J.Mol.Evol.6,99-115 (1975) © by Springer-Verlag 1975

Crystallization and Solid-State Reaction as a Route to Asymmetric Synthesis from Achiral Starting Materials* BERNARD S. GREEN and MEIR LAHAV Department of Structural Chemistry, The Weizmann Institute of Science, Rehovot, Israel Received January 13, 1975; March 3, 1975

Summary. Many molecules which are achiral can crystallize in chiral (enantiomorphic) crystals and, under suitable conditions, crystals of only one chirality may be obtained. The formation of right- or lefthanded crystals in excess is equally probable. Lattice-controlled (topochemical) photochemical or thermal solid-state reactions may then afford stable, optically active products. In the presence of the chiral products, achiral reactants may preferentially produce crystals of one chirality, leading to a feedback mechanism for the generation and amplification of optical activity. Amplification of optical activity can also be achieved by solid-state reactions. The optical synthesis of biologically relevant compounds by such routes may be envisaged.

Key words: Origin of Optical Activity - Chiral Crystals - Abiotic Asymmetric Synthesis - Enantiomorphic

INTRODUCTION

The

i n t e r e s t in r e a c t i o n s in o r g a n i z e d s y s t e m s and the r e c ognition that many biological reactions o c c u r in h i g h l y o r g a n i z e d m e d i a m a k e a s t u d y of r e a c t i o n s in crystals, where t h e o r d e r is a m e n a b l e to exact definition by the methods of X-ray crystallography, particularly important. In recent years attention has focused, in particular, on the reactivity of molecules comprising chiral crystals a n d t h i s w o r k is e s pecially relevant to the topic "Generation and Amplification of A s y m m e t r y " .

Presented at the "International Symposium on Generation and Amplification of Asymmetry in Chemical Systems", J~lich, September 24-26

(1973).

99

The o r i g i n s of o p t i c a l a c t i v i t y in the m o l e c u l e s of l i v i n g m a t t e r have p u z z l e d and i n t r i g u e d s c i e n t i s t s since s h o r t l y after the p h e n o m e n o n was f i r s t r e c o g n i z e d . In this paper we d e s c r i b e s e v e r a l e x p e r i m e n t a l a p p r o a c h e s , b a s e d on the c h i r a l i t y of crystals, w h i c h have, in the a b s e n c e of any o u t s i d e d i s s y m m e t r i c agents, y i e l d e d stable, o p t i c a l l y active p r o d u c t s w i t h s i g n i f i c a n t e n a n t i o m e r excess, from a c h i r a l s t a r t i n g m a t e r i a l s . It is then shown that, in principle, the r e a c t i o n s can be a u t o c a t a l y t i c : once g e n e r a t e d , an o p t i c a l l y a c t i v e p r o d u c t can a m p l i f y the p r o d u c t i o n of more of that e n a n t i o m e r . F i n a l l y , one can c o n c e i v e of p a t h ways w h e r e b y c h i r a l p o l y m e r s as well as chiral, b i o l o g i c a l l y s i g n i f i c a n t m a t e r i a l s can be p r o d u c e d by c h e m i c a l r e a c t i o n s in the solid.

CHIRAL CRYSTALS C r y s t a l s can, in general, be c l a s s i f i e d on the basis of their space groups I into two classes: I. chiral (sometimes c a l l e d e n a n t i o m o r p h i c , o p t i c a l l y active, c o n g l o m e r i c , or d i s s y m metric) crystals and 2. racemic (or achiral) crystals. (Scheme I). The c r y s t a l s of the former, chiral c r y s t a l class c o n t a i n only s y m m e t r y e l e m e n t s (rotation and translation) w h i c h do not i n t e r c o n v e r t r i g h t - and l e f t - h a n d e d o b j e c t s and any single c r y s t a l of a s u b s t a n c e c r y s t a l l i z i n g in this class m u s t c o n t a i n o n l y m o l e c u l e s 2 of one (either r i g h t - or left-) h a n d e d n e s s . C r y s t a l s of the latter class c o n t a i n a m o n g s t their s y m m e t r y e l e m e n t s at least one (mirror or glide plane, center of inversion) w h i c h i n t e r c o n v e r t s r i g h t - and lefth a n d e d objects; any single c r y s t a l c o n t a i n s either symm e t r i c a l l y a c h i r a l m o l e c u l e s or an equal n u m b e r of s y m m e t r y r e l a t e d r i g h t - and l e f t - h a n d m o l e c u l e s . The p r o c e s s of c r y s t a l l i z a t i o n of a r a c e m i c m i x t u r e m a y then be p i c t u r e d as in S c h e m e I. R

-

S

~

{R} + { s } Chiral crystals Spontaneous resolution 3 Scheme i

100

or

R ~

S Solution or melt

ization

{R,s} Racemic crystals

It is i m p o r t a n t to n o t e t h a t w h e n t h e e n a n t i o m e r i c forms (R,S) a r e r a p i d l y i n t e r c o n v e r t a b l e w i t h r e s p e c t to t h e r a t e of c r y s t a l l i z a t i o n , t h e n u m b e r of r i g h t - a n d l e f t - h a n d e d crystals (for a s u b s t a n c e w h i c h u n d e r g o e s spontaneous reso l u t i o n ) w i l l not, in g e n e r a l , b e t h e s a m e b e c a u s e of s e e d i n g e f f e c t s , and, u n d e r s u i t a b l e c o n d i t i o n s of c r y s t a l l i z a t i o n , t h e e n t i r e , r a c e m i c , s a m p l e c a n b e c o n v e r t e d to a c r y s t a l l i n e chirality. T h a t is, if R a n d S c a n s a m p l e of o n e h o m o g e n o u s equilibrate in t h e p h a s e f r o m w h i c h the c r y s t a l s s e p a r a t e , the entire sample can eventually e x i s t as {R} (or, w i t h e q u a l probability, as {S}) c r y s t a l s . Solution or m e l t R

