analysis of geometric

7/28/2019 Analysis of Geometric

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Proc . Ind ian A cad . Sci . (Chem . Sci. ), VoL 108 , No . 5 , Oc tob er 1996, pp . 459 -468 . P r i n t ed i n I n d i a .

A n a l y s is o f g e o m e t r ic a n d s t r ai n e ff ec ts i n h o m o - D i e l s - A l d e r r e a c ti o n sA N I M E S H P R A M A N I K a n d JA Y A R A M A N C H A N D R A S E K H A R *D epa r tme nt o f Organic C hemis t ry , Indian Ins t i tu te o f Science, Bangalore 560 012,IndiaM S received 12 August 1996Abstract. M olecular mechanics ca lcula tions have been car r i ed out to q uant i fy thekey geom et r ic and s t ra in e f fec ts which a re l ike ly to cont ro l the hom o-D ie l s -A lderreac t iv i ty of 1 ,4-d ienes . The c r i te r i a cons idered inc lude C1 . . C5 and C2 . .C 4 d i s tan-ces in the diene, twist angle of the two n uni ts , and the ma gn i tude of s t rain increase asa resul t of cyc loaddi t ion . By fi rs t cons ider ing these fac tors in a num ber of non-conjuga ted d ienes w i th know n reac t iv i ty , the ranges of va lues wi th in w hich thereac t ion i s favoured a re proposed . Calcula t ions a re a l so repor ted on severa lsubstrates wh ich have no t been invest igated so far . Prom ising systems fo r experi -mental s tudy are suggested which, in addi t ion to being int r insical ly interest ing,wou ld p lace the present propo sa l s on a f i rm basi s.Keywords. H om o-D iels-A lde r react ion; m olecu lar mechanics; s t rain; m odell ing.

1. IntroductionT h e h o m o - D i e l s - A l d e r ( H D A ) r e a c t io n i n v o l v in g a n o n - c o n j u g a t e d 1, 4 - d ie n e a n da d i e n o p h i l e is a p o t e n t i a l l y u s e fu l m e t h o d f o r t h e s y n t h e s is o f b r i d g e d p o l y c y c l i cc o m p o u n d s , p r o d u c i n g t w o C - C a b o n d s a n d a c y c lo p r o p a n e ri ng in o n e s te p( s c h em e 1). T h e r e a c t i o n , k n o w n f o r o v e r 3 d e c a d e s ( U l l m a n 1 9 58 ; B l o m q u i s t a n dM e i n w a l d 1 9 5 9 ; H a l l 1 9 6 0 ; C r i s t o l et al 19 62 ; C o o k s o n a n d D a n c e 1 96 2; M o r i a r t y1 96 3; C o o k s o n et a11964; S c h r a u z e r a n d G l o c k n e r 1 96 4; H u e b n e r et a11966; T u f a r i e l l oet al 1966 ; Sas ak i et al 1 97 2), r e p r e s e n t s a s p e c i f ic e x a m p l e o f a m o r e g e n e r a l c l a s s o fI 2 + 2 + 2 ] c y c l o a d d i ti o n s . H o w e v e r , c o m p a r e d t o t h e D i e l s - A l d e r r e a c t io n , t h em e c h a n i s t ic d e ta i ls o f t h e H D A r e a c t io n a r e l es s u n d e r s t o o d a n d t h e m e t h o d o l o g y isu n d e r e x p l o i t e d in o r g a n i c s y n th e s is .T h e r e a c t i o n is g e n e r a l ly t h o u g h t o f a s a s l u g g is h p r o c e s s l a c k i n g s t e r e o - e l e c t r o n i cc o n t r o l. T h e r e a c t a n t s i n v o l v e n o n - c o n j u g a t e d s p e c ie s a n d h e n c e a r e n o t a m e n a b l e t oe l e c t r o n i c a c t i v a ti o n . W h i l e s te r e o s p e c i fi c i ty a n d c o n c e r t e d p a t h w a y s h a v e i n d e e d b e e np r o p o s e d i n c e r t a i n c a s e s ( K o b u k e et al 1 9 7 2 ; T a b u s h i et al 1 9 7 5 ; J e n n e r a n dP a p a d o p o u l o s 1 98 2), a n d r e g i o s e le c t iv i t y i n c o b a l t - c a t a l y z e d r e a c t i o n s ( L a u t e n s a n dE d w a r d s 1 99 1), t h e r e a c t i o n i n g e n e r a l i s l ik e l y t o i n v o l v e b i r a d i c a l o i d i n t e r m e d i a t e s .T h e f a c t o rs w h i c h d e t e r m i n e H D A r e a c ti v it y a re t h e r e fo r e li k el y t o b e p u r e l y g e o m e t r ici n n a t u r e .

T h e f ir s t s y s t e m a t i c in v e s t i g a t i o n o f t h e s c o p e o f t h e H D A r e a c t i o n i n v o l v i n g v a r i o u sd i e n es w i th a c o m m o n r e a ct iv e d i e n o p h i l e c o n f i r m e d t h e a b o v e v ie w (F i c k es a n d M e t z1 97 8). T h e e a s e o f r e a c t i o n o f 1 - 7 w i t h t e t r a c y a n o e t h y l e n e ( T C N E ) w a s s u g g e s t e d to b e

* Fo r co r r e s pondence4 5 9


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460 Animesh Pramanik and Jayaraman Chandrasekhar

N C NC N

Scheme 1. Representative hom o-D iels-A lder reaction.

