The Haloform Reaction: A mechanistic examination using computational chemistry Ben Norris Department of Chemistry, University of itts!

urgh "une, #$$%

Learning goals: &n this assignment, you 'ill explore the haloform reaction using computational chemistry( )ou 'ill use heat of formation calculations to un*erstan* the relative aci*ities of car!on aci*s, an* the implications these aci*ities have for the mechanism of the !ase+promote* +halogenation reaction an* the haloform reaction( )ou shoul* !e generally familiar 'ith enolate chemistry ,Chapter -. in /olhar*t an* 0chore, for example1 !efore completing this assignment( )ou may 'ish to revie' aci*2!ase e3uili!ria, heats of formation an* enthalpies of reaction from your 4eneral Chemistry text!oo5 !efore 'or5ing on this assignment( revious experience 'ith computational chemistry ,such as that from the 6rganic Chemistry 7a! Course1 is not re3uire*( A gui*e for using the CAChe program as it pertains to this assignment is inclu*e* in an appen*ix at the en*( Overview: The haloform reaction is a reaction of a methyl 5etone ,a #+al5anone1 in !asic solution in the presence of excess halogen( The organic pro*ucts of this reaction are the haloform ,trihalomethane1 an* a car!oxylate anion( The overall reaction is sho'n !elo'(
O R + 4 OH+ 3 X2 O R O + CHX3 + 3 H2 O + 3 X-

The haloform reaction is uni3ue to methyl 5etones( 6ther 5etones 'ill un*ergo !ase+promote* +halogenation, !ut 'ill react no further( &f the halogen use* is io*ine, the reaction !ecomes the io*oform test reaction( &o*oform is a !right yello' soli*, an* its formation can !e use* as a 3ualitative test for the presence of a methyl 5etone( Part I: Base-promoted -halogenation The first part of the haloform reaction is a !ase+promote* +halogenation reaction( This reaction can !e exhaustive 8 the presence of excess !ase an* halogen can lea* to multiple halogenations( During the first part of this assignment you 'ill use CAChe to examine 'hy this reaction is exhaustive(

Exercise 1: Dra' the mechanism for the !ase+promote* +halogenation of acetone to -,-,-+trihaloacetone(
O X2 NaOH X O X X

Exercise 2: The follo'ing ta!le outlines the three *eprotonation reactions 'hen using chlorine as the halogen atom( Use CAChe to *etermine the heats of formation for each of the species in the ta!le, an* then *erive the enthalpies of reaction for each of the three reactions( Use the 9 :; geometry in 'ater< since the haloform reaction is often *one in a3ueous solution( 1. Hf #( Hf ;(
Cl O O

OH

: H

H2O

Hrxn ______

______
O Cl

______ + OH-

______
O
: H

______ + H2O

Cl

______
O Cl

______ + OH-

______
O
: Cl

______ + H2O

______

Cl

Hf

______

______

______

______

______

Do the enthalpies of reaction sho' a tren* 'ith increasing chlorination= >hat *o these *ata suggest a!out the relative aci*ity of the three 5etones=

Exercise 3: ?ill in the heats of formation on the follo'ing ta!les an* calculate the enthalpies of reaction for the *eprotonation reactions for !romine an* io*ine as 'ell( Bromine 1. Hf #( Hf ;(
Br O O

OH-

: H

H2O

Hrxn ______

______
O Br

______ + OH-

______
O
: H

______ + H2O

Br

______
O Br

______ + OH-

______
O
: Br

______ + H2O

______

Br

Hf

______

______

______

______

______

&o*ine 1. Hf #( Hf ;(
& O O

OH-

: H

H2O

Hrxn ______

______
O &

______ + OH-

______
O
: H

______ + H2O

&

______
O &

______ + OH-

______
O
:

______ + H2O

______

&

&

Hf

______

______

______

______

______

Do you o!serve the same tren* for !romine an* io*ine as you *i* for chlorine= &n general, ho' *oes increasing +halogenation affect the aci*ity of an +hy*rogen on the same car!on=

Using 'hat you have learne* in the a!ove exercises, provi*e an explanation as to 'hy the !ase+ promote* +halogenation reaction is exhaustive(

Part 2: N cleophilic !c"l # $stit tion The secon* part of the haloform reaction is a nucleophilic acyl su!stitution ,a**ition2elimination1 reaction( This is the part of the haloform reaction that only 'or5s 'ith methyl 5etones( After exhaustive !ase* promote* +halogenation, a methyl 5etone is converte* to a trihalomethyl 5etone( The trihalomethyl 5etone reacts 'ith a hy*roxi*e anion to generate a car!oxylate anion an* a haloform molecule( This is the part of the haloform reaction that is uni3ue to methyl 5etones( During the secon* part of this assignment you 'ill explore 'hy only trihalomethyl 5etones un*ergo this type of reaction(

O R

OH X2

O R X X X

OH

O R O +

H X

X X

Exercise %: Dra' the mechanism of the reaction of -,-,-+trihaloacetone 'ith hy*roxi*e anion(
O X X X OH
-

O O +

H X

X X

Exercise &: The first step of a nucleophilic acyl su!stitution is the attac5 of the nucleophile( Dra' -,-,-+trichloroacetone, -,-+*ichloroacetone, ;,;+*ichloro+#+!utanone, an* acetone in CAChe an* optimiAe their geometries using 9 :; geometry in 'ater<( Then construct the electrostatic potential on electron *ensity surface using 9Current geometry 'ith B..+7) D?T 'avefunction<( Then fin* the partial charge at the car!onyl car!on( ?ill in the ta!le( Color of Blectron Density at Car!onyl Car!on artial Charge at Car!onyl Car!on

