Inverse Molecular Design in Stable Radical...
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with and Inverse Molecular Design in Stable Radical Chemistry F. De Vleeschouwer 1 , A. Chankisjijev 1 , W. Yang, 2 P. Geerlings 1 , F. De Proft 1 1 Eenheid Algemene Chemie (ALGC), Vrije Universiteit Brussel (VUB), Pleinlaan 2, B-1050 Brussels, Belgium 2 Department of Chemistry, Duke University, Durham, North Carolina 27708, USA [email protected] ABSTRACT The design of molecules with optimal properties still remains an important challenge in chemistry. The main problem is the large number of possible structures that are accessible through systematic variation of the composition of a molecular system. The inverse molecular design approach aims to overcome this obstacle: one uses the computation of certain quantities to design molecules with an optimal target property. In the methodology of Beratan and Yang, the design of molecules is translated to finding an optimal external potential of the system, generating a molecular system with the associated target property. [1,2] This approach requires the computing of only a tiny fraction of the predefined chemical space to acquire the optimal structure in that chemical space. [2,3] In a recent study, for the first time inverse design was applied to search for intrinsically stable radical systems. [4] The thiadiazinyl radical, that consists of two joined six-membered rings, of which one of the rings contains a sulfur atom accompanied by two nitrogen atoms, was chosen as a case study because of its interesting architecture with heteroatomic radical centers and possibly enhanced delocalization over the adjacent ring. We focused predominantly on thermodynamic stabilization effects, such as resonance stabilization. The best-first-search methodology, [2,3] was used with the intrinsic stability – which can be computed via a previously established bond dissociation enthalpy model [5] – as the target property. The resulting optimal structure is found to be highly (intrinsically) stable, more than other well-known stable radicals, such as verdazyls and N,N-diphenyl-N'-picrylhydrazyl, and rivaling the intrinsic stability of nitrogen monoxide. In addition, we are applying at the moment inverse molecular design with boundary conditions to obtain an intrinsically stable thiadiazinyl radical that is as electrophilic or as nucleophilic as possible. [6] REFERENCES [1] M.L. Wang, X. Hu, D.N. Beratan and W. Yang, J. Am. Chem. Soc., 128, 3228 (2006) [2] D. Balamurugan, W. Yang, D.N. Beratan, J. Chem. Phys., 129, 174105 (2008) [3] F. De Vleeschouwer, W. Yang, D.N. Beratan, P. Geerlings, F. De Proft, Phys. Chem. Chem. Phys., 14, 16002 (2012) [4] F. De Vleeschouwer, A. Chankisjijev, W. Yang, P. Geerlings, F. De Proft, J. Org. Chem., 78, 3151 (2013) [5] F. De Vleeschouwer, V. Van Speybroeck, M. Waroquier, P. Geerlings, F. De Proft, J. Org. Chem., 73, 9109 (2008) [6] F. De Vleeschouwer, A. Chankisjijev, W. Yang, P. Geerlings, F. De Proft, in preparation. ACKNOWLEDGEMENTS F.D.V. acknowledges the Research Foundation-Flanders (FWO) for a post-doctoral fellowship. ( ) ( ) ! " # $ $ + $ $ + + < $ < $ $ $ + + = % otherwise , stab stab 0 and 0 if , stab stab B) BDE(A B A B A B A B A B A B A & & ' ' & & ' ' b a a 2 ! = " # # 3 ! = " # # 5 sites 21 substituents / site + size of chemical space: 5 21 ≅ 5 x 10 14 molecules [# substituents ] i i =1 # sites ! ! #$%&# ! ! #'(#%) # *&+ #%,'-%',& ,.*/01 -20$-& ,./$-.3 4,.1&+0,5 -016'%& #%.($3$%7 $%&' 8 1$* 1$* #$%& ( #'(#% ) -2.*9& 1$* #.:& #'(#%) -2.*9& %0 #.:&/ #'(#%) 0* #$%& ( *&+ 06%) ( ;< ) ;< ) ;< ) = #*+ ) = #*+ ,- ./$ ./$ ./$ ,- ,- .