!- - Z- - 3- - 4

R

5 a : R = C H 3 6s b : R=H -- 2 8i n v e rs e l y r e l a te d t o t h e d i s t a n c e b e t w e e n t h e d o u b l e b o n d s e s t i m a t e d f r o m m o d e l s .O n l y t w o e x c e p t io n s w e r e n o t e d . T h e u n r e a c t i v e n a t u r e o f a c y cl ic 1 w a s a t t r i b u t e d t ot h e u n f a v o u r a b l e e n t r o p i c t e rm . F o r 7 , e s t i m a t e s o f s tr a i n e n e rg i e s in d i c a t e d t h a t t h ef o r m a t i o n o f a t h r e e - m e m b e r e d r i n g i s h i g h l y u n f a v o u r a b l e .T h e p r es e n ce o f a n a d d i t i o n a l f a c to r c o n t r o l li n g H D A r e a c ti v it y w a s r e v e a le d b y t h efac ile reac t ion o f t r icyc lo I-5 .3 .1 .04 '9]undeca-2 ,5-diene , 8 w i th T C N E (Y am agu chi et al1 98 4). B o t h M M 2 a n d ab initio (STO -3G) ca lcu la t ions ind ica ted a f a i r ly l a rge sepa ra t io nbetween the reac tive s i tes of the d iene ( ~ 3 .4 ~) . Th e rem arkable reac t iv i ty of 8 was expla inedon the ba si s o f the m utua l o r i en ta tion o f the n bonds . The n lobes a re d i rect ed towards eachothe r al lowin g for stron g throug h-spa ce interactions. Th e or bital t i l t is a lso ideally suited formaxim ising over lap wi th an approa ching d ienophile. I t was co nc luded tha t c lose proximi ty ofthe do ub le bon ds is n o t a prerequisi te for significant H D A reactivity.

I n t h i s p a p e r , w e a t t e m p t t o p l a c e g e o m e t r i c a n d s t r a i n f a c to r s w h i c h d e t e r m i n e t h ef e a si b il it y o f H D A r e a c t i o n o n a q u a n t i t a t i v e b as is . M o l e c u l a r m e c h a n i c s c a l c u l a t i o n sh a v e b e e n u s e d f o r t h is p u r p o s e . F i r s t, s e v e ra l d i en e s w h i c h h a v e b e e n e x p e r i m e n t a l l ye x a m i n e d a r e c o n s i d e r e d . A f t e r o b t a i n i n g g e n e r a l c r i te r i a f o r H D A r e a c ti v i ty , a d d i -t i o n a l s y s t e m s n o t y e t e x p e r i m e n t a l l y s t u d i e d a r e e v a l u a t e d . S u i t a b le s u b s t r a t e s f o rf u r t h e r i n v e s t i g a t io n t o q u a n t i f y o u r p r o p o s a l s a r e s u g g e s te d .

2. R esults and discussion

2.1 Computational modelG e o m e t r y o p t i m i s a t i o n u s i n g t h e M M 2 f o r ce f ie ld ( A l li n g er 1 97 7) w a s c a r r ie d o u t o na n u m b e r o f n o n - c o n j u g a t e d d i en e s. T h e r e a c ti v it y o f t h e d ie n e s t o w a r d s T N C E o rr e l a t e d a c t i v a t e d d i e n o p h i l e s w a s c o r r e l a t e d w i t h s p e c i f i c s t r u c t u r a l p a r a m e t e r s .A m o n g t h e v a r i o u s p o s s i b le f a c to r s w h i c h c a n i n f l u en c e H D A r e a c ti v i ty , t h e C 1 . . C 5a n d C 2 . . C 4 d i s t a n c e s o f t h e 1 , 4 -d i e n e ( f ig u r e la ) a r e i m p o r t a n t . S h o r t e r d i s t a n c e s w i l l


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Ana lysis o f homo-Diels-Alder reactions 461( a ) ~ 2H H ~ ( b )

H H 1 o

12H H 1 3

%..'~-__ ' ( j , , , ~ HeSHF i g u r e 1.(a) A tom num berin g for a represen tat ive 1,4-diene used in the def ini t ionof geomet r ica l param eters in the t ex t. (b) Twis t a t the t e rmina l carbo n a toms whichwo uld favo ur s tabi lising orbi tal interact ion s with a n ap proa chin g dienophi le .

e n h a n c e t h r o u g h - s p a c e i n t e r a c ti o n s b e tw e e n t h e d o u b l e b o n d s . F u r t h e r , t h e t e r m i n a lc a r b o n a t o m s o f t h e d i e n e w o u l d b e i d ea l ly p o i se d f o r in t e r a c t io n w i t h t h e a p p r o a c h i n gd i e n o p hi le , w h i le t h e in t e r n a l c a r b o n a t o m s c a n f o r m a n e w C - C b o n d m o r e r e ad i ly .

