorbate? what is the electron valency of Cu. I can not find anything on this

Sorry for the many questions!

Nescafe.
« Last Edit: May 16, 2014, 11:25:02 PM by Nescafe »

Offline phth

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Re: Click Chemistry - MOs
« Reply #3 on: May 17, 2014, 12:33:07 AM »
Water does act as a weak base.  Because the alkyne has 3 p orbitals involved in the tripple bond, the s orbital holds the proton to it. The electrons are closer to the Carbon nucleus protons; therefore, the CH is a weaker bond (s character) than a sp[sup3[/sup] orbital. Waters acidity constant is over 10 orders of magnitude greater (pKA 14 vs estimated pKa 26). Therefore water is a horrible base, but it does deprotonate it; the pi orbitals of the tripple bond will complex with Cu+ via sandwich bonding http://en.wikipedia.org/wiki/Sandwich_compound.   Pi double bond HOMO->Cu LUMO-> stable sandwich complex.  Now the pi bond can fluctuate between its HOMO and LUMO .  The electron density will not be uniform because of the R group stabilizing the negative charge.  The acidic side will become more acidic, and now water or a weak base are strong enough to deprotonate the alkyne.

Its pretty crazy how simple alignment causes such amazing catalysis.  Another example of this phenomenon are cleavage reactions in proteins/enzymes; efficiency of those reactions usually unachievable otherwise.
 
Either solvent in a mixture like that can act as the base and both do.  Why that solvent mixture is used is because of solubility.  Bicarb is be there to protect the alkyne from hydrolosis.  A weak base (e.g. NH4OH) is used to prevent precipitation of copper hydroxide (Ksp on the order of 10-20).

The Ln notation was confusing to me at first too.  It just means some ambiguous ligand.  If the reaction was in water, then the ligands would be water.  In the butanol/water example, butanol is the better answer because the alkane side chains stabilize (lower energy barrier=faster and larger cone angle [advanced off topic]) the association equilibrium of the alkyne anion.  However, the reaction proceeds with water as a ligand as well.

The outer shell electron valency of Cu+ is 10 (5 d orbitals filled). This is a good reference to easily check, and a useful study tool: http://ptable.com/#Orbital.  4 open sp3 orbitals open allow for 4 ligands to bond.  They add 8 electrons to coppers valency (18 allowed by VESPR theory), but they do not change the charge of copper. A ligand associating with copper in this way causes LCAO stabilization for both.  If you have any more questions or if someone wants to correct me ask away..:)

Offline Nescafe

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Re: Click Chemistry - MOs
« Reply #4 on: May 17, 2014, 12:48:25 AM »
That was very useful, thanks so much, helped me a lot!

The only thing I have left to figure out is how Sodium ascorbate acts as a reducing agent to produce Cu(I) in situ. So I read that Cu(II)SO4. 5H2O is used as the Cu(I) source and sodium ascorbate as the reducing agent. So this means that the ascorbate donates an electron and itself becomes oxidized. I have searched to find the mechanism by which this happens, any insight?

Thanks again for the thorough explanation,

Nescafe.

Offline Nescafe

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Re: Click Chemistry - MOs
« Reply #5 on: May 18, 2014, 12:44:49 PM »
Hi,

I am just going to revisit one point about water acting as a base to deprotonate the Alkyne proton which due to Cu coordination drops in Pka from 25 to about 15. I do not see how water can deprotonate this since the pKah of water is -1.7. When we think of water as a base from my understanding is that we look at its Pkah (-1.7 which is pka of H3O+) and not  Pka (15). I think it more so has to do with the energetically favored formation of the sigma-copper acetylide bond

Please let me know what you think,

Nescafe.

Offline phth

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Re: Click Chemistry - MOs
« Reply #6 on: May 20, 2014, 03:45:30 AM »
Yeah, maybe I made a mistake but based on that then it should be the most basic 1,2,3-triazole product. "the reaction is assisted by the copper, which, when coordinated with the acetylide lowers the pKa of the alkyne C-H by up to 9.8 units. Thus under certain conditions, the reaction may be carried out even in the absence of a base"
« Last Edit: May 20, 2014, 04:00:10 AM by disjigaboo »

Offline Nescafe

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Re: Click Chemistry - MOs
« Reply #7 on: May 22, 2014, 10:51:44 PM »
Just to bring up one last thing about this mechanism, I still can not wrap my head around the last step where a H+ kicks of/replaces the C-Cu. How can it do that and what is the source, water is the only thing in most reactions where the conditions are simply source of copper/H2O/ButOH and sodium ascorbate.

Thanks in advance,

Nescafe.

Offline phth

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Re: Click Chemistry - MOs
« Reply #8 on: May 24, 2014, 06:41:19 PM »
It is almost the exact same equilibrium as deprotonation of the alkyne to the metal but in reverse; the disassociation sp2 equilibrium K is larger because the reverse reaction energy barrier is larger. There is a rate determining step always, and not everything is reacting which infers that only a small portion of the alkyne must be deprotonated; this is the RDS.  The imbalance of just these two equilibrium constants shows that the reaction will move forward.

For the top picture, the mechanism is wrong. I just pulled it off google images quickly.  Kinetics say that it is a second order process with respect to copper.  Attached is a review which that quote came from  which is a comprehensive answer (highlighted). 

Cu(I) salts probably go bad fast, so ascorbate is used; can easily form radicals which are transferred to Cu(II).

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