->0* -0*/$>0* $*6'% #%,'-%',& :.,$.(3& -0'*%&, $*%&,*.3 :.,$.(3& -0*:&,9&/ ?*.3 06>1'1 ./$ ,- @AB CDEFD (C)-NHCH 3 (C)-SOCH 3 (C)-OCH 3 (C)-SCH 3 (C)-SO 3 H (C)-COOH (C)-CF 3 (C)-CH 3 (C)-CHO (C)-CFO (C)-OOH (C)-SOH (C)-NH 2 (C)-OH (C)-SH (C)-CN (C)-H (C)-F (C)-Cl (C)-Br (N) INTRODUCTION: STABILITY CONCEPT Thermodynamic stability: delocalizing spin over multiple atomic centers heteroatomic radical center Kinetic stability: steric protection of the radical center through the incorporation of bulky substituents around the radical center Rough initial definition of intrinsic radical stability by Coote et al.: “a measure of the general tendency of a radical to react across a range of different chemical environments” to a lesser degree GOAL OF THIS WORK Can we find thiadiazinyl derivatives that are considerably more stable than the reference structure? STRUCTURE OF INTEREST MOLECULAR DESIGN 0.327 0.319 0.291 thiadiazinyl radical system potential reactive radical centers Ideal case study: an interesting architecture with heteroatomic radical centers and possibly enhanced delocalization over the adjacent ring, depending on the type of substituents on that ring. chemical space contains an immense amount of accessible stable molecules search of molecules with some optimal property is a daunting task INVERSE DESIGN MOLECULAR DESIGN INVERSE MOLECULAR DESIGN find an optimal external potential of the system, generating a molecular system with the associated target properties 1. molecular framework of interest a. determine # sites that can be modified b. determine # substituents per site 2. define property of interest 3. choice of the property optimizing method 1. molecular framework of interest The discrete best-first-search algorithm: • optimizes the property of a molecule by making chemical changes and evaluating the influence of those changes on the property of interest • chemical changes through the independent site approximation , so the various sites are optimized individually 1. construct Z-matrix for a randomly chosen initial structure 2. go to site 1 and compute the property for every possible functional group on site 1 while keeping the other sites fixed 3. the structure with the optimal property value becomes the new starting point 4. perform the same procedure for sites 2-5 5. repeat steps 2-4 until convergence is reached 3. choice of the property optimizing method 2. define property of interest In 2008, we constructed a BDE model that breaks down BDEs into parts that (only) incorporate intrinsic properties of the radical fragments, like intrinsic radical stability (stab), electrophilicity (ω) and Pauling electronegativity (χ): NO OC6H5 NO2 NF2 phenylsulfonyl tosyl SCH3 SCH2CH3 OCH2C(CH3)3 SH Br OCH2CH3 OCH3 CH2CHCH2 C(CN)(CH3)2 CH2C6H4(CN) CH2C6H4(OCH3) CH2C6H4(CH3) CH2C6H5 CH2C6H4(F) 2,2-dimethyl-4,6-dioxo-1 CH2CN Cl CCl3 tert-butoxycarbonylmethy OH C(CH3)3 C(OH)(CH3)2 CH2OH HC(O) NH2 CH(CH3)2 CH3C(O) CH2CH3 F CH2CH2CH3 CH3 CF2CH3 CF3 CHCH2 H C6H5 C6H4(CH3) C6H4(OCH3) C6H4(CN) C6H4(F) CN 0 50 100 150 200 250 300 unstable radicals 302.2 241.9 241.8 241.6 239.5 238.4 235.8 229.8 226.0 200.7 190.6 183.9 181.6 180.9 176.0 172.6 171.7 169.7 169.6 165.6 165.5 159.6 158.4 156.2 145.2 144.7 133.4 131.1 130.9 129.5 128.6 127.1 122.0 118.1 110.6 107.5 107.1 106.5 104.3 97.4 96.9 70.7 70.7 65.8 61.7 34.4 5.9 stability in kJ mol -1 stable radicals (un) Radical stability scale for 47 small radical systems small stab value = small contribution to BDE = stable radical system RESULTS AND DISCUSSION To maximize the intrinsic stability and therefore minimize stab, we made use of an approximated BDE model: site 1 site 2 