T h e m u t u a l a l ig n m e n t o f t h e d o u b l e b o n d s is al so a k e y f a c t o r w h i c h d e t e rm i n e st h r o u g h - s p a c e i n t e r a c t i o n s a n d t h e a b i li t y to i n t e r a c t w i t h a d i e n o p h i l e . T h e r e l a t iv eo r i e n t a t i o n s o f th e ~r l o b e s o f a d o u b l e b o n d a t e a c h c a r b o n c e n t r e c a n b e q u a n t i f i e d b yt w o d i h e d r a l a n g l e s , v i z. , t h e i n n e r t il t a n g l e a n d t h e o u t e r t i lt a n g l e , w h i c h w e d e f i n e a sf o l l o w s ( f ig u r e l a ) . A t t h e t e r m i n a l c a r b o n a t o m s ( a t C 1 a n d C s ) , th e i n n e r t il t a n g l e s( ~ a i) a r e t h e d i h e d r a l a n g l e s H vC a C 2 C 4 a nd H 9 C s C 4C 2 . F o r a s y m m e t r i c a l d i e n e th ea b s o l u t e v a l u e s o f th e s e t w o d i h e d r a l a n g l e s a r e e q u a l . S i m i l a rl y t h e o u t e r t i lt a n g l e s(dp1o) a r e c h o s e n a s t h e d i h e d r a l a n g l e s H 6 C 1 C 2 C 4 a n d H s C 5 C 4 C 2 , w h o s e a b s o l u t ev a l u e s a r e a g a i n e q u a l f o r a s y m m e t r i c a l d i e n e . W h e n t h e n l o b e s a t t h e t e r m i n a l c a r b o na t o m s ( a t C a a n d C s ) o f t h e d i e n e a r e p a r a l le l t o e a c h o t h e r a n d h a v e t h e l e a s t d i r e c to v e r l a p , t h e i n n e r t il t a n g le s a r e z e r o a n d t h e o u t e r t il t a n g l e s a r e 1 8 0 A s t h e i n n e r t i lta n g l e in c r e a s e s a n d t h e o u t e r t il t a n g l e c o r r e s p o n d i n g l y d e cr e a s es , t h e p - l o b e s o f th ed o u b l e b o n d s a t t h e t e r m i n a l c a r b o n a t o m s a r e t w is te d t o w a r d s e a c h o t h e r ( se ef ig u r e l b ). T h i s is f a v o u r a b l e f o r H D A r e a c t i v it y b e c a u s e t h e d i e n e c a n i n t e r a c t s t r o n g l yw i t h t h e a p p r o a c h i n g d i e n op h i le .

T h e C 1 - C 2 a n d C 4 - C s b o n d s a r e n o t n e c e s s a r i ly p a r a l le l in m o s t 1 , 4 -d i en e s . I nt y p ic a l u n s y m m e t r i c a l s t r u c tu r e s , i n t r a m o l e c u l a r t h r o u g h - s p a c e i n t e r a c t io n s i n v o l v i n g t h ei n t e rn a l c a r b o n a t o m s C 2 a n d C Aw i ll be l a r ge r t han t hose i nvo l v i ng t he t e r m i na l a t o m s C~and C 5. The r e f o r e , i t i s i m po r t an t t o co ns i de r t he m u t u a l o r i en t a t i on o f t he p ( l t) - lobes a t C za n d C A a ls o . T h e r e l at i v e a l i g n m e n t c a n b e q u a n t i fi e d b y t h e i n n e r a n d o u t e r t i lt a n g l e s i na w a y s i m i la r t o t h a t d o n e i n t h e c a s e o f t e r m i n a l c a r b o n a t o m s . T h u s , t h e i n n e r t i lt a n g le s( ~2 i) a r e C aC 2C 1C 5 and C3 C4 C5 C1 d i hed r a l ang l e s, w h i l e the o u t e r t il t ang le s ((1)2o)a r eH ~ o C 2 C 1 C 5 a n d H a l C 4 C s C a t o r s io n a n g le s. F o r a s y m m e t r ic a l d ie n e, s u ch a s 2 , t h eabso l u t e va l ue s o f bo t h t he i nn e r t il t ang l e s a s w e l l a s t he o u t e r t i l t ang le s a r e equa l . T het h r o u g h - s p a c e i n t e r a c t i o n b e t w e e n t h e p - l o b e s a t t h e in t e r n a l c a r b o n a t o m s i s m a x i m u m i ft he i nne r and ou t e r t i lt ang l e s a r e - 90 and 90 r e spec ti ve ly .

S i n c e a c y c l o p r o p y l r i n g is f o r m e d i n t h e H D A r e a c t i o n , s t ra i n e f fe c ts a l s o n e e d t o b ea s se s se d . M o l e c u l a r m e c h a n i c s p r o v i d e s a s o u n d b a s is f o r s t u d y i n g s u c h e ff ec ts . T h ei n c re a s e i n s tr a in e n e r g y o n g o i n g f r o m t h e d i e n e to t h e H D A a d d u c t u s i n g e t h y l e n e a sa m o d e l d i e n o p h i l e (A E s~ ra i,) h a s b e e n c a l c u l a t e d f o r v a r i o u s 1 , 4 - d ie n e s .

T h e c a l c u l a t e d d i s ta n c e s , ti lt a n g le s a n d s t ra i n e n e r g y c h a n g e s f o r c y c l o a d d u c tf o r m a t i o n f o r 1 - 7 a r e g i v e n i n t a b l e 1. T h e d a t a p r o v i d e a q u a n t i t a t i v e b a s i s f o re v a l u a t i n g t h e r e a c t i v i ty o f t h e d i e n e s w i t h a c o m m o n d i e n o p h i l e . F o r a d i r e c t


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462 Animesh Pramanik and Jayaraman ChandrasekharTable 1. M M 2 geometric parameters and the increase in strain energy (A E s t r a i n ) o ngoing from the d iene to the hom o-Die ls-A lder adduct for var ious 1 ,4-dienes.Bo nd lengths in/~ ; angles in degrees; strain energy in kcal/mol.

1,4- C 1 . . C 5 C 2 . . C aD i e n e (A ) ( ~ k ) ( I ) 1 i ( I ) l o ( I ) 2 i ( 1 )2 o A E s t r a i n! 3.41 2.45 38 -1 4 1 - 3 7 141 30.22 2-40 2.40 33 - 1 4 5 - 3 3 145 21.32"39 2'39 29 --151 - 2 9 151 31'92"41 2"4l 24 --1 56 --2 4 156 43'65a 2'58 2-58 30 - 148 -- 3 0 148 30'55b 2'60 2"60 30 -- 149 - 3 0 149 34-22 '38 2-38 30 -1 4 9 - 3 0 149 24-0Z 2"51 2"51 1 - 1 7 9 - 1 179 46"53"46 2-31 51 --1 30 -- 45 130 31-5

a s s es s m e n t, a s u m m a r y o f a v ai la b le e x p e r im e n t a l i n f o r m a t i o n o n H D A r e a c ti o n si n v o l v i n g t h e s e d ie n e s i s p r o v i d e d i n t a b l e 2 ( B l o m q u i s t a n d M e i n w a l d 1 95 9; K r e s p a net a11961; Z i m m e r m a n a n d S w e n t o n 1 964; G r a n t et a11965; S a s a k i et a11972; I w a m u r aet al 1 9 7 6 ; F i c k e s a n d M e t z 1 9 7 8 ; Y a m a g u c h i et al 1984b) . S ince the expe r imen ta ls t u d i es h a v e b e e n c a r r ie d o u t u n d e r d i f f er e n t c o n d i t i o n s , th e d a t a a r e u s e d o n l y t o m a k ea q u a l i t a ti v e j u d g e m e n t o f th e e a s e o f h o m o - D i e l s - A l d e r r e a c ti o n o f th e v a r i o u ss u b s t r a t e s .

2.2 Analysis of systems with known reactivityT h e c a l c u l a t e d r es u l ts i n t a b l e 1 a r e o f c o n s i d e r a b l e in t e r p r e t iv e v a l u e. T h e d a t a h a v ea m o r e q u a n t i t a t i v e b a s is t h a n t h e p r e v i o u s a n a l y s i s ( F i c k e s a n d M e t z 1 97 8) u s i n gD r e i d i n g m o d e l s . I n te r e s t in g l y , a m o n g t h e b i c y cl ic d i e n e s 2 - 4 , t h e v a r i a t i o n i n t h eC 1 . . C s d i s t a n c e i s n o t a s l a r g e a s h a d b e e n s u g g e s t e d b y t h e s e a u t h o r s . H e n c e , t h ei m p o r t a n c e o f t h i s f a c t o r in t h e s e d i e n e s h a d b e e n o v e r e m p h a s i z e d . O n t h e b a s i s o fM M 2 c a l c u l a ti o n s , t h e g e o m e t r i c f a c t o rs a r e q u i t e s i m i l a r in t h e s e d ie n e s . T h e k e yd i ff e re n c e i s f o u n d i n t h e s t r a i n e n e r g y i n c re a s e o n H D A a d d i t i o n . W h i l e t h e i n c re a s e i so n l y 2 1 k c a l / m o l f o r n o r b o r n a d i e n e , i t b e c o m e s p r o g r e s s iv e l y l a rg e r , b y o v e r1 0 k c a l / m o l , f o r t h e b i c y c l o o c t a d i e n e (3 ) a n d t h e b i c y c l o n o n a d i e n e ( 4) d e r i v a ti v e s .T h e r e f o r e , t h e r a p i d f a ll i n t h e H D A r e a c t iv i t y o f t h e s e d i e n e s w i t h T C N E m a y b eu n d e r s t o o d o n t h e b a s is o f t h e s t r a i n fa c t o r al o n e . T h e g e o m e t r i c a n d s t r a i n f ac t o r sc o m p u t e d f o r t h e D e w a r b e n z e n e s (5 a , b ) a n d b a r r e l e n e (6) a re a l s o w i t h i n t h ea c c e p t a b l e r a n g e f o r fa c il e h o m o - D i e l s - A l d e r r e a c ti o n .

A s p o i n t e d o u t e a rl i er ( Y a m a g u c h i et al 1984b), t h e re ac t iv i ty o f the t r i cy c l i c d i en e_8c a n b e u n d e r s t o o d i n t e r m s o f t h e s i g n i f ic a n t t il t o f t h e ~ l o b e s t o w a r d s e a c h o t h e r . T h ed a t a i n t a b le 1 p r o v i d e a u s e f u l c o m p a r i s o n . A m o n g t h e v a r i o u s d i e n e s s h o w n i nt a b l e 1, t h e i n n e r t i l t a t t h e t e r m i n a l c a r b o n a t o m i s th e l a r g e s t ( 5 1 ) f o r _8. T h e i n n e r t i lta t t h e i n t e r n a l c a r b o n a t o m is a l s o q u i t e la r g e ( - - 45 ) t o p r o d u c e s t r o n g t h r o u g h - s p a c ei n t e r a c t i o n s b e t w e e n t h e d o u b l e b o n d s . T h e s t r a i n e n e r g y i n c r e a s e , a l t h o u g h l a r g e rt h a n i n 2 , i s c o m p a r a b l e t o t h a t o b t a i n e d f o r th e r e l a ti v e l y r e a c ti v e d i e n e 3. T h e s ef a v o u r a b l e f a c t o rs e n a b l e t h e d i e n e t o b e r e a c t iv e t o w a r d s T C N E i n s p i te o f a r e l at i v el yl a rg e s e p a r a t i o n o f 3 .4 6 ,~ b e t w e e n t h e t e r m i n a l o l e fi n ic c a r b o n a t o m s .


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Analysis of homo-Diels-Alder reactions 4 6 3Tab l e 2. Reac t ion condi t ions and y ie lds for the hom o-D ie l s -Ald er reac t ions ofseveral 1,4-dienes with v ariou s dienophiles.