O Cl O Cl Cl O Cl O Cl Cl Cl

Base* on the information *etermine* in Bxercise C, 'hich car!onyl compoun* 'oul* !e most suscepti!le to nucleophilic attac5=

Exercise ': The secon* step of a nucleophilic acyl su!stitution reaction is the loss of the leaving group( This is usually the rate+*etermining step( 4oo* leaving groups are often the conDugate !ases of strong aci*s( Compare the aci*ity of methane, chloromethane, *ichloromethane, an* chloroform( Determine the enthalpies of reaction for the follo'ing aci* *issociation reactions, using the :; geometry in 'ater( 1. Hf 2. Hf 3. Hf 4. Hf CH4 ______ H3CCl ______ H2CCl2 ______ HCCl3 ______ + + + + H2O ______ H2O ______ H2O ______ H2O ______ H3C______ H2ClC______ HCl2C______ Cl3C______ + + + + H3O+ ______ H3O+ ______ H3O+ ______ H3O+ ______ Hrxn ______ Hrxn ______ Hrxn ______ Hrxn ______

Ran5 the follo'ing four compoun*s in or*er of increasing aci*ity( CH@ CH;Cl CH#Cl# CHCl;

>hich of the follo'ing four anions is the !est leaving group= Bxplain your choice !ase* on the *ata in the ta!le a!ove( H;C+ H#ClC+ HCl#C+ Cl;C+

Exercise (: Compare the aci*ity of chloroform, an* -,-+*ichloroethane( Calculate the enthalpies of reaction for the follo'ing reactions using the :; geometry in 'ater( 1. HCCl3 + H2O Cl3C:+ H3O+ Hrxn

Hf 2. Hf

______ H3CCHCl2 ______

______ H2O ______

______ H3CCl2C:______

______ H3O+ ______

______ Hrxn ______

>hich of the follo'ing tetrahe*ral interme*iates is more li5ely to 5ic5 out the car!anion leaving group= Bxplain using the *ata in the ta!le a!ove(
O H3C HO CCl3 O H3C HO CCl2CH3

Base* on the exercises you have complete* in art #, explain 'hy the haloform reaction is uni3ue to methyl 5etones(

!ppendix: )ips *or sing +!+he *or this assignment &ntro*uctory 3uic5 tips for using the CAChe >or5space program can !e foun* at: http:22cheme*(chem(pitt(e*u2cacc2*o'nloa*s2>0F3uic5Ftips(p*f :ore *etaile* CAChe tutorials can !e foun*, if you are intereste*, at: http:22cheme*(chem(pitt(e*u2cacc2CACheTutorial2in*ex(htm +alc lating ,eats o* -ormation Dra' the molecule or ion of interest( The charge of atoms can !e change* using the tool!ar imme*iately a!ove the *ra'ing area( Beautify the molecule( Run a ne' experiment to optimiAe the geometry( Un*er 9 roperty of< select Chemical Sample, an* un*er 9 roperty< select optimized geometry. 0ince most of the calculations in this assignment 'ill use the PM3 geometry in water, select this metho* from the 9Using< menu( Clic5 90tart< to run the experiment( 0elect 9)es< if as5e* to save the molecule !efore the experiment( :; is a semi+empirical metho* that is partially !ase* on empirical parameters( &t is a goo* metho* for *etermining optimum geometry of simple organic compoun*s, an* is capa!le of calculating 3ualitatively relia!le heats of formation 'ith a relatively short calculation time( >hen the experiment is finishe*, the heat of formation is returne* as a line of text in the Experiment Status 'in*o'( &t shoul* loo5 li5e the follo'ing:

The heat of formation of this molecule is +-;($E; 5cal2mol(

+onstr cting an Electrostatic Potential on Electron .ensit" # r*ace ?irst, *ra', !eautify, an* optimiAe the geometry of a molecule or ion as *escri!e* previously( Then, run a ne' experiment( This time select electrostatic potential on electron density as the 9 roperty<( 0elect current geometry with B88- !P "#$ wa%e&unction un*er the 9Using< menu( Clic5 90tart< to run the experiment( 0elect 9)es< if as5e* to save the molecule !efore the experiment( .

This calculation uses *ensity functional theory ,D?T1( The :; metho* is not very goo* at examining electron *ensity, !ut D?T is very goo* at it( 6ptimiAing a moleculeGs geometry using D?T is a tas5 that ta5es much longer than optimiAing using :;( Ho'ever, D?T can calculate electron *ensity relatively 3uic5ly if given a goo* geometry to start 'ith( This is 'hy 'e optimiAe 'ith :; first( >hen the calculation is complete, go to the 'nalyze menu at the top of the 'in*o', an* select 90ho' 0urfaces<( 0elect the HHH(csf(BonD surface ,'here HHH is the filename1, an* clic5 96I<( The surface 'ill then overlay on top of the molecule( The surface is color co*e* !y electron *ensity( >arm colors represent areas of less electron *ensity, an* cool colors represent areas of more electron *ensity( &n or*er of increasing electron *ensity, the colors are: >hiteJre*Jyello'JgreenJs5y !lueJ!lueJmagentaJpurple /iewing Partial +harges artial charges can only !e *etermine* after running experiments( art of running any experiment involves assigning partial charges to all the atoms( As partial charges have to *o 'ith electron *ensity aroun* an atom, a D?T calculation 'ill give a !etter partial charge than a :; calculation ,though any :; calculation 'ill generate partial charges1( After running an experiment, select the atom of interest( 0elect 9Atom Attri!utes< on the (iew menu( 6n the 97a!el< ta!, put a chec5 !y 9 artial Charge<( The partial charge la!el 'ill no' appear over the atom of interest(