site 3 site 4 site 5 average 32.1 48.2 54.2 33.5 18.6 median 27.9 48.5 73.8 34.5 15.0 MAX - MIN 44.2 69.1 75.7 41.3 30.5 # within 10 kJ mol -1 of opt. 1 1 4 2 12 # within 20 kJ mol -1 of opt. 11 3 7 4 18 Radical stab[H] stab[CH 3 ] stab[t-Bu] Thiadiazinyl_ref 69.5 33.6 2.3 Thiadiazinyl_opt 13.1 -23.1 -37.1 Thiadiazinyl_opt_OH 18.8 -25.1 -21.6 Triphenylmethyl 81.8 48.3 -42.3 Phenalenyl 20.3 8.4 -16.1 Verdazyl_H 32.5 9.5 6.0 Verdazyl_Ph 34.3 4.4 -27.7 N,N-diphenyl-N'-picrylhydrazyl 85.6 0.1 -96.3 H 235.8 CH 3 190.6 t-Bu 165.5 For more bulky radicals: • with H as partner: thermodynamic intrinsic stability • with t-Bu as partner: kinetic stabilization of the radical Work scheme: BDE (R-H) = E R ! 1361.4 ! E R-H ( ) ! 29.2 = stab R + 235.7 ( ) + 8.7 Resulting optimal structures: CONCLUSIONS Comparison with other known stable radical structures: stab [OOH] = 13.1 kJ mol -1 and stab [OH] = 18.8 kJ mol -1 Influence of substituents on each site for the last global iteration: The more the peaks (for a given site) vary in height, the more important the optimal substituent and therefore in some way also that particular site is to obtain a more stable system. It is clear that site 5 shows the smallest variations between the different substituents. Sites 2, 3 and 4 seem to have the biggest impact: site 2 and site 4 for having almost no structures with a stab value close enough to the optimum and site 3 for being a mix between structures that have either a relatively low or a relatively high intrinsic stability. However, only the methylamino group on site 4 is clearly participating in stabilizing the π-radical through the overlap of p-orbitals, which is supported by both the spin densities and the bond lengths. Other functional groups on site 4 resulting in structures for which about the same intrinsic stability was estimated as the optimum, like hydroxyl and amino share that same mesomerically electron-donating ability. stab [t ! Bu] ! stab [H] ! kinetic stabilization 1. best-first-search approach very effective 2. optimum more than 40 kJ mol -1 more stable than the isolable thiadiazinyl radicals 3. intrinsic stability of optimum close to that of nitrogen monoxide 4. placing a mesomerically electron-donating functional group on site 4 seems to be crucial 5. the much higher stability of certain radicals can be traced back to kinetic stabilization The BDE model can evaluate both the thermodynamic and the kinetic stability through the calculation of only two properties. Our optimum is found to be intrinsically the most stable radical system, followed closely by its derivative Thiadiazinyl_opt_OH and phenalenyl and the slightly less stable verdazyl radicals. The triphenylmethyl and N,N-diphenyl-N'-picrylhydrazyl radicals are found to be intrinsically the least stable among the eleven investigated structures. Remark that this thermodynamic stability definition (stab[H]) indeed separates those radical systems that are stable through electronic effects from those that are stable mainly because of steric protection of the radical center. The influence of the bulky substituents around the radical center is visible when the larger tert-butyl is taken as the reaction partner. Going from H to t -Bu, the N,N-diphenyl-N'-picrylhydrazyl radical is now 181.9 kJ mol -1 more stable than before. Also the stability of the triphenylmethyl radical improves greatly with a stab decrease of 124.1 kJ mol -1 . The smallest decreases are observed for phenalenyl (36.4 kJ mol -1 ) and Verdazyl_H (26.5 kJ mol -1 ), demonstrating the effect of the extra phenyl group in Verdazyl_Ph as a steric protector (decrease of 62.0 kJ mol -1 in stab).