Reac t ion1,4- cond i t ions* Yield Diene Dieno phi le t ime/ temp(h/C) Solvent (%)1 TC N E 52 /145 C6H 6 N o r xn_2 T C N E 0"5/rflx C 6 H 6 100Dimethylace ty lene-dicar box ylate 12/rf lx C 6 H 6 50Cyan oace ty lene 40/145 N on e 31Cy anoace ty lene 69/90 C 6 H 6 26N- t -buty l -propio lam ide 100/165 N on e Very lowC h l o r o c y a n o -acetylene 40/80 C 6H 6 503 T C N E 30/r flx c6 n 6 85T C N E 1 1 / 1 0 0 c 6 n 6 53Dimethylace ty lene-dicarboxyla te 36/100 C6 H6 N o r xn4 TC N E 15 /145 C6H 6 24Dimethylace ty lene-dicarboxy la te 24/150 C6 H6 N o rxn5__aa T C N E Reflu x C6 H~ C! 856 D i cyanoace t y lene RT 957 T C N E N o r xn8_ T C N E 1/rflx C6H 6 100M aleic anh ydr ide 12/rf lx o-C6 H4 C12 81Dimethylace ty lene-dicarboxy ta te o-C 6H 4 C12 22*rflx = reflux; + " N o rxn " indicates "n o reac t ion"

I t is k n o w n t h a t 3 , 3 - d i m e t h y l - l , 4 - p e n t a d i e n e ( ! ) a n d 3 , 3 , 6 , 6 - t e tr a m e t h y l - l ,4 - c y c -l o h e x a d i e n e (7 ) d o n o t u n d e r g o t h e H D A r e a c t io n e v e n w i th t h e h i g h ly a c t iv a t e dd i e n o p h i l e T C N E ( t ab l e 2). M M 2 c a l c u l a t i o n s h o w s t h a t 3 , 3 - d i m e t h y l - 1 , 4 - p e n t a d i e n eh a s a C 1 . . C 5 d i s t a n c e o f 3 .4 1 ~ a n d a s t r a in e n e r g y in c r e a s e o f 3 0 k c a l / m o l . T h e s ev a l u e s a r e c o m p a r a b l e t o t h o s e o b t a i n e d f o r t h e r e a c t iv e d i e n e 8 . T h e t il t a n g le s a t t h et e r m i n a l c a r b o n a t o m s ( 3 8 a n d - 1 48 ) a s w e ll as a t t h e i n t e r n a l c a r b o n a t o m s ( - 3 7 a n d 1 41 ) a l s o s u g g e s t r e a s o n a b l e m u t u a l a l i g n m e n t o f t h e ~ r l o b e s f o r f a v o u r a b l eo v e r la p . T h e r e f o r e th e f ai lu r e o f 1 t o u n d e r g o t h e H D A r e a c t io n w i t h T C N E m a y b ed u e t o t h e e n t r o p i c f a c t o r, a s s u g g e s t e d b e f o r e ( F i c k es a n d M e t z 1 97 8). I n t h e c a s e o f 7 ,o n l y t h e d i s t a n c e c r i t e r i o n f o r e f fi c ie n t H D A r e a c t i o n i s m e t ( t a b l e 1). T h e g r o u n d s t a t eg e o m e t r y o f t h e d i e n e is p l a n a r a t t h e M M 2 l ev e l, i n a g r e e m e n t w i t h ab initioc a l c u l a t i o n s ( B i r c h et al 1 98 1). H e n c e t h e a b s e n c e o f a n y t il t o f t h e d o u b l e b o n d sp r e c l u d e s s i g n if ic a n t t h r o u g h - s p a c e i n t e r a c t i o n s . T h e u n f a v o u r a b l e s t r a in e f fe c t p o s t u -l a t e d e a r li e r (F i c k e s a n d M e t z 1 9 78 ) o n t h e b a s is o f r a t e s o f m o d e l r e a c t i o n s i s a ls oc o n f i r m e d b y t h e p r e s e n t c a l c u la t io n s . T h e i n c r e a s e in s t r a i n f o l lo w i n g a d d i t i o n t o 7 i s


6/10

46 4 Animesh ramanik and Jayaraman Chandrasekharg r e a t e r t h a n 4 6 k c a l /m o l . T h e n o n - r e a c t i v i ty o f t h is d i e n e w i t h T C N E i s c o n s i s t e n t w i t ht h e M M 2 r es u lt s.

O n t h e b a s i s o f t h e a b o v e c o m p a r i s o n o f c a l c u l a te d p a r a m e t e r s a n d e x p e r i m e n t a lr e s u l ts , a s e t o f g u i d e l i n e s c a n b e p r o p o s e d f o r p r e d i c t i n g t h e H D A r e a c t i v i t y o fa n o n - c o n j u g a t e d i e n e . T h e C 2 . . C 4 d i s t an c e i s r e l at i ve l y u n i m p o r t a n t . D i e n e s w i t ha C 1 . . C 5 s e p a r a t i o n o f e v e n 3 "5 /~ c a n b e r e a c t i v e p r o v i d e d t h e r e i s s u f f i c ie n t t i lt o f t h e7z l o b e s a t t h e i n t e r n a l a n d t e r m i n a l c a r b o n a t o m s . T h e i n c r e a s e in s t r a i n f o l l o w i n ga d d i t i o n s h o u l d n o t e x c e ed 4 0 k c a l / m o l .