-

S

Crystallization

{R}

{s}

Although racemic crystals predominate, t h e n u m b e r of c h i r a l c r y s t a l s is q u i t e l a r g e ( C o l l e t et al., 1972) in a v a r i e t y of c h e m i c a l s y s t e m s - i n c l u d i n g o r g a n i c , i n o r g a n i c , clathrate inclusion and organometallic compounds and comp l e x e s . A s a m p l i n g of s u b s t a n c e s w h o s e t i m e - a v e r a g e d molecules l a c k a n y e l e m e n t s of c h i r a l i t y (are a c h i r a l in s o l u t i o n ) but which form chiral, optically a c t i v e , c r y s t a l s is g i v e n in T a b l e I. The crystallization p r o c e s s m a y be c o n s i d e r e d as an e l e m e n t a r y r e a c t i o n s i n c e t h e v a r i e t y of c o n f o r m a t i o n s which a r e p r e s e n t in d i s p e r s e d p h a s e s are t r a n s f o r m e d , in g e n e r a l ,

1

2

The symmetry notation for a crystalline sample is denoted by its space group, and for a given specimen this can generally be assigned in a straight-forward manner after several single-crystal X-ray photographs. These may sometimes be more correctly considered as enantiomeric molecular conformations, and in some cases, perhaps only as enantiomeric en-

vironments. 3 Another possibility should also be recognized. Crystallization in the f o r m of "racemic solid solutions" can occur, whereby molecules of opposite chirality crystallize with disorder and occupy the same, chiral or racemic, crystal sites (Eliel, 1962). Several such systems are presently being studied in this laboratory (Lahav et al., 1974; Addadi et al., 1974).

101

Table

i. Some s u b s t a n c e s w h i c h afford chiral crystals

Compound

Spacegroup

Reference

P212121

Gupta and Prasud,1971

P212121

Shahat,1953

P3121

Brown and Sadanaga, 1965

P2~

Benghiat and Leiserowitz, 1972

P212121

Klug,1950

Si02 (quartz)

P31,221 ;P62,421

Wei,1935

Os04

I2

Zalkin and Templeton, 1953

NaC103

P2~3

Huber, 1940

12N H2"~t~"N H2 • CH3(CH2)14CH3

C6~2

Smith,1952

Nal'[~(O

P21212~

Bush and Truter, 1970

CH3CH2-Li

P2122

Brown and Rogers, 1957

/--h NC---~/N • CuCN --

P212121

Cromer and Larson, 1972

0 /~L~CH2Br 0 0 0 ~ 0 CHs-C=C-COOH

I

0

I

C ' ~ H ~ CH2)4

to a s i n g l e h o m o g e n o u s c o n f o r m a t i o n (Cohen & Green, in s o m e c a s e s t h e r e a r e c h a n g e s in c o n f i g u r a t i o n or functional groups. When a racemic substance affords t i o m e r i c c r y s t a l s in d i f f e r e n t a m o u n t s , a n a b s o l u t e metric synthesis can be considered to have occurred. the first such experiments involved sodium chlorate

102

1973); e v e n in enanasymSome of (Landolt,

1896; K i p p i n g & Pope, 1898). A b e a u t i f u l d e m o n s t r a t i o n of the c o n v e r s i o n of a r a c e m i c m i x t u r e to an e n a n t i o m e r i c a l l y h o m o g e n o u s sample by m e a n s of r a c e m i z a t i o n in s o l u t i o n and c r y s t a l l i z a t i o n in a chiral c r y s t a l s t r u c t u r e was first rep o r t e d by H a v i n g a (1941, 1954) who found that c h l o r o f o r m s o l u t i o n s of m e t h y l e t h y l a l l y l a n i l i n i u m iodide m a y d e p o s i t c r y s t a l s w h i c h give a stable, m e a s u r a b l e o p t i c a l r o t a t i o n w h e n d i s s o l v e d in water, but w h i c h give no r o t a t i o n w h e n d i s s o l v e d in o r g a n i c solvents. E v a p o r a t i o n of the latter s o l u t i o n s can r e g e n e r a t e o p t i c a l l y active, (+) or (-), salt. Thus the chiral m o l e c u l e s r a c e m i z e r a p i d l y in o r g a n i c solvents from w h i c h chiral crystals can grow. This e q u i l i b r a t i o n of e n a n t i o m e r s p r o c e e d s via the c o n f o r m a t i o n a l l y labile amine and allyl iodide (Scheme 2).4

C6Hsl+ ~:6Hs +[C6Hs 43CH2--N --CH 3 I - ~ C H 3 - C H 2 - N - C H 3+ CH2=CH-CH21~CH3CH2- N-CH2-CH=CH 2 f I CH2-CH=CH2 CH3