Transcript of Inverse Molecular Design in Stable Radical...
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with and
Inverse Molecular Design in Stable Radical Chemistry F. De Vleeschouwer1, A. Chankisjijev1, W. Yang,2 P. Geerlings1, F. De Proft1
1 Eenheid Algemene Chemie (ALGC), Vrije Universiteit Brussel (VUB), Pleinlaan 2, B-1050 Brussels, Belgium 2 Department of Chemistry, Duke University, Durham, North Carolina 27708, USA [email protected]
ABSTRACT The design of molecules with optimal properties still remains an important challenge in chemistry. The main problem is the large number of possible structures that are accessible through systematic variation of the composition of a molecular system. The inverse molecular design approach aims to overcome this obstacle: one uses the computation of certain quantities to design molecules with an optimal target property. In the methodology of Beratan and Yang, the design of molecules is translated to finding an optimal external potential of the system, generating a molecular system with the associated target property. [1,2] This approach requires the computing of only a tiny fraction of the predefined chemical space to acquire the optimal structure in that chemical space. [2,3]
In a recent study, for the first time inverse design was applied to search for intrinsically stable radical systems. [4] The thiadiazinyl radical, that consists of two joined six-membered rings, of which one of the rings contains a sulfur atom accompanied by two nitrogen atoms, was chosen as a case study because of its interesting architecture with heteroatomic radical centers and possibly enhanced delocalization over the adjacent ring. We focused predominantly on thermodynamic stabilization effects, such as resonance stabilization. The best-first-search methodology, [2,3] was used with the intrinsic stability – which can be computed via a previously established bond dissociation enthalpy model [5] – as the target property. The resulting optimal structure is found to be highly (intrinsically) stable, more than other well-known stable radicals, such as verdazyls and N,N-diphenyl-N'-picrylhydrazyl, and rivaling the intrinsic stability of nitrogen monoxide. In addition, we are applying at the moment inverse molecular design with boundary conditions to obtain an intrinsically stable thiadiazinyl radical that is as electrophilic or as nucleophilic as possible. [6]
REFERENCES [1] M.L. Wang, X. Hu, D.N. Beratan and W. Yang, J. Am. Chem. Soc., 128, 3228 (2006) [2] D. Balamurugan, W. Yang, D.N. Beratan, J. Chem. Phys., 129, 174105 (2008) [3] F. De Vleeschouwer, W. Yang, D.N. Beratan, P. Geerlings, F. De Proft, Phys. Chem. Chem. Phys., 14, 16002 (2012) [4] F. De Vleeschouwer, A. Chankisjijev, W. Yang, P. Geerlings, F. De Proft, J. Org. Chem., 78, 3151 (2013) [5] F. De Vleeschouwer, V. Van Speybroeck, M. Waroquier, P. Geerlings, F. De Proft, J. Org. Chem., 73, 9109 (2008) [6] F. De Vleeschouwer, A. Chankisjijev, W. Yang, P. Geerlings, F. De Proft, in preparation.
ACKNOWLEDGEMENTS F.D.V. acknowledges the Research Foundation-Flanders (FWO) for a post-doctoral fellowship.