T h e a b o v e c r it e ri a w e r e t es t e d a g a i n s t t h e k n o w n r e a c t iv i t y p a t t e r n o f 1 , 3, 5, 7-t e t r a m e t h y l e n e c y c l o o c t a n e @ ) t o w a r d s d i e n o p h il e s . I n p r i n c ip l e , t h e m o l e c u l e 9 c a nu n d e r g o a h o m o - D i e l s - A l d e r t y p e a d d i t i o n t o g i v e 1 0 o r a 2 + 2 + 2 c y c l o a d d i t i o ni n v o l v i n g th e e x o c y c l i c d o u b l e b o n d s a t C 1 a n d C 5 t o y i e ld 1 1 ( s c h e m e 2 ). E x p e r i m e n -t a ll y , o n l y t h e l a t t e r m o d e o f c y c l o a d d i t i o n is o b s e r v e d ( W i ll ia m s a n d B e n s o n 1 96 2).T h i s c a n b e r a t i o n a l is e d o n t h e b a s is o f g e o m e t r i c a n d s t r a i n c o n s i d e r a t i o n s .

T h r e e c o n f o r m a t i o n s a r e r e a s o n a b l e f o r 9 ( f ig u r e 2). I n t h e D2af o r m 9 a , t h e e x o c y c l i cd o u b l e b o n d s a t C 1 a n d C 5 a r e o r i e n t e d i d e a ll y f o r i n t e r a c t i o n w i t h a n a p p r o a c h i n gd i e n o p h i le . I n c o n t r a s t , t h e g e o m e t r y o f th e C2hc o n f o r m e r , 9 b , p e r m i t s o n l y a h o m o -D i e l s - A l d e r t y p e c y c l o a d d i t i o n . B o t h c y c l o a d d i t i o n m o d e s a r e p o s s i bl e , i n p r i n ci p le ,fo r c o n fo rm er 9._ccw i t h C 4v s y m m e t r y . A l l t h r e e f o rm s w e r e o p t i m i s e d a t t h e M M 2 l ev el .S t r a i n e n e r g y c h a n g e s f o r c y c l o a d d i t i o n to e t h y l e n e w e r e a l s o c o m p u t e d .

T h e r e q u ir e m e n t s f o r h o m o - D i e l s - A l d e r r e a c ti o n a r e f a i rl y m e t i n c o n f o r m e r 9 b( ta b l e 3 ). T h e t e r m i n a l c a r b o n a t o m s a r e s e p a r a t e d b y 3 -4 /~ , w h i le t h e i n t e r n a l c a r b o na t o m s a r e 2-5 ~, a p a r t . T h e rc b o n d s a r e p a r t i a l l y ti l te d t o w a r d s e a c h o t h e r a n d t h e s t r a i ne n e r g y i n c r ea s e f o r c y c l o a d d i t i o n i s m o d e s t ( t a b le 3). H o w e v e r , t h i s c o n f o r m e r is t h el e a s t s t a b l e o f t h e t h r e e c o n s i d e r e d ( A H I = 5 2- 5 k c a l / m o l ) .

T h e h o m o - D i e l s - A l d e r m o d e s h o u l d b e f a v o u r e d i n t h e m o r e s t a b l e f o r m 9__.cc l s o( A H I = 4 8 . 6 k c a l / m o l ) , a l t h o u g h t h e c r i t e r ia a r e s l i g h t l y l es s f a v o u r a b l e t h a n i n 9 b( ta b l e 3 ). T h e d o u b l e b o n d s a t C 1 a n d C 5 a r e t o o w i d e l y s e p a r a t e d ( t e r m i n a l d is -t a n c e = 5 -1 /~ , i n t e r n a l d i s t a n c e = 3-5 . ~) t o f a v o u r t h e f o r m a t i o n o f 1 1 .

T h e p r e f e r r ed f o r m a t i o n o f 1 1 i s s u p p o r t e d b y t h e g e o m e t r y a n d s t r a i n o f t h e m o s ts t ab le co nf o r m a t i on 9.__~a A H I = 45 .9 kca l /m ol ) . T he t e rm ina l c a rb on a to m s o f ther e a c t iv e e n d s o f 9_~a h a v e t h e l e a s t s e p a r a t i o n o f t h e t h r e e c o n f o r m e r s c o n s i d e r e d(3" 1 7 ~ ) , w h i l e t h e i n t e r n a l c a r b o n a t o m s a r e a l s o q u i t e c l o se , 2 . 7 9/ ~ ( t a b l e 3 ). F u r t h e r ,

_ _ 9

10

==cN)Z(CN)211

Scheme 2. Possib le cyc loaddi t ion mod es of 9 wi th TC N E


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Analys i s o f homo-Die l s -Alder reac t ions 4 6 5

\\

J9 o ( D 2 d )

9c ( C4v )Figure 2 . Th ree opt imised conform at ions of t e t raene 9 .

9._.bb C 2h)

Tab l e 3. M M 2 geom et r ic param eters and the increase in s t ra in energy (AE tr ,a, )for cyc loadduct format ion for var ious co nform at ions of 9.r in A ; angles in degrees; s t rain en ergy in kcal /mol .

Co nfo rm er rterm r i . . . ~ l l ~lo ~2i O2o AE strain9a 3-17 2"79 90 - 90 - 90 90 17"09b 3-40 2"51 34 - 1 4 5 - 3 4 145 21"99__cc 3"59 2"48 39 - 1 4 0 - 3 9 140 23"2

t h e zc b o n d s a r e f a v o u r a b l y o r i e n t e d t o w a r d s e a c h o t h e r ( f ig u r e 2 ). M o s t i m p o r t a n t l y ,t h e 2 + 2 + 2 c y c l o a d d i t i o n r e a c t i o n d o e s n o t l e a d t o t h e f o r m a t i o n o f a 3 - m e m b e r e dr in g , b u t t o a l e ss s tr a i n e d 5 - m e m b e r e d r in g . T h e o v e r a l l st r a i n e n e r g y i n c r e a s e o nc y c l o a d d i t i o n is j u s t 1 7 .0 k c a l /m o l . T h u s , a l l g e o m e t r i c a n d s t r a in e n e r g y c r i t e r i a c l e a r lyf a v o u r t h is m o d e o f re a c ti o n .