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(C)-NHCH3 (C)-SOCH3 (C)-OCH3 (C)-SCH3 (C)-SO3H
(C)-COOH
(C)-CF3
(C)-CH3 (C)-CHO
(C)-CFO
(C)-OOH
(C)-SOH
(C)-NH2 (C)-OH
(C)-SH
(C)-CN
(C)-H
(C)-F
(C)-Cl
(C)-Br
(N)
INTRODUCTION: STABILITY CONCEPT
§ Thermodynamic stability: § delocalizing spin over multiple atomic centers § heteroatomic radical center
§ Kinetic stability: § steric protection of the radical center through the incorporation of bulky
substituents around the radical center Rough initial definition of intrinsic radical stability by Coote et al.: “a measure of the general tendency of a radical to react across a range of
different chemical environments”
to a lesser degree
GOAL OF THIS WORK
Can we find thiadiazinyl derivatives that are considerably more stable than the reference structure?
STRUCTURE OF INTEREST
MOLECULAR DESIGN
0.327
0.319
0.291
thiadiazinyl radical system
potential reactive radical centers
Ideal case study: an interesting architecture with heteroatomic radical centers and possibly enhanced delocalization over the adjacent ring, depending on the type of substituents on that ring.
chemical space contains an immense amount of accessible stable molecules
search of molecules with some optimal property is a daunting task
INVERSE DESIGN
MOLECULAR DESIGN
INVERSE MOLECULAR DESIGN
find an optimal external potential of the system, generating a molecular system with the associated target properties 1. molecular framework of interest
a. determine # sites that can be modified b. determine # substituents per site
2. define property of interest 3. choice of the property optimizing method
1. molecular framework of interest
The discrete best-first-search algorithm: • optimizes the property of a molecule by making chemical changes and evaluating the
influence of those changes on the property of interest • chemical changes through the independent site approximation, so the various sites are
optimized individually
1. construct Z-matrix for a randomly chosen initial structure
2. go to si te 1 and compute the property for every possible functional group on site 1 while keeping the other sites fixed
3. the structure with the optimal property value becomes the new starting point
4. perform the same procedure for sites 2-5
5. repeat steps 2-4 until c o n v e r g e n c e i s reached
3. choice of the property optimizing method 2. define property of interest
In 2008, we constructed a BDE model that breaks down BDEs into parts that (only) incorporate intrinsic properties of the radical fragments, like intrinsic radical stability (stab), electrophilicity (ω) and Pauling electronegativity (χ):
NOOC6H5
NO2NF2
phenylsulfonyltosyl
SCH3SCH2CH3
OCH2C(CH3)3SHBr
OCH2CH3OCH3
CH2CHCH2C(CN)(CH3)2
CH2C6H4(CN)CH2C6H4(OCH3)
CH2C6H4(CH3)CH2C6H5
CH2C6H4(F)2,2-dimethyl-4,6-dioxo-1
CH2CNCl
CCl3tert-butoxycarbonylmethy
OHC(CH3)3
C(OH)(CH3)2CH2OHHC(O)
NH2CH(CH3)2CH3C(O)CH2CH3
FCH2CH2CH3
CH3CF2CH3
CF3CHCH2
HC6H5
C6H4(CH3)C6H4(OCH3)
C6H4(CN)C6H4(F)
CN
0 50 100 150 200 250 300
unstable radicals
302.2241.9241.8241.6
239.5238.4
235.8229.8
226.0200.7190.6
183.9181.6180.9
176.0172.6171.7
169.7169.6
165.6165.5
159.6158.4156.2
145.2144.7
133.4131.1130.9129.5128.6127.1
122.0118.1
110.6107.5107.1106.5104.3
97.496.9
70.770.7
65.861.7
34.45.9
stability in kJ mol-1
stable radicals
(un)
Radical stability scale for 47 small radical systems
small stab value = small contribution to BDE = stable radical system
RESULTS AND DISCUSSION
To maximize the intrinsic stability and therefore minimize stab, we made use of an approximated BDE model:
site 1 site 2 site 3 site 4 site 5 average 32.1 48.2 54.2 33.5 18.6 median 27.9 48.5 73.8 34.5 15.0
MAX - MIN 44.2 69.1 75.7 41.3 30.5 # within 10 kJ mol-1 of opt. 1 1 4 2 12 # within 20 kJ mol-1 of opt. 11 3 7 4 18 !
Radical stab[H] stab[CH3] stab[t-Bu] Thiadiazinyl_ref 69.5 33.6 2.3 Thiadiazinyl_opt 13.1 -23.1 -37.1
Thiadiazinyl_opt_OH 18.8 -25.1 -21.6 Triphenylmethyl 81.8 48.3 -42.3
Phenalenyl 20.3 8.4 -16.1 Verdazyl_H 32.5 9.5 6.0 Verdazyl_Ph 34.3 4.4 -27.7
N,N-diphenyl-N'-picrylhydrazyl 85.6 0.1 -96.3 H 235.8
CH3 190.6 t-Bu 165.5
!
For more bulky radicals: • with H as partner: thermodynamic intrinsic stability • with t-Bu as partner: kinetic stabilization of the radical
Work scheme:
BDE(R-H) = ER !1361.4!ER-H( )! 29.2 = stabR + 235.7( )+8.7
Resulting optimal structures:
CONCLUSIONS
Comparison with other known stable radical structures:
stab [OOH] = 13.1 kJ mol-1 and stab [OH] = 18.8 kJ mol-1
Influence of substituents on each site for the last global iteration:
The more the peaks (for a given site) vary in height, the more important the optimal substituent and therefore in some way also that particular site is to obtain a more stable system. It is clear that site 5 shows the smallest variations between the different substituents.
Sites 2, 3 and 4 seem to have the biggest impact: site 2 and site 4 for having almost no structures with a stab value close enough to the optimum and site 3 for being a mix between structures that have either a relatively low or a relatively high intrinsic stability. However, only the methylamino group on site 4 is clearly participating in stabilizing the π-radical through the overlap of p-orbitals, which is supported by both the spin densities and the bond lengths. Other functional groups on site 4 resulting in structures for which about the same intrinsic stability was estimated as the optimum, like hydroxyl and amino share that same mesomerically electron-donating ability.
stab[t ! Bu]! stab[H] ! kinetic stabilization
1. best-first-search approach very effective 2. optimum more than 40 kJ mol-1 more stable than the
isolable thiadiazinyl radicals 3. intrinsic stability of optimum close to that of nitrogen
monoxide 4. placing a mesomerically electron-donating functional
group on site 4 seems to be crucial 5. the much higher stability of certain radicals can be
traced back to kinetic stabilization
The BDE model can evaluate both the thermodynamic and the kinetic stability through the calculation of only two properties.
Our optimum is found to be intrinsically the most stable radical system, followed closely by its derivative Thiadiazinyl_opt_OH and phenalenyl and the slightly less stable verdazyl radicals. The triphenylmethyl and N,N-diphenyl-N'-picrylhydrazyl radicals are found to be intrinsically the least stable among the eleven investigated structures. Remark that this thermodynamic stability definition (stab[H]) indeed separates those radical systems that are stable through electronic effects from those that are stable mainly because of steric protection of the radical center. The influence of the bulky substituents around the radical center is visible when the larger tert-butyl is taken as the reaction partner. Going from H to t-Bu, the N,N-diphenyl-N'-picrylhydrazyl radical is now 181.9 kJ mol-1 more stable than before. Also the stability of the triphenylmethyl radical improves greatly with a stab decrease of 124.1 kJ mol-1. The smallest decreases are observed for phenalenyl (36.4 kJ mol-1) and Verdazyl_H (26.5 kJ mol-1), demonstrating the effect of the extra phenyl group in Verdazyl_Ph as a steric protector (decrease of 62.0 kJ mol-1 in stab).