2 .3 Pred ic t ions f or new subs t ra t esI t w o u l d b e o f c o n s i d e r a b l e in t e r e s t t o c ri t ic a l ly e v a l u a t e t h e a b o v e p r o p o s a l s w i t ha d d i t i o n a l d i e n e s . In p a r t i c u l a r , t h e o u t e r l i m i ts f o r t h e d i s t a n c e c r i t e r i o n a n d t h e s t r a i nf a c t o r n e e d t o b e e v a l u a te d . W i t h t h e s e g o a ls i n m i n d , w e h a v e c o m p u t e d t h e g e o m e t r i c


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4 6 6 Animesh Pramanik and Jayaraman Chandrasekhara n d e n e rg e t i c fa c t o rs o f i m p o r t a n c e in H D A r e a ct iv i ty f or a n u m b e r o f n o n - c o n j u g a t e dd i e n e s w h i c h h a v e n o t b e e n s t u d i e d e x p e r i m e n t a l l y . A f t e r a n a n a l y s i s , t h e s y s t e m si d e a ll y s u it e d f o r f u r th e r s t u d y w h i c h w o u l d e n a b l e a q u a n t i t a t i v e d e f i n it i o n o f th es c o p e o f th e H D A r e a c t i o n a r e i d e n ti fi ed .

T w o s e r ie s o f 1 , 4 -d i e n es h a v e b e e n c o n s i d e r e d . T h e f i r s t i s a s e t o f b i c y c l o [ 3 -3 . n]d i e n e s (1 2-1 5.5 ). T h e s e a r e c l e a r l y r e l a t e d t o t h e b i c y c l ic d ie n e s 2 - 6 w h i c h h a v e b e e ns t u d i e d e x t e n s iv e l y . T h e s e c o n d i s a s e t o f r e l a t iv e l y r ig i d m o l e c u l e s ( 1 6 - 2 1 ) i n w h i c h t h et e r m i n a l u n i ts o f t h e d i e n e a r e g e o m e t r i c a l ly c a p a b l e o f r e s p o n d i n g f le x ib l y t oa d i e n o p h i l e . I n o u r t e r m i n o l o g y , t h e i n n e r a n d t h e o u t e r t i l t a n g l e s a t t h e t e r m i n a lc a r b oi a a t o m s a r e n o t c o n s t r a i n e d b y t h e r i n g s k e l e t o n s i n th e s e s y s te m s . T h e c a l c u l a te dM M 2 g e o m e t r i c p a r a m e t e r s o f i n t er e s t a n d t h e in c r e a s e i n s t r a in e n e r g y d u e t o H D Aa d d i t i o n f o r t h e t w o s e r ie s o f c o m p o u n d s a r e p r o v i d e d i n ta b l e 4.

T h e M M 2 r e s u l ts i n ta b l e 4 s h o w t h a t t h e s e r i e s o f b i c y c l o [ 3 .3 . n ] d i e n e s ( 1 2 - t 5 ) h a v eC 1 -. C 5 d i s t a n c e s o f 3- 5 ~ o r m o r e . T h e v a l u e s a r e s i g n i f i c a n t l y l a r g e r c o m p a- ~ ed - ~o t h o s e

Tab l e 4 . M M 2 geom e t r ic pa r am e te r s and t he i nc r ease i n s t r a in ene rgy (A E s t r a i n ) o ngoing f rom the d iene to the hom o-D ie ls -A lder add uct for addi t iona l 1 ,4-d ienes .Bon d lengths in ~ ; angles in degrees; s t ra in energ y in kca l /mo l1,4- C 1 .C 5 C 2 .C,~D ien e ('~) (~ ) ~11 ~1o q~2i ~2o AEs~r~i,12 3"85 2"50 35 - 1 4 3 -- 30 148 38"013 3-54 2"40 43 - 1 3 7 - 4 2 135 37"414 3-57 2-49 38 - 1 4 2 - 3 7 141 46"015 3 -53 2"48 36 - 1 4 3 - 4 0 138 46 -016 4"09 2"54 40 - 1 3 9 - 4 0 138 34"217 4"07 2 '38 48 - 1 3 1 - 4 7 131 26-018 4-40 2"44 44 --1 35 --4 3 137 31-319 4"59 2"48 38 = 140 - 37 143 28'120 4-37 2-44 43 - 135 - 4 4 135 36'021 4 '71 2"30 44 - 1 3 6 - 4 4 135 45-6

1 2m 1 3- - 1 4

16 17 1~ 19

z o z ~


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Analysis o f hom o-Diels-AIder reactions 467o f t h e b i cy c l o [2 -2 -n ] d i en es ( 2 - 7 ) b u t c l o s e t o t h e p r o p o s ed u p p e r l im i t o f th e p a r am e t e rfo r observ ab le H D A reac t iv i t y . In t e res ti ng ly , t he ca l cu l a t ed t il t ang l es fo r the se r i es a reco n s i s ten t ly mo r e f av o u r ab l e co m p ar e d t o t h e s e r ie s o f b i cy c l o [ 2- 2-n ] d ien es . H o w ev e r ,t h e s tr a i n en e r g y f ac t o r i s c a l cu l a t ed t o b e m o r e u n f av o u r ab l e i n t h e b i cy c l o [ 3 .3 .n]d i enes t han in t he co r respond ing b i cyc lo [2 .2 .n ] d i enes . For example , b i cyc lo [3 -3"11n o n a - 2 ,7 - d i en e ( 1 3 ) i s co mp u t ed t o h av e a s t r a i n en e r g y i n c r ea s e o f 3 7 .4 k ca l / mo l( t ab le 4 ) , wh i l e the v a lue fo r no rb orn ad iene i s on ly 21 kca l /m ol ( t ab l e 1). Th e i ncrea se i ns t r a in energy i s much h igher i n d i enes wi th l a rger methy lene b r idges .

O n t h e b a s i s o f t h e ab o v e r e s u lt s , i t w o u l d b e w o r t h w h i l e t o ex ami n e t h e h o m o -D ie l s -A lder r eac t i v i t y o f b i cyc lo [3 .3 .11 nona -2 ,7 -d i ene (13). I f t he m olecu l e doe su n d e r g o t h e r eac t io n , t h e p r o p o s ed em p i r ica l c r i te r i a w o u l d b e v a l i d a ted .

The t e rmina l C1 . .C5 d i s t ances i n t he nex t se r i es o f 1 ,4 -d i enes 16-21 cons idered i nth i s s t udy a re found to be h igher t han in a l l t he p rev ious ly examined sys t ems~ be ingcons i s t en t ly mo re t ha n 4 -0 /~ ( t ab l e 4 ). How eve r , t he t i lt ang l es a re qu i t e f avo urab l e int h e ex o - me t h y l en e d e ri v a t iv e s co m p ar e d t o t h a t o f t h e b i cy c li c d i en es 2 - 6 an d t h eb i cy c l o [ 3.3 .n ] d i en es 1 6 - 2 1 . F u r t h e r , t h e s t r a i n en e r g y i n c rea s e s o n H D A ad d i t i o n a r ea l so found to be r e l a t i ve ly smal l . A par t i cu l a r ly i n t e res t i ng case i s t he d i ene 2 ,6 -d imethy l idene-b i cyc lo [2 -2 .1 ]hep tane (17) fo r wh ich t he i ncrease i n s t r a in energy i son ly 26 kca l /m ol . Al tho ugh the C~ . .C 5 d i s t ance i s 4 .07 /~ i n t h is sys t em , on t he bas i s o ffavo urab l e ti lt ang l es (48 , - 131 a t t e rm ina l a nd - 47 , 131 a t i n t e rna l c ar bo n a tom s)and the r e l a t i ve ly modes t i ncrease i n s t r a in energy , i t i s a l so a wor thy cand ida t e fo rexpe r imen ta l exa m ina t ion as a H D A subs t r a t e . I f 17 i s r eac t ive , t he limi t fo r t he C ~ .. C5d i s tan ce o f th e 1 ,4- d ien e fo r H D A r eac t i o n n eed s t o b e ex t en d ed . A l s o , a s u b s eq u en ts t u d y o f 1 8 - 2 0 may b e a t t emp t ed . I n t h e s e d i en es , t h e t i l t an g l e s an d s t r a i n en e r g yi n c r ea s e s a r e w i t h i n t h e l i m i t s p r o p o s ed ab o v e . Th e o n l y u n f av o u r ab l e f ea t u r e i sca l cu l a ted t o b e t h e d i s tan ce b e t w een t h e te r mi n a l c a r b o n a t o ms . H en ce , t h e r eac t i v i tyo f t h e s e s y st ems w o u l d e s t ab li s h t h e u p p e r b o u n d f o r t h e g eo m e t r i c c r i te r i o n f o r t h eH D A r e a c ti o n.

3. ConclusionsC o m p u t e d g eo m e t r ie s an d s t ra i n en e r g ie s o f s ev e r a l 1 , 4- d ien es w i t h k n o w n H D Ar eac t iv i ty s u g g es t p o s s i b le f ac t o rs w h i ch m ay b e c r uc i al . B a s ed o n av a i l ab le ex p e r i men -t a l in f o r ma t i o n , a f ew e s s en ti a l r eq u i r eme n t s f o r H D A r eac t iv i ty h av e b ee n p r o p o s ed .Th e r eac t i ve d i enes have a C 1 . . C5 sep ara t i on o f less t han 3"5 /~ , ti lt o f n l ob es o f over3 0 an d m o d e s t s t r a i n en e r g y i n c r ea s e ( le ss t h an 4 0 k ca l / mo l ) f o r cy c l o ad d u c t f o r m a-t ion . Add i t i ona l sub s t r a t es fo r expe r imen ta l s t ud y a re sugges t ed t o es t ab l i sh t he l imi t sm o r e p r e ci se ly a n d t o e n h a n c e t h e s c o p e o f t h e H D A r e ac ti on . T h e s e p r o p o s a l s m a y b eo f u s e f o r a q u i ck ap p r a i s a l o f p o t en t i a l H D A r eac t iv i ty o f a n o n - co n j u g a t ed d i en e.

I t wo u ld be o f i n t e res t t o eva lua t e t he r e l i ab i l it y o f t he c r i t e r i a der ived f ro mmo l ecu l a r mech an i c s ca l cu l a t io n s b y d e te r mi n i n g t h e g eo me t r i e s an d en e r g ie s o ft r an s it io n s t a te s f o r r ep r e s en t a ti v e s u b s t r a t e s t h r o u g h q u an t i t a t i v e M O p r o ced u r e s .The r esu l t s o f t hese s tud i es , cu r ren t ly un derw ay , wi ll be r epor t ed shor t l y .AcknowledgementA P thanks the Co unci l of Scienti fic and Indust r ial Research, N ew Delhi for a fel lowship .


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analysis of